TY - JOUR T1 - Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1995 A1 - Tracy, R P A1 - Bovill, E G A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Carotid Stenosis KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Humans KW - Multivariate Analysis KW - Prospective Studies KW - Regression Analysis KW - Risk Factors AB -

No studies have examined the associations of coagulation factor levels with measures of subclinical cardiovascular disease (CVD) in the elderly. The Cardiovascular Health Study (CHS) is a prospective, population-based cohort study of CVD in persons older than 65 years. At the baseline examination, we measured fibrinogen, factor VII, and factor VIII levels in 5024 of the 5201 participants of the CHS and examined the associations of these coagulation factors with measures of subclinical CVD in a cross-sectional analysis. Subclinical CVD measures were based on electrocardiography, carotid ultrasonography, echocardiography, and ankle-arm blood pressure measurements (AAI). For analyses, we used the full cohort as well as two mutually exclusive subgroups: those with prevalent clinical CVD at baseline and those without. Fibrinogen and to a lesser extent factor VIII showed positive associations with a variety of subclinical CVD measures. In age-adjusted analyses, fibrinogen and factor VIII were significantly associated with 8 of 10 measures. In multivariate analyses, fibrinogen was significantly associated with carotid artery stenosis, internal (but not common) carotid artery wall thickness, and AAI. Factor VIII was associated with abnormal wall motion and AAI in the full cohort only. Factor VII was not consistently associated with subclinical disease measures. In bivariate analyses that included data from all three groups, there were 5 positive subclinical disease associations and 5 negative associations for factor VII. In multivariate analyses, there were no significant associations between factor VII and subclinical CVD in the full cohort or in either subgroup. We conclude that in these cross-sectional analyses, fibrinogen and to a lesser extent factor VIII are associated with subclinical CVD in the elderly, even in those without symptoms or a history of clinical CVD. Factor VII, however, was not associated with subclinical CVD in the elderly.

VL - 15 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7670938?dopt=Abstract ER - TY - JOUR T1 - Temporal patterns of antihypertensive medication use among older adults, 1989 through 1992. An effect of the major clinical trials on clinical practice? JF - JAMA Y1 - 1995 A1 - Psaty, B M A1 - Koepsell, T D A1 - Yanez, N D A1 - Smith, N L A1 - Manolio, T A A1 - Heckbert, S R A1 - Borhani, N O A1 - Gardin, J M A1 - Gottdiener, J S A1 - Rutan, G H KW - Aged KW - Antihypertensive Agents KW - Clinical Trials as Topic KW - Data Interpretation, Statistical KW - Drug Utilization Review KW - Female KW - Humans KW - Hypertension KW - Male KW - Practice Patterns, Physicians' KW - United States AB -

OBJECTIVE: To describe the changing patterns of antihypertensive medication use in the years immediately before and after the publication of the results of three major clinical trials of the treatment of hypertension in older adults.

DESIGN: In this cohort study, adults 65 years or older were examined annually on four occasions between June 1989 and May 1992, and the use of antihypertensive medications was assessed by inventory at each visit. The four visits defined the boundaries of three study periods. For each study period, participants receiving antihypertensive therapy were either continuous users (n = 1667, 1643, and 1605, respectively) or starters (n = 157, 142, 120) of hypertensive therapy. The large clinical trials that convincingly proved the efficacy and safety of low-dose diuretic therapy in older adults were published during the latter parts of period 2 and the early parts of period 3.

RESULTS: Among starters, the proportion initiating therapy on diuretics increased from 35.9% in period 2 to 47.5% in period 3, significantly so among women (P = .04). The proportions initiating other drugs displayed no significant trends. Among continuous users, the use of diuretics, beta-blockers, and vasodilators generally decreased over the 3-year period, while the use of calcium channel blockers and angiotensin-converting enzyme inhibitors increased significantly in each of the three periods (P < .05). The decline of 2.7% in the prevalence of diuretic use in period 1 abated during period 2 (1.8% decline), and it slowed significantly (P = .03) to almost a complete halt during period 3 (0.2% decline). The rate of increase in the use of calcium channel blockers slowed significantly (P = .01) between period 1 (+6.7%) and period 3 (+2.8%).

CONCLUSIONS: Although other factors such as cost may have been important, the temporal trends in antihypertensive drug therapy coincided in time with and may have reflected in part the influence of the major clinical trials on the patterns of clinical practice.

VL - 273 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7723157?dopt=Abstract ER - TY - JOUR T1 - Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. JF - Am J Epidemiol Y1 - 1996 A1 - Cushman, M A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J A1 - Tracy, R P KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Linear Models KW - Logistic Models KW - Male KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - United States AB -

The cross-sectional correlates of three hemostatic factors--fibrinogen, factor VII, and factor VIII--were examined in the Cardiovascular Health Study, a population-based cohort study of 5,201 subjects over age 65 years. Subjects were recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In multivariate linear regression models, cardiac risk factors significantly associated with fibrinogen were current smoking, race, lipids, and white blood count. In women, alcohol use, obesity, physical activity, and insulin level were also significant, while in men hypertension was correlated. The significant correlates of factor VII were lipids and white blood count in men and estrogen use, alcohol use, race, lipids, insulin level, white blood count, and obesity in women. The independent correlates of factor VIII were insulin, glucose, and race in both sexes; low density lipoprotein cholesterol, white blood count, and diuretic use in men; and alcohol use in women. In multivariate models, factors known to be modifiable risk factors for cardiovascular disease accounted for more of the population variance of these hemostatic factors in women than in men, especially for factor VII. The hemostatic factors may mediate some effects of risk factors on disease, and this should be considered in longitudinal studies.

VL - 143 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8651228?dopt=Abstract ER - TY - JOUR T1 - Clinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C KW - Aged KW - Aged, 80 and over KW - Brain KW - Brain Diseases KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male AB -

PURPOSE: To determine the prevalence of clinically serious findings unrelated to stroke on cranial magnetic resonance (MR) images in a population of community-dwelling elderly people.

MATERIALS AND METHODS: Neuroradiologists reviewed MR images of 3,672 people aged 65 years and older who were enrolled in a longitudinal, population-based study of cardiovascular and cerebrovascular disease. The neuroradiologists alerted MR imaging field centers about potentially serious abnormalities. Clinical information was obtained from clinical examinations performed before MR imaging, hospital discharge summaries, and the field centers at which MR imaging was performed.

RESULTS: On 3,672 image sets, 64 (1.74%) clinically serious abnormalities were found. Among the presumptive diagnoses were 19 meningiomas (0.52%), six pituitary adenomas (0.16%), five cavernous malformations (0.14%), eight vascular stenoses (0.22%), four aneurysms (0.11%), two intraventricular masses (0.05%), two subdural fluid collections (0.05%), and two other tumors (0.05%). Only nine participants with these abnormalities required surgery. All but one of the meningiomas were in women, and the prevalence of the tumor decreased with increasing age.

CONCLUSION: Physicians should be alert to the possible presence of clinically serious conditions in otherwise asymptomatic elderly individuals.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988190?dopt=Abstract ER - TY - JOUR T1 - Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. JF - Stroke Y1 - 1997 A1 - Price, T R A1 - Manolio, T A A1 - Kronmal, R A A1 - Kittner, S J A1 - Yue, N C A1 - Robbins, J A1 - Anton-Culver, H A1 - O'Leary, D H KW - Aged KW - Aged, 80 and over KW - Cerebral Infarction KW - Cognition KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Neurologic Examination AB -

BACKGROUND AND PURPOSE: Infarctlike lesions are frequently detected in symptomatic and asymptomatic older persons undergoing cerebral MRI, but their significance in older adults has not been examined. We determined the prevalence of MRI infarcts in a population-based sample of men and women aged > or = 65 years and related these findings to demographic, cognitive, and neurological status.

METHODS: MRI scanning was performed in 3660 Cardiovascular Health Study (CHS) participants after brief neurological examinations and tests of cognitive function. MRIs were read centrally for the presence of an infarct > or = 3 mm in diameter or smaller infarctlike lesions.

RESULTS: MRI infarcts were detected in 1131 of 3647 participants with readable infarct information (31%) and in 961 of the subgroup of 3397 participants (28%) without known prior stroke ("silent" MRI infarcts). Smaller infarctlike lesions were found in 196 of 2516 participants who had no MRI infarcts > or = 3 mm. MRI infarcts were more common in participants who were older, had prior stroke, impaired cognition, visual field deficits, slowed repetitive finger tapping (all P < .0001), weakness on toe and heel walking, and history of memory loss, coma, or migraine headaches. Multivariate analysis in those without prior stroke showed strong associations of silent MRI infarcts with older age, history of migraines, lower digit symbol scores, and more abnormalities on neurological examination.

CONCLUSIONS: MRI evidence of brain infarction is common in older men and women without a clinical history of stroke. Their strong associations with impaired cognition and neurological deficits suggest that they are neither silent nor innocuous.

VL - 28 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9183343?dopt=Abstract ER - TY - JOUR T1 - Sulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Arnold, A M A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C A1 - Bryan, R N KW - Aged KW - Aged, 80 and over KW - Aging KW - Brain KW - Cardiovascular Diseases KW - Cerebral Ventricles KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Reproducibility of Results KW - Sex Factors AB -

PURPOSE: To determine the distribution of changes in sulcal size, ventricular size, and white matter signal intensity depicted on cranial magnetic resonance (MR) images, with stratification according to age, race, and sex.

MATERIALS AND METHODS: Ventricular size, sulcal size, and white matter signal intensity changes were graded on cranial MR images of 3,660 community-living, elderly participants in the Cardiovascular Health Study. A healthier subgroup was also defined. Summary statistics for both groups were generated for age, race, and sex.

RESULTS: Regression models of the entire imaged cohort showed higher grades of all variables with increasing age, and higher ventricular and sulcal grades in men and in nonblack individuals. White matter grade was greater in women and in black individuals. Regression models of the healthier subgroup showed similar associations, except for a lack of association of sulcal and ventricular size with race.

CONCLUSION: Sulcal width, ventricular size, and white matter signal intensity change with age, sex, and race. Knowledge of these changes is important in appropriate interpretation of MR images of the elderly.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988189?dopt=Abstract ER - TY - JOUR T1 - The effects of measurement error in response variables and tests of association of explanatory variables in change models. JF - Stat Med Y1 - 1998 A1 - Yanez, N D A1 - Kronmal, R A A1 - Shemanski, L R KW - Bias KW - Linear Models AB -

Biomedical studies often measure variables with error. Examples in the literature include investigation of the association between the change in some outcome variable (blood pressure, cholesterol level etc.) and a set of explanatory variables (age, smoking status etc.). Typically, one fits linear regression models to investigate such associations. With the outcome variable measured with error, a problem occurs when we include the baseline value of the outcome variable as a covariate. In such instances, one can find a relationship between the observed change in the outcome and the explanatory variables even when there is no association between these variables and the true change in the outcome variable. We present a simple method of adjusting for a common measurement error bias that tends to be overlooked in the modelling of associations with change. Additional information (for example, replicates, instrumental variables) is needed to estimate the variance of the measurement error to perform this bias correction.

VL - 17 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9839350?dopt=Abstract ER - TY - JOUR T1 - Factors Associated With Hospital Utilization in the Elderly: From the Cardiovascular Health Study. JF - Am J Geriatr Cardiol Y1 - 1998 A1 - Robbins, J. A. A1 - Yanez, D. A1 - Powe, N. R. A1 - Savage, P. J. A1 - Ives, D. G. A1 - Gardin, J. M. A1 - Lyles, M. AB -

OBJECTIVE: Analyze clinical, accepted biochemical, physiologic, and socioeconomic risk factors and correlate them with hospital utilization in an elderly population. DESIGN: Prospective, observational study in a defined, randomly recruited population. PARTICIPANTS: 5201 Medicare participants enrolled in the Cardiovascular Health Study (CHS). METHODS: Medicare recipients were randomly assigned to participate in an observational study. Baseline data were compared to hospital admissions and days of hospitalization over four years. DATA ANALYSIS: Data were grouped by type of risk factor and analyzed by Tobit analysis and logistic regression. RESULTS: Baseline variables associated with hospital use (p is less than 0.0001) were history of CHF, stroke, angina, hypertension, ln (timed walk), ln (blocks walked/week), age, gender, and clinic site. Factors not entering the model (p is greater than 0.05) were income, education, smoking, diabetes, weight, dietary fat, marital status, depression, and measures of mental function. CONCLUSIONS: In the elderly, existing health status is the major determinant of hospitalization and overwhelms many classic "risk factors" for morbidity.

VL - 7 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11416456?dopt=Abstract ER - TY - JOUR T1 - Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JF - JAMA Y1 - 2000 A1 - Nieto, F J A1 - Young, T B A1 - Lind, B K A1 - Shahar, E A1 - Samet, J M A1 - Redline, S A1 - D'Agostino, R B A1 - Newman, A B A1 - Lebowitz, M D A1 - Pickering, T G KW - Adult KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Hypertension KW - Logistic Models KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Sleep Apnea Syndromes KW - Snoring AB -

CONTEXT: Sleep-disordered breathing (SDB) and sleep apnea have been linked to hypertension in previous studies, but most of these studies used surrogate information to define SDB (eg, snoring) and were based on small clinic populations, or both.

OBJECTIVE: To assess the association between SDB and hypertension in a large cohort of middle-aged and older persons.

DESIGN AND SETTING: Cross-sectional analyses of participants in the Sleep Heart Health Study, a community-based multicenter study conducted between November 1995 and January 1998.

PARTICIPANTS: A total of 6132 subjects recruited from ongoing population-based studies (aged > or = 40 years; 52.8% female).

MAIN OUTCOME MEASURES: Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas per hour of sleep, with apnea defined as a cessation of airflow and hypopnea defined as a > or = 30% reduction in airflow or thoracoabdominal excursion both of which are accompanied by a > or = 4% drop in oxyhemoglobin saturation) [corrected], obtained by unattended home polysomnography. Other measures include arousal index; percentage of sleep time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication.

RESULTS: Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing SDB measures, although some of this association was explained by body mass index (BMI). After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol intake and smoking, the odds ratio for hypertension, comparing the highest category of AHI (> or = 30 per hour) with the lowest category (< 1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03-1.83; P for trend = .005). The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (> or = 12% vs < 0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified analyses, associations of hypertension with either measure of SDB were seen in both sexes, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring.

CONCLUSION: Our findings from the largest cross-sectional study to date indicate that SDB is associated with systemic hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds.

VL - 283 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10770144?dopt=Abstract ER - TY - JOUR T1 - Cognitive test performance and presence of subclinical cardiovascular disease in the cardiovascular health study. JF - Neuroepidemiology Y1 - 2000 A1 - Saxton, J A1 - Ratcliff, G A1 - Newman, A A1 - Belle, S A1 - Fried, L A1 - Yee, J A1 - Kuller, L KW - Aged KW - Cardiovascular Diseases KW - Cognition Disorders KW - Female KW - Humans KW - Hypertension KW - Male KW - Severity of Illness Index KW - Wechsler Scales AB -

The purpose of the present study was to investigate the relationship between performance on a comprehensive battery of neuropsychological tests and the presence of clinical, subclinical or no cardiovascular disease in an elderly community-dwelling population. The results confirm previous reports of significant associations of age, education and gender with test performance. When performance was examined controlling for these variables, significant associations of disease group were seen with five measures emphasizing speed of performance; Parts A and B of the Trail Making Test, the WAIS-R Digit Symbol and Block Design subtests and category verbal fluency. These results add to the evidence that, in addition to other health implications, cardiovascular disease is related to cognitive functioning in the elderly even at subclinical levels.

VL - 19 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11060505?dopt=Abstract ER - TY - JOUR T1 - Does snoring predict sleepiness independently of apnea and hypopnea frequency? JF - Am J Respir Crit Care Med Y1 - 2000 A1 - Gottlieb, D J A1 - Yao, Q A1 - Redline, S A1 - Ali, T A1 - Mahowald, M W KW - Adult KW - Aged KW - Arousal KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Risk Factors KW - Sleep Apnea, Obstructive KW - Snoring KW - Wakefulness AB -

Obstructive apneas and hypopneas during sleep are a well recognized cause of excessive daytime sleepiness. Snoring is also associated with excess sleepiness, although it is not known whether this reflects an independent effect of snoring or whether snoring is simply a marker for obstructive sleep apnea. To further explore the relation of snoring to sleepiness, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study. The study sample comprises 2,737 men and 3,040 women with a mean age of 64 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Snoring history was obtained via a self-completion questionnaire. The respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, was measured during in-home polysomnography. The ESS score increased progressively with increasing RDI, from a mean of 7.1 (4.2) in subjects with RDI < 1.5 to 8.8 (4.8) in subjects with RDI >/= 15 (p < 0.001). A progressive increase in ESS score was also seen across five categories of snoring frequency, from 6.4 (4.2) in current nonsnorers to 9.3 (4.8) in subjects who snored six to seven nights per week (p < 0.001). The prevalence of excessive daytime sleepiness, defined as an ESS score >/= 11, increased from 15% in never-snorers to 39% in those who snored six to seven nights per week. The relation of snoring to sleepiness was seen at all levels of RDI, with no significant change in the relation of snoring to ESS score after adjustment for RDI in multivariate models. The effects of snoring and RDI on sleepiness were little affected by adjustment for age, sex, race, body mass index, or questionnaire evidence of insufficient sleep time or nocturnal leg jerks or cramps. We conclude that both snoring and RDI are independently associated with excess sleepiness in community-dwelling, middle-aged and older adults.

VL - 162 IS - 4 Pt 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11029370?dopt=Abstract ER - TY - JOUR T1 - Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. JF - Neurology Y1 - 2000 A1 - Yaffe, K A1 - Haan, M A1 - Byers, A A1 - Tangen, C A1 - Kuller, L KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Carotid Stenosis KW - Estrogen Replacement Therapy KW - Female KW - Genotype KW - Humans KW - Mental Status Schedule KW - Neuropsychological Tests KW - Risk Factors AB -

OBJECTIVE: APOE-epsilon4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-epsilon4 and cognitive decline.

METHOD: - As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (> or =65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on > or =2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening.

RESULTS: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with epsilon4-negative women, epsilon4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and epsilon4 presence (p = 0.037). Among epsilon4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among epsilon4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in epsilon4-negative women but not in epsilon4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.

CONCLUSIONS: Estrogen use was associated with less cognitive decline among epsilon4-negative women but not epsilon4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation.

VL - 54 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10822435?dopt=Abstract ER - TY - JOUR T1 - Negative and positive health effects of caring for a disabled spouse: longitudinal findings from the caregiver health effects study. JF - Psychol Aging Y1 - 2000 A1 - Beach, S R A1 - Schulz, R A1 - Yee, J L A1 - Jackson, S KW - Aged KW - Anxiety KW - Caregivers KW - Depression KW - Disabled Persons KW - Female KW - Health Behavior KW - Health Status KW - Humans KW - Longitudinal Studies KW - Male KW - Mental Health KW - Risk-Taking KW - Spouses AB -

Data from the first 2 waves of the Caregiver Health Effects Study (n = 680) were analyzed to examine the effects of changes in caregiving involvement on changes in caregiver health-related outcomes in a population-based sample of elders caring for a disabled spouse. Caregiving involvement was indexed by levels of (a) spouse physical impairment, (b) help provided to the spouse, and (c) strain associated with providing help. Health-related outcomes included perceived health, health-risk behaviors, anxiety symptoms, and depression symptoms. Increases in spouse impairment and caregiver strain were generally related to poorer outcomes over time (poorer perceived health, increased health-risk behaviors, and increased anxiety and depression), whereas increased helping was related to better outcomes (decreased anxiety and depression). Results suggest that caring for a disabled spouse is a complex phenomenon that can have both deleterious and beneficial consequences.

VL - 15 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10879581?dopt=Abstract ER - TY - JOUR T1 - Orthostatic Hypotension in the Elderly: Contributions of Impaired LV Filling and Altered Sympathovagal Balance. JF - Am J Geriatr Cardiol Y1 - 2000 A1 - Gottdiener, John S. A1 - Yanez, David A1 - Rautaharju, Penttii A1 - Gardin, Julius M. A1 - Bild, Diane E. A1 - Lima, Joao A1 - Newman, Anne B. AB -

Orthostatic hypotension, which occurs in 5%-18% of the elderly, may contribute to age-related disability. While autonomic dysfunction and alterations of cardiac structure and function likely to impair postural maintenance of blood pressure are common in the elderly, these have not been jointly studied in large cohorts. The authors evaluated the association of orthostatic hypotension with echocardiographic measures of cardiac structure and function, and with autonomic function determined by analysis of heart rate variability, in a large population of community-dwelling elderly. A total of 5201 men and women, aged 65-100 years and living in four geographically separate communities, were recruited from Medicare eligibility lists. In this prospective, observational cohort study, measurements included clinical questionnaires, standing and supine blood pressures, mini-glucose tolerance testing, echocardiography, and 24-hour Holter recording for assessment of heart rate variability. Orthostatic hypotension, defined as a decrease in standing systolic blood pressure of 20 mm Hg or more, was positively associated in bivariate analyses with left ventricular wall thickness, peak velocity of late diastolic filling, vagal tone on heart rate variability analysis, supine systolic pressure, supine diastolic pressure, age, and diabetes, and inversely associated with body weight. After statistical adjustment for the presence of myocardial infarction, stroke, and use of antihypertensive medication, the associations were maintained, and a previous trend toward an association with decreased left ventricular cavity size became statistically significant. The data suggest that in elderly, community-based individuals, orthostatic hypotension is associated with increased blood pressure and decreased weight; it possibly acts mechanistically via altered sympathovagal balance, increased left ventricular wall thickness, decreased left ventricular preload, and alterations of left ventricular diastolic filling. (c) 2000 by CVRR, Inc.

VL - 9 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11416580?dopt=Abstract ER - TY - JOUR T1 - Prevalence, predisposing factors, and prognosis of clinically unrecognized myocardial infarction in the elderly. JF - J Am Coll Cardiol Y1 - 2000 A1 - Sheifer, S E A1 - Gersh, B J A1 - Yanez, N D A1 - Ades, P A A1 - Burke, G L A1 - Manolio, T A KW - Aged KW - Cause of Death KW - Coronary Disease KW - Cross-Sectional Studies KW - Databases, Factual KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Myocardial Infarction KW - Prognosis KW - Risk Factors KW - Stroke KW - Survival Rate AB -

OBJECTIVES: This study was designed to determine the prevalence of unrecognized myocardial infarction (UMI), as well as risk factors, and to compare prognosis after detection of previously UMI to that after recognized myocardial infarction (RMI).

BACKGROUND: Past studies revealed that a significant proportion of MIs escape recognition, and that prognosis after such events is poor, but the epidemiology of UMI has not been reassessed in the contemporary era.

METHODS: The Cardiovascular Health Study (CHS) database, composed of individuals > or =65, was queried for participants who, at entry, demonstrated electrocardiographic evidence of a prior Q-wave MI, but who lacked a history of this diagnosis. The features and outcomes of this group were compared to those of individuals with prevalent RMI.

RESULTS: Of 5,888 participants, 901 evidenced a past MI, and 201 (22.3%) were previously unrecognized. The independent predictors of UMI were the absence of angina and the absence of congestive heart failure (CHF). Six-year mortality did not significantly differ between the two groups.

CONCLUSIONS: 1) In the elderly, UMI continues to represent a significant proportion of all MIs; 2) associations with angina and CHF may reflect complex neurological issues, but they also may represent diagnosis bias; 3) these individuals can otherwise not be distinguished from those with recognized infarctions; and 4) mortality rates after UMI and RMI are similar. Future studies should address screening for UMI, risk stratification after detection of previously UMI, and the role of standard post-MI therapies.

VL - 35 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10636269?dopt=Abstract ER - TY - JOUR T1 - Weight change in old age and its association with mortality. JF - J Am Geriatr Soc Y1 - 2001 A1 - Newman, A B A1 - Yanez, D A1 - Harris, T A1 - Duxbury, A A1 - Enright, P L A1 - Fried, L P KW - Aged KW - Analysis of Variance KW - Body Weight KW - Chi-Square Distribution KW - Female KW - Health Status KW - Humans KW - Longitudinal Studies KW - Male KW - Mortality KW - Proportional Hazards Models KW - Risk Factors KW - United States KW - Weight Gain KW - Weight Loss AB -

OBJECTIVES: Previous studies of weight change and mortality in older adults have relied on self-reported weight loss, have not evaluated weight gain, or have had limited information on health status. Our objective was to determine whether 5% weight gain or loss in 3 years was predictive of mortality in a large sample of older adults.

DESIGN: Longitudinal observational cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand seven hundred fourteen community-dwelling older adults, age 65 and older.

MEASUREMENTS: Weight gain or loss of 5% in a 3-year period was examined in relationship to baseline health status and interim health events. Risk for subsequent mortality was estimated in those with weight loss or weight gain compared with the group whose weight was stable.

RESULTS: Weight changes occurred in 34.6% of women and 27.3% of men, with weight loss being more frequent than gain. Weight loss was associated with older age, black race, higher weight, lower waist circumference, current smoking, stroke, any hospitalization, death of a spouse, activities of daily living disability, lower grip strength, and slower gait speed. Weight loss but not weight gain of 5% or more was associated with an increased risk of mortality that persisted after multivariate adjustment (Hazard ratio (HR) = 1.67, 95% CI = 1.29-2.15) and was similar in those with no serious illness in the period of weight change. Those with weight loss and low baseline weight had the highest crude mortality rate, although the HR for weight loss was similar for all tertiles of baseline weight and for those with or without a special diet, compared with those whose weight was stable.

CONCLUSIONS: This study confirms that even modest decline in body weight is an important and independent marker of risk of mortality in older adults.

VL - 49 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11890489?dopt=Abstract ER - TY - JOUR T1 - Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Young, Terry A1 - Shahar, Eyal A1 - Nieto, F Javier A1 - Redline, Susan A1 - Newman, Anne B A1 - Gottlieb, Daniel J A1 - Walsleben, Joyce A A1 - Finn, Laurel A1 - Enright, Paul A1 - Samet, Jonathan M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Predictive Value of Tests KW - Residence Characteristics KW - Risk Factors KW - Sex Factors KW - Sleep Apnea Syndromes KW - Snoring AB -

BACKGROUND: Sleep-disordered breathing (SDB) is common, but largely undiagnosed in the general population. Information on demographic patterns of SDB occurrence and its predictive factors in the general population is needed to target high-risk groups that may benefit from diagnosis.

METHODS: The sample comprised 5615 community-dwelling men and women aged between 40 and 98 years who were enrolled in the Sleep Heart Health Study. Data were collected by questionnaire, clinical examinations, and in-home polysomnography. Sleep-disordered breathing status was based on the average number of apnea and hypopnea episodes per hour of sleep (apnea-hypopnea index [AHI]). We used multiple logistic regression modeling to estimate cross-sectional associations of selected participant characteristics with SDB defined by an AHI of 15 or greater.

RESULTS: Male sex, age, body mass index, neck girth, snoring, and repeated breathing pause frequency were independent, significant correlates of an AHI of 15 or greater. People reporting habitual snoring, loud snoring, and frequent breathing pauses were 3 to 4 times more likely to have an AHI of 15 or greater vs an AHI less than 15, but there were weaker associations for other factors with an AHI of 15 or greater. The odds ratios (95% confidence interval) for an AHI of 15 or greater vs an AHI less than 15 were 1.6 and 1.5, respectively, for 1-SD increments in body mass index and neck girth. As age increased, the magnitude of associations for SDB and body habitus, snoring, and breathing pauses decreased.

CONCLUSIONS: A significant proportion of occult SDB in the general population would be missed if screening or case finding were based solely on increased body habitus or male sex. Breathing pauses and obesity may be particularly insensitive for identifying SDB in older people. A better understanding of predictive factors for SDB, particularly in older adults, is needed.

VL - 162 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11966340?dopt=Abstract ER - TY - JOUR T1 - A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. JF - Blood Y1 - 2002 A1 - Folsom, Aaron R A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Aleksic, Nena A1 - Heckbert, Susan R A1 - Boland, Lori L A1 - Tsai, Albert W A1 - Yanez, N David A1 - Rosamond, Wayne D KW - Activated Protein C Resistance KW - Aged KW - Cohort Studies KW - Continental Population Groups KW - Factor V KW - Genotype KW - Haplotypes KW - Humans KW - Incidence KW - Longitudinal Studies KW - Middle Aged KW - Odds Ratio KW - Prospective Studies KW - Risk Factors KW - Thromboembolism KW - Venous Thrombosis AB -

The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.

VL - 99 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11929758?dopt=Abstract ER - TY - JOUR T1 - A regression model for longitudinal change in the presence of measurement error. JF - Ann Epidemiol Y1 - 2002 A1 - Yanez, N David A1 - Kronmal, Richard A A1 - Shemanski, Lynn R A1 - Psaty, Bruce M KW - Aged KW - Bias KW - Coronary Disease KW - Humans KW - Lipoproteins KW - Models, Statistical KW - Regression Analysis KW - Risk Factors AB -

PURPOSE: The analysis of change in measured variables has become quite popular in studies where data are collected repeatedly over time. The authors describe some of the potential pitfalls in the analysis of change when the variable for change is measured with error. They show that regression analysis is often biased, possibly leading to erroneous results.

METHODS: A simple method to correct for measurement error bias in regression models that model change is presented.

RESULTS AND CONCLUSIONS: The two examples illustrate how measurement error can adversely affect an analysis. The bias-corrected approach yields valid results.

VL - 12 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11750238?dopt=Abstract ER - TY - JOUR T1 - The relationship between chronically disrupted sleep and healthcare use. JF - Sleep Y1 - 2002 A1 - Kapur, Vishesh K A1 - Redline, Susan A1 - Nieto, F Javier A1 - Young, Terry B A1 - Newman, Anne B A1 - Henderson, Jeffrey A KW - Adult KW - Chronic Disease KW - Cohort Studies KW - Community Health Services KW - Cross-Sectional Studies KW - Disorders of Excessive Somnolence KW - Female KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Patient Acceptance of Health Care KW - Polysomnography KW - Prevalence KW - Severity of Illness Index KW - Sleep Apnea, Obstructive KW - Sleep Deprivation AB -

STUDY OBJECTIVES: To determine whether chronic sleep deprivation, sleep disruption, sleepiness, insomnia, and OSA are associated with increased healthcare use in a community-based population.

DESIGN: Cross-sectional study.

SETTING/PARTICIPANTS: 6440 Sleep Heart Health Study (SHHS) participants recruited from ongoing cohort studies.

INTERVENTIONS: N/A.

MEASUREMENTS: Polysomnography results (Apnea Hypopnea Index (AHI), percent of sleep time with oxyhemoglobin saturation below 90% (CT90), arousal index) as well as data on sleep related symptoms, medication use, and chronic illness. The indirect measure of predicted healthcare utilization was the modified Chronic Disease Score (CDS) calculated from medication data.

RESULTS: After adjustment for age, gender, BMI and study site, subjects in the highest quartiles of AHI, CT90 and Epworth score had CDS that were 6%-9% higher than the lowest quartiles. The adjusted mean CDS for subjects with sleep apnea was similar to that for subjects with hypertension, chronic bronchitis or asthma and 18% greater than the mean CDS for subjects without sleep apnea. Among subjects who did not have significant sleep-disordered breathing, complaints of insomnia, sleepiness, fatigue, and not getting enough sleep were associated with increased CDS.

CONCLUSIONS: This study demonstrated an association between subjective complaints of daytime sleepiness, inadequate sleep time, insomnia as well as objective measures of severity of SDB, and an indirect measure of healthcare utilization in a community-based sample. Though the percent increases in healthcare utilization observed were modest, the prevalence of these factors in the general population is high, and may therefore be associated with a substantial cost burden to the healthcare system.

VL - 25 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12003159?dopt=Abstract ER - TY - JOUR T1 - Short-term variability of respiration and sleep during unattended nonlaboratory polysomnography--the Sleep Heart Health Study. [corrected]. JF - Sleep Y1 - 2002 A1 - Quan, Stuart F A1 - Griswold, Michael E A1 - Iber, Conrad A1 - Nieto, F Javier A1 - Rapoport, David M A1 - Redline, Susan A1 - Sanders, Mark A1 - Young, Terry KW - Adult KW - Aged KW - Aged, 80 and over KW - Apnea KW - Arousal KW - Body Mass Index KW - Circadian Rhythm KW - Electrocardiography KW - Electromyography KW - Electrooculography KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxygen Consumption KW - Polysomnography KW - Respiration KW - Sleep Apnea Syndromes KW - Sleep Stages KW - Time Factors AB -

STUDY OBJECTIVES: To determine the short-term variability of indices of disturbed respiration and sleep during 2 nights of unattended nonlaboratory polysomnography conducted several months apart.

DESIGN: Participants were randomly selected using a block design with stratification on preliminary estimates of 2 criteria: respiratory disturbance index [RDI3% (apnea or hypopnea events associated with > or = 3% O2 desaturation): < 15/hour total sleep time, > or = 15/hour total sleep time] and sleep efficiency (SEff: < 85% and > or = 85%). The RDI and sleep data from initial and repeated polysomnography were compared.

SETTING: NA.

PARTICIPANTS: A subset of 99 participants in the Sleep Heart Health Study who agreed to have a repeat polysomnogram within 4 months of their original study.

INTERVENTIONS: NA.

MEASUREMENTS AND RESULTS: Acceptable repeat polysomnograms were obtained in 91 subjects (mean study interval: 77 +/- 18 [sd] days; range: 31-112 days). There was no significant bias in RDI between study nights using several different RDI definitions including RDI3% and RDI4% (apnea or hypopnea events associated with > or = 4% O2 desaturation). Variability between studies estimated using intraclass correlations (ICC) ranged from 0.77 to 0.81. For subjects with a RDI3% < 15, variability increased as a function of increasing RDI, but for those with a RDI3% > or = 15, variability was constant. Body mass index, SEff, gender, or age did not directly predict RDI variability. Using RDI4% cutpoints of < or = 5, < or = 10 and < or = 15 events per hour of sleep demonstrated that 79.1%, 85.7%, and 87.9% of subjects, respectively, had the same classification of SDB status on both nights of study. There also was no significant bias in sleep staging, sleep efficiency, or arousal index between studies. However, variability was greater with ICC values ranging from 0.37 (% time in REM) to 0.76 (arousal index).

CONCLUSION: In the Sleep Heart Health Study, accurate estimates of the severity of sleep-disordered breathing and the quality of sleep were obtained from a single night of unattended nonlaboratory polysomnography. These findings may be applicable to other large epidemiologic studies provided that similar recording techniques and quality-assurance procedures are followed.

VL - 25 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12489889?dopt=Abstract ER - TY - JOUR T1 - The association between time since last meal and blood pressure in older adults: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2003 A1 - Smith, Nicholas L A1 - Psaty, Bruce M A1 - Rutan, Gale H A1 - Lumley, Thomas A1 - Yanez, David A1 - Chaves, Paulo H M A1 - Kronmal, Richard A KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Eating KW - Female KW - Humans KW - Hypotension KW - Male KW - Postprandial Period KW - Prospective Studies KW - Risk Factors KW - Time Factors AB -

OBJECTIVES: To demonstrate a postprandial hypotensive (PPH) phenomenon in older adults.

DESIGN: Observational, prospective cohort study composed of baseline and nine follow-up visits.

SETTING: Cardiovascular Health Study, an epidemiological study of risk factors for cardiovascular disease in older adults.

PARTICIPANTS: Five thousand eight hundred eighty-eight community-dwelling adults aged 65 and older.

MEASUREMENTS: Blood pressure and time since last meal were recorded synchronously at baseline and at follow-up clinic visits. Generalized estimating equations were used to estimate associations between time since last meal and blood pressure and to adjust variance estimates to account for repeated blood pressure measures within subjects across fasting times.

RESULTS: Mean systolic and diastolic blood pressures were lower in the first hour after the last meal and were progressively higher through the fourth hour after the last meal than blood pressures measured immediately after the last meal (0 hour: 133.7/68.8 mmHg; 1st hour: 130.1/66.6 mmHg; 4th hour: 136.5/71.1 mmHg). Changes were significant for systolic and diastolic measures (P <.001 for both). Exploratory analyses suggested that the systolic PPH association was more pronounced in women. Little evidence was found that the degree of systolic or diastolic PPH varied by age, race, prevalent cardiovascular disease, heart rate, ejection fraction, treated hypertension or diabetes mellitus, or body mass index.

CONCLUSION: These data support previous observations that there is a significant drop in blood pressure within 1 hour after a meal in older adults. Time since last meal may be an important factor to consider when measuring blood pressure in older adults, and perhaps national standards need to be set.

VL - 51 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12757570?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy and sleep-disordered breathing. JF - Am J Respir Crit Care Med Y1 - 2003 A1 - Shahar, Eyal A1 - Redline, Susan A1 - Young, Terry A1 - Boland, Lori L A1 - Baldwin, Carol M A1 - Nieto, F Javier A1 - O'Connor, George T A1 - Rapoport, David M A1 - Robbins, John A KW - Age Distribution KW - Aged KW - Body Mass Index KW - Causality KW - Cohort Studies KW - Confidence Intervals KW - Estrogen Replacement Therapy KW - Female KW - Humans KW - Logistic Models KW - Middle Aged KW - Multivariate Analysis KW - Odds Ratio KW - Polysomnography KW - Postmenopause KW - Prevalence KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Sleep Stages KW - United States AB -

Disordered breathing during sleep is more common among postmenopausal women than among their premenopausal counterparts, possibly because of declining levels of estrogen and progesterone. We examined the relationship between the use of replacement hormones and sleep-disordered breathing in a sample of 2,852 noninstitutionalized women, 50 years of age or older, who participated in the Sleep Heart Health Study. The frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index) was determined by unattended, single-night polysomnography at the participant's home. The prevalence of sleep-disordered breathing (apnea-hypopnea index of 15 or more) among hormone users (61 of 907) was approximately half the prevalence among nonusers (286 of 1,945). Multivariable adjustment for known determinants of the disorder, including age, body mass index, and neck circumference, has attenuated the association, but only moderately (adjusted odds ratio, 0.55; 95% confidence interval, 0.41 to 0.75). The inverse association between hormone use and sleep-disordered breathing was evident in various subgroups and was particularly strong among women 50 to 59 years old (adjusted odds ratio, 0.36; 95% confidence interval, 0.21 to 0.60). If the observed associations are causal, hormone replacement therapy could have a role in preventing or alleviating sleep-disordered breathing.

VL - 167 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12531779?dopt=Abstract ER - TY - JOUR T1 - Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Am J Hematol Y1 - 2003 A1 - Tsai, Albert W A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Heckbert, Susan R A1 - Rosamond, Wayne D A1 - Aleksic, Nena A1 - Yanez, N David A1 - Psaty, Bruce M A1 - Folsom, Aaron R KW - Aged KW - Aging KW - Animals KW - Case-Control Studies KW - Cohort Studies KW - Factor V KW - Female KW - Genotype KW - Homocysteine KW - Humans KW - Longitudinal Studies KW - Male KW - Methylenetetrahydrofolate Reductase (NADPH2) KW - Middle Aged KW - Odds Ratio KW - Oxidoreductases Acting on CH-NH Group Donors KW - Polymorphism, Genetic KW - Prospective Studies KW - Risk Factors KW - Venous Thrombosis AB -

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

VL - 72 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12605391?dopt=Abstract ER - TY - JOUR T1 - APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. JF - Neurology Y1 - 2004 A1 - Gottlieb, D J A1 - DeStefano, A L A1 - Foley, D J A1 - Mignot, E A1 - Redline, S A1 - Givelber, R J A1 - Young, T KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Alleles KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Sleep Apnea, Obstructive KW - Smoking AB -

BACKGROUND: Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association.

METHODS: A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHI > or = 15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship.

RESULTS: At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p = 0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those > or =75 years old (OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE epsilon4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without.

CONCLUSION: The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results.

VL - 63 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15326239?dopt=Abstract ER - TY - JOUR T1 - Age-dependent associations between sleep-disordered breathing and hypertension: importance of discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study. JF - Circulation Y1 - 2005 A1 - Haas, Donald C A1 - Foster, Gregory L A1 - Nieto, F Javier A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Robbins, John A A1 - Young, Terry A1 - Pickering, Thomas G KW - Adult KW - Age Factors KW - Aged KW - Antihypertensive Agents KW - Cross-Sectional Studies KW - Diastole KW - Female KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Risk Factors KW - Sleep Apnea Syndromes KW - Sleep Apnea, Central KW - Systole AB -

BACKGROUND: Sleep-disordered breathing (SDB) is associated with hypertension in the middle-aged. The association is less clear in older persons. Most middle-aged hypertensives have systolic/diastolic hypertension, whereas isolated systolic hypertension (ISH) is common among persons over 60 years. Mechanistically, only systolic/diastolic hypertension is expected to be associated with SDB, but few studies of SDB and hypertension distinguish systolic/diastolic hypertension from ISH. Prior investigations may have underestimated an association between SDB and systolic/diastolic hypertension in the elderly by categorizing individuals with ISH as simply hypertensive.

METHODS AND RESULTS: We conducted cross-sectional analyses of 6120 participants in the Sleep Heart Health Study, stratified by age: 40 to 59 (n=2477) and > or =60 years. Outcome measures included apnea-hypopnea index (AHI; average number of apneas plus hypopneas per hour of sleep), systolic/diastolic hypertension (> or =140 and > or =90 mm Hg), and ISH (> or =140 and <90 mm Hg). With adjustment for covariates, ISH was not associated with SDB in either age category. In those aged<60 years, AHI was significantly associated with higher odds of systolic/diastolic hypertension (AHI 15 to 29.9, OR=2.38 [95% CI 1.30 to 4.38]; AHI > or =30, OR=2.24 [95% CI 1.10 to 4.54]). Among those aged > or =60 years, no adjusted association between AHI and systolic/diastolic hypertension was found.

CONCLUSIONS: SDB is associated with systolic/diastolic hypertension in those aged <60 years. No association was found between SDB and systolic/diastolic hypertension in those aged > or =60 years or between SDB and ISH in either age category. These findings have implications for SDB screening and treatment. Distinguishing between hypertensive subtypes reveals a stronger association between SDB and hypertension for those aged <60 years than previously reported.

VL - 111 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15699282?dopt=Abstract ER - TY - JOUR T1 - Factors associated with incidence and persistence of symptoms of disturbed sleep in an elderly cohort: the Cardiovascular Health Study. JF - Am J Med Sci Y1 - 2005 A1 - Quan, Stuart F A1 - Katz, Ronit A1 - Olson, Jean A1 - Bonekat, William A1 - Enright, Paul L A1 - Young, Terry A1 - Newman, Anne KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Depression KW - Female KW - Health Status KW - Humans KW - Incidence KW - Logistic Models KW - Male KW - Odds Ratio KW - Prevalence KW - Risk Factors KW - Sex Factors KW - Sleep Initiation and Maintenance Disorders KW - Surveys and Questionnaires AB -

BACKGROUND: There are limited data pertaining to the factors influencing the incidence and persistence of sleep symptoms in the elderly. The purpose of this study was to determine the incidence and nonremission rates of the following sleep symptoms: trouble falling asleep (TFA), frequent awakenings (FA), and excessive daytime sleepiness (EDS) in the Cardiovascular Health Study (CHS), a prospective multicenter study of cardiovascular disease in a large cohort of elderly adults. Factors influencing these rates were assessed as well.

METHODS: 4467 participants in CHS were surveyed for the presence of TFA, FA, and EDS as well as other health problems at their baseline examination and at a follow-up examination 1 to 4 years later.

RESULTS: Annualized incidence and nonremission rates were the following: TFA (2.8% and 15.4%), FA (12.3% and 22.7%), and EDS (4.4% and 13.4%). Women were more likely to have incident and persistent TFA. Depression was the primary factor predicting the incidence of all three sleep symptoms. However, other health conditions, including respiratory symptoms and cardiovascular disease, and limitation in activities of daily living were important as well. Depression also was the most important factor associated with persistence of these sleep symptoms. The role of other health conditions in determining nonremission was much more limited.

CONCLUSIONS: Incidence of sleep disturbances in the elderly is related to depression, health conditions, and physical functioning. However, persistence of sleep disturbances is best predicted by the presence of depression.

VL - 329 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15832098?dopt=Abstract ER - TY - JOUR T1 - Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. JF - Arch Intern Med Y1 - 2005 A1 - Newman, Anne B A1 - Foster, Greg A1 - Givelber, Rachel A1 - Nieto, F Javier A1 - Redline, Susan A1 - Young, Terry KW - Body Weights and Measures KW - Causality KW - Cohort Studies KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Humans KW - Linear Models KW - Male KW - Middle Aged KW - Obesity KW - Odds Ratio KW - Sex Distribution KW - Sleep Apnea Syndromes KW - United States KW - Weight Gain KW - Weight Loss AB -

BACKGROUND: The relationship of weight changes to the incidence, progression, and remission of sleep-disordered breathing (SDB) is not well defined. This study aims to determine the relationship between change in weight and progression or remission of SDB by polysomnography.

METHODS: We performed a longitudinal cohort study of the cardiovascular consequences of sleep apnea in diverse US communities. Sleep apnea and polysomnographic indicators of SDB were assessed 5 years apart.

RESULTS: A total of 2968 men and women (mean age, 62 years) participated in the study. Men were more likely to have an increase in Respiratory Disturbance Index (RDI) with a given increase in weight than were women, and this was not explained by differences in starting weight, waist circumference, age, or ethnicity. In a linear regression analysis, both men and women had a greater increase in RDI with weight gain than a decrease in RDI with weight loss. In a categorical analysis of larger degrees of change, this sex difference was also evident. Associations were similar in diverse ethnic groups. However, SDB progressed over time, even in those with stable weight.

CONCLUSION: Modest changes in weight were related to an increase or decrease in SDB, and this association was stronger in men than in women.

VL - 165 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16287771?dopt=Abstract ER - TY - JOUR T1 - Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. JF - Arch Gen Psychiatry Y1 - 2006 A1 - Barnes, Deborah E A1 - Alexopoulos, George S A1 - Lopez, Oscar L A1 - Williamson, Jeff D A1 - Yaffe, Kristine KW - Aged KW - Cerebrovascular Disorders KW - Cognition Disorders KW - Comorbidity KW - Dementia KW - Dementia, Vascular KW - Depressive Disorder KW - Female KW - Follow-Up Studies KW - Geriatric Assessment KW - Humans KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Psychiatric Status Rating Scales KW - Risk Factors KW - Sampling Studies KW - Vascular Diseases AB -

CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons.

OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease.

DESIGN: Prospective, population-based, longitudinal study.

SETTING: Random sample of adults 65 years or older recruited from 4 US communities.

PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria.

MAIN OUTCOME MEASURE: Diagnosis of MCI.

RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0%, 13.3%, and 19.7% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics.

CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.

VL - 63 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16520432?dopt=Abstract ER - TY - JOUR T1 - Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. JF - Circulation Y1 - 2007 A1 - Yeboah, Joseph A1 - Crouse, John R A1 - Hsu, Fang-Chi A1 - Burke, Gregory L A1 - Herrington, David M KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Biomarkers KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease-Free Survival KW - Endothelium, Vascular KW - Female KW - Hemorheology KW - Humans KW - Hyperemia KW - Male KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Reproducibility of Results KW - Risk Factors KW - Stress, Mechanical KW - Tourniquets KW - Ultrasonography KW - United States KW - Vasodilation AB -

BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults.

METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model.

CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.

VL - 115 IS - 18 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17452608?dopt=Abstract ER - TY - JOUR T1 - The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. JF - Eur J Epidemiol Y1 - 2007 A1 - Danesh, J A1 - Erqou, S A1 - Walker, M A1 - Thompson, S G A1 - Tipping, R A1 - Ford, C A1 - Pressel, S A1 - Walldius, G A1 - Jungner, I A1 - Folsom, A R A1 - Chambless, L E A1 - Knuiman, M A1 - Whincup, P H A1 - Wannamethee, S G A1 - Morris, R W A1 - Willeit, J A1 - Kiechl, S A1 - Santer, P A1 - Mayr, A A1 - Wald, N A1 - Ebrahim, S A1 - Lawlor, D A A1 - Yarnell, J W G A1 - Gallacher, J A1 - Casiglia, E A1 - Tikhonoff, V A1 - Nietert, P J A1 - Sutherland, S E A1 - Bachman, D L A1 - Keil, J E A1 - Cushman, M A1 - Psaty, B M A1 - Tracy, R P A1 - Tybjaerg-Hansen, A A1 - Nordestgaard, B G A1 - Frikke-Schmidt, R A1 - Giampaoli, S A1 - Palmieri, L A1 - Panico, S A1 - Vanuzzo, D A1 - Pilotto, L A1 - Simons, L A1 - McCallum, J A1 - Friedlander, Y A1 - Fowkes, F G R A1 - Lee, A J A1 - Smith, F B A1 - Taylor, J A1 - Guralnik, J A1 - Phillips, C A1 - Wallace, R A1 - Blazer, D A1 - Khaw, K T A1 - Jansson, J H A1 - Donfrancesco, C A1 - Salomaa, V A1 - Harald, K A1 - Jousilahti, P A1 - Vartiainen, E A1 - Woodward, M A1 - D'Agostino, R B A1 - Wolf, P A A1 - Vasan, R S A1 - Pencina, M J A1 - Bladbjerg, E M A1 - Jorgensen, T A1 - Moller, L A1 - Jespersen, J A1 - Dankner, R A1 - Chetrit, A A1 - Lubin, F A1 - Rosengren, A A1 - Wilhelmsen, L A1 - Lappas, G A1 - Eriksson, H A1 - Bjorkelund, C A1 - Cremer, P A1 - Nagel, D A1 - Tilvis, R A1 - Strandberg, T A1 - Rodriguez, B A1 - Bouter, L M A1 - Heine, R J A1 - Dekker, J M A1 - Nijpels, G A1 - Stehouwer, C D A A1 - Rimm, E A1 - Pai, J A1 - Sato, S A1 - Iso, H A1 - Kitamura, A A1 - Noda, H A1 - Goldbourt, U A1 - Salomaa, V A1 - Salonen, J T A1 - Nyyssönen, K A1 - Tuomainen, T-P A1 - Deeg, D A1 - Poppelaars, J L A1 - Meade, T A1 - Cooper, J A1 - Hedblad, B A1 - Berglund, G A1 - Engstrom, G A1 - Döring, A A1 - Koenig, W A1 - Meisinger, C A1 - Mraz, W A1 - Kuller, L A1 - Selmer, R A1 - Tverdal, A A1 - Nystad, W A1 - Gillum, R A1 - Mussolino, M A1 - Hankinson, S A1 - Manson, J A1 - De Stavola, B A1 - Knottenbelt, C A1 - Cooper, J A A1 - Bauer, K A A1 - Rosenberg, R D A1 - Sato, S A1 - Naito, Y A1 - Holme, I A1 - Nakagawa, H A1 - Miura, H A1 - Ducimetiere, P A1 - Jouven, X A1 - Crespo, C A1 - Garcia-Palmieri, M A1 - Amouyel, P A1 - Arveiler, D A1 - Evans, A A1 - Ferrieres, J A1 - Schulte, H A1 - Assmann, G A1 - Shepherd, J A1 - Packard, C A1 - Sattar, N A1 - Cantin, B A1 - Lamarche, B A1 - Després, J-P A1 - Dagenais, G R A1 - Barrett-Connor, E A1 - Wingard, D A1 - Bettencourt, R A1 - Gudnason, V A1 - Aspelund, T A1 - Sigurdsson, G A1 - Thorsson, B A1 - Trevisan, M A1 - Witteman, J A1 - Kardys, I A1 - Breteler, M A1 - Hofman, A A1 - Tunstall-Pedoe, H A1 - Tavendale, R A1 - Lowe, G D O A1 - Ben-Shlomo, Y A1 - Howard, B V A1 - Zhang, Y A1 - Best, L A1 - Umans, J A1 - Onat, A A1 - Meade, T W A1 - Njolstad, I A1 - Mathiesen, E A1 - Lochen, M L A1 - Wilsgaard, T A1 - Gaziano, J M A1 - Stampfer, M A1 - Ridker, P A1 - Ulmer, H A1 - Diem, G A1 - Concin, H A1 - Rodeghiero, F A1 - Tosetto, A A1 - Brunner, E A1 - Shipley, M A1 - Buring, J A1 - Cobbe, S M A1 - Ford, I A1 - Robertson, M A1 - He, Y A1 - Ibanez, A M A1 - Feskens, E J M A1 - Kromhout, D A1 - Collins, R A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Lewington, S A1 - Orfei, L A1 - Pennells, L A1 - Perry, P A1 - Ray, K A1 - Sarwar, N A1 - Scherman, M A1 - Thompson, A A1 - Watson, S A1 - Wensley, F A1 - White, I R A1 - Wood, A M KW - Albumins KW - Biomarkers KW - Cardiovascular Diseases KW - Databases, Factual KW - Far East KW - Humans KW - Inflammation KW - Leukocyte Count KW - Lipids KW - Lipoproteins, HDL KW - Prospective Studies KW - Risk Factors KW - Triglycerides AB -

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

VL - 22 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17876711?dopt=Abstract ER - TY - JOUR T1 - Inflammation biomarkers and near-term death in older men. JF - Am J Epidemiol Y1 - 2007 A1 - Jenny, Nancy Swords A1 - Yanez, N David A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Hirsch, Calvin H A1 - Tracy, Russell P KW - Age Distribution KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Diabetes Complications KW - Epidemiologic Studies KW - Female KW - Fibrinogen KW - Follow-Up Studies KW - Humans KW - Hypercholesterolemia KW - Hypertension KW - Inflammation KW - Male KW - Middle Aged KW - Obesity KW - Population Surveillance KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Risk Factors KW - Sex Distribution KW - Smoking KW - Time Factors KW - United States AB -

Associations of C-reactive protein (CRP) and fibrinogen with death may weaken over time. Combining both markers may improve prediction of death in older adults. In 5,828 Cardiovascular Health Study participants (United States, 1989-2000), 383 deaths (183 cardiovascular disease (CVD)) in years 1-3 (early) and 914 deaths (396 CVD) in years 4-8 (late) occurred. For men, when comparing highest to lowest quartiles, hazard ratios for early death were 4.1 (95% confidence interval (CI): 2.7, 6.3) for CRP and 4.1 (95% CI: 2.7, 6.4) for fibrinogen in models adjusted for CVD risk. For early CVD death, hazard ratios were 4.3 (95% CI: 2.2, 8.4) and 3.4 (95% CI: 1.8, 6.3), respectively. When comparing men in the highest quartiles of both biomarkers with those in the lowest, hazard ratios were 9.6 (95% CI: 4.3, 21.1) for early death and 13.5 (95% CI: 3.2, 56.5) for early CVD death. Associations were weaker for late deaths. For women, CRP (hazard ratio = 2.3, 95% CI: 1.4, 3.9), but not fibrinogen (hazard ratio = 1.3, 95% CI: 0.8, 2.2), was associated with early death. Results were similar for CVD death. Neither was associated with late deaths. CRP and fibrinogen were more strongly associated with death in older men than women and more strongly associated with early than late death. Combining both markers may identify older men at greatest risk of near-term death.

VL - 165 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17215383?dopt=Abstract ER - TY - JOUR T1 - Age-specific prevalence and years of healthy life in a system with three health states. JF - Stat Med Y1 - 2008 A1 - Diehr, Paula A1 - Yanez, David A1 - Derleth, Ann A1 - Newman, Anne B KW - Age Factors KW - Biometry KW - Health Status KW - Humans KW - Life Tables KW - Longitudinal Studies KW - Middle Aged KW - Models, Statistical KW - Probability KW - Quality-Adjusted Life Years AB -

Consider a 3-state system with one absorbing state, such as Healthy, Sick, and Dead. Over time, the prevalence of the Healthy state will approach an 'equilibrium' value that is independent of the initial conditions. We derived this equilibrium prevalence (Prev:Equil) as a function of the local transition probabilities. We then used Prev:Equil to estimate the expected number of years spent in the healthy state over time. This estimate is similar to the one calculated by multi-state life table methods, and has the advantage of having an associated standard error. In longitudinal data for older adults, the standard error was accurate when a valid survival table was known from other sources, or when the available data set was sufficient to estimate survival accurately. Performance was better with fewer waves of data. If validated in other situations, these estimates of prevalence and years of healthy life (YHL) and their standard errors may be useful when the goal is to compare YHL for different populations.

VL - 27 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17847058?dopt=Abstract ER - TY - JOUR T1 - Albuminuria and dementia in the elderly: a community study. JF - Am J Kidney Dis Y1 - 2008 A1 - Barzilay, Joshua I A1 - Fitzpatrick, Annette L A1 - Luchsinger, Jose A1 - Yasar, Sevil A1 - Bernick, Charles A1 - Jenny, Nancy S A1 - Kuller, Lewis H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Brain KW - Cognition KW - Cross-Sectional Studies KW - Dementia KW - Female KW - Humans KW - Incidence KW - Magnetic Resonance Imaging KW - Male KW - Odds Ratio KW - Population Surveillance KW - Prognosis KW - Retrospective Studies KW - Risk Factors AB -

BACKGROUND: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney.

STUDY DESIGN: Cross-sectional analysis.

SETTING & PARTICIPANTS: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria.

PREDICTOR: Doubling of albuminuria.

OUTCOME: Dementia defined according to neuropsychological and clinical evaluation.

MEASUREMENTS: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition.

RESULTS: 283 participants (12.2%) had dementia, 344 (14.9%) had mild cognitive impairment, and 1,689 (72.9%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.

LIMITATIONS: Results are cross-sectional; causality cannot be imputed.

CONCLUSIONS: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults.

VL - 52 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18468749?dopt=Abstract ER - TY - JOUR T1 - Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. JF - Atherosclerosis Y1 - 2008 A1 - Yeboah, Joseph A1 - Sutton-Tyrrell, Kim A1 - McBurnie, Mary Ann A1 - Burke, Gregory L A1 - Herrington, David M A1 - Crouse, John R KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Hemorheology KW - Humans KW - Male KW - Peripheral Vascular Diseases KW - ROC Curve KW - Ultrasonography KW - Vasodilation AB -

BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.

METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/-0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17714717?dopt=Abstract ER - TY - JOUR T1 - Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2008 A1 - Shiffman, Dov A1 - O'Meara, Ellen S A1 - Bare, Lance A A1 - Rowland, Charles M A1 - Louie, Judy Z A1 - Arellano, Andre R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Iakoubova, Olga A1 - Luke, May M A1 - Young, Bradford A A1 - Malloy, Mary J A1 - Kane, John P A1 - Ellis, Stephen G A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Americans KW - Aged KW - Aged, 80 and over KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - United States AB -

OBJECTIVE: We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older.

METHODS AND RESULTS: Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42).

CONCLUSIONS: Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.

VL - 28 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17975119?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study. JF - Clin J Am Soc Nephrol Y1 - 2008 A1 - Mittalhenkle, Anuja A1 - Stehman-Breen, Catherine O A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Katz, Ronit A1 - Young, Bessie A A1 - Seliger, Stephen A1 - Gillen, Daniel A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Siscovick, David KW - Acute Kidney Injury KW - Aged KW - Cardiovascular Diseases KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND AND OBJECTIVES: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries.

RESULTS: Acute renal failure developed in 225 (3.9%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness.

CONCLUSIONS: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.

VL - 3 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18256380?dopt=Abstract ER - TY - JOUR T1 - Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Yeboah, Joseph A1 - Burke, Gregory L A1 - Crouse, John R A1 - Herrington, David M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Brachial Artery KW - Carotid Arteries KW - Carotid Artery Diseases KW - Cohort Studies KW - Female KW - Hemorheology KW - Humans KW - Male KW - Tunica Intima KW - Tunica Media KW - Ultrasonography KW - Vasodilation AB -

OBJECTIVE: The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.

BACKGROUND: Brachial flow-mediated dilation (FMD) is a physiologic measure and carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.

METHODS: Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72-98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender and race/ethnicity, BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.

RESULTS: Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient=-0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient=-0.006, p=0.470).

CONCLUSION: Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17804000?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. JF - Am J Respir Crit Care Med Y1 - 2008 A1 - Punjabi, Naresh M A1 - Newman, Anne B A1 - Young, Terry B A1 - Resnick, Helaine E A1 - Sanders, Mark H KW - Aged KW - Apnea KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Oxyhemoglobins KW - Polysomnography KW - Sleep Apnea Syndromes KW - Terminology as Topic AB -

RATIONALE: Epidemiologic studies on the consequences of sleep-disordered breathing invariably use the apnea-hypopnea index as the primary measure of disease severity. Although hypopneas constitute a majority of disordered breathing events, significant controversy remains about the best criteria used to define these events.

OBJECTIVES: The current investigation sought to assess the most appropriate definition for hypopneas that would be best correlated with cardiovascular disease.

METHODS: A community sample of middle-aged and older adults was recruited as part of the Sleep Heart Health Study. Full-montage polysomnography was conducted and hypopneas were defined using different thresholds of oxyhemoglobin desaturation with and without arousals. Prevalent cardiovascular disease was assessed based on self-report. Logistic regression analysis was used to characterize the independent association between the hypopnea index and prevalent cardiovascular disease.

MEASUREMENTS AND MAIN RESULTS: Using a sample of 6,106 adults with complete data on cardiovascular disease status and polysomnography, the current study found that hypopneas associated with an oxyhemoglobin desaturation of 4% or more were associated with prevalent cardiovascular disease independent of confounding covariates. The adjusted prevalent odds ratios for quartiles of the hypopnea index using a 4% desaturation criterion were as follows: 1.00 (<1.10 events/h), 1.10 (1.01-3.20 events/h), 1.33 (3.21-7.69 events/h), and 1.41 (>7.69 events/h). Hypopnea measures based on less than 4% oxyhemoglobin desaturation or presence of arousals showed no association with cardiovascular disease.

CONCLUSIONS: Hypopneas comprise a significant component of sleep-disordered breathing in the general community. By varying the criteria for defining hypopneas, this study demonstrates that hypopneas with a desaturation of at least 4% are independently associated with cardiovascular disease. In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturations or arousals.

VL - 177 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18276938?dopt=Abstract ER - TY - JOUR T1 - Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2009 A1 - Sink, Kaycee M A1 - Leng, Xiaoyan A1 - Williamson, Jeff A1 - Kritchevsky, Stephen B A1 - Yaffe, Kristine A1 - Kuller, Lewis A1 - Yasar, Sevil A1 - Atkinson, Hal A1 - Robbins, Mike A1 - Psaty, Bruce A1 - Goff, David C KW - Aged KW - Angiotensin-Converting Enzyme Inhibitors KW - Blood-Brain Barrier KW - Cognition KW - Dementia KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.

METHODS: Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).

RESULTS: Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (-0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs.

CONCLUSIONS: While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.

VL - 169 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597068?dopt=Abstract ER - TY - JOUR T1 - Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Dehghan, Abbas A1 - Yang, Qiong A1 - Peters, Annette A1 - Basu, Saonli A1 - Bis, Joshua C A1 - Rudnicka, Alicja R A1 - Kavousi, Maryam A1 - Chen, Ming-Huei A1 - Baumert, Jens A1 - Lowe, Gordon D O A1 - McKnight, Barbara A1 - Tang, Weihong A1 - de Maat, Moniek A1 - Larson, Martin G A1 - Eyhermendy, Susana A1 - McArdle, Wendy L A1 - Lumley, Thomas A1 - Pankow, James S A1 - Hofman, Albert A1 - Massaro, Joseph M A1 - Rivadeneira, Fernando A1 - Kolz, Melanie A1 - Taylor, Kent D A1 - van Duijn, Cornelia M A1 - Kathiresan, Sekar A1 - Illig, Thomas A1 - Aulchenko, Yurii S A1 - Volcik, Kelly A A1 - Johnson, Andrew D A1 - Uitterlinden, André G A1 - Tofler, Geoffrey H A1 - Gieger, Christian A1 - Psaty, Bruce M A1 - Couper, David J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C A1 - Strachan, David P A1 - Smith, Nicholas L A1 - Folsom, Aaron R KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract ER - TY - JOUR T1 - Common variants at ten loci influence QT interval duration in the QTGEN Study. JF - Nat Genet Y1 - 2009 A1 - Newton-Cheh, Christopher A1 - Eijgelsheim, Mark A1 - Rice, Kenneth M A1 - de Bakker, Paul I W A1 - Yin, Xiaoyan A1 - Estrada, Karol A1 - Bis, Joshua C A1 - Marciante, Kristin A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Sotoodehnia, Nona A1 - Smith, Nicholas L A1 - Rotter, Jerome I A1 - Kors, Jan A A1 - Witteman, Jacqueline C M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Larson, Martin G A1 - Stricker, Bruno H Ch KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Chromosome Mapping KW - Death, Sudden, Cardiac KW - Electroencephalography KW - ERG1 Potassium Channel KW - Ether-A-Go-Go Potassium Channels KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - Humans KW - KCNQ1 Potassium Channel KW - Meta-Analysis as Topic KW - Muscle Proteins KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Voltage-Gated KW - Risk Factors KW - Sodium Channels AB -

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

VL - 41 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19305408?dopt=Abstract ER - TY - JOUR T1 - Depressed mood is not a risk factor for incident dementia in a community-based cohort. JF - Am J Geriatr Psychiatry Y1 - 2009 A1 - Becker, James T A1 - Chang, Yue-Fang A1 - Lopez, Oscar L A1 - Dew, Mary Amanda A1 - Sweet, Robert A A1 - Barnes, Deborah A1 - Yaffe, Kristine A1 - Young, Jeffrey A1 - Kuller, Lewis A1 - Reynolds, Charles F KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cognition Disorders KW - Dementia KW - Depression KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Mental Status Schedule KW - Prospective Studies KW - Psychiatric Status Rating Scales KW - Residence Characteristics KW - Risk Factors AB -

OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals.

DESIGN: Longitudinal and observational.

SETTING: Community-based cohort study.

PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years).

MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams.

RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood.

CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.

VL - 17 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19634208?dopt=Abstract ER - TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. JF - Br J Haematol Y1 - 2009 A1 - Yamagishi, Kazumasa A1 - Cushman, Mary A1 - Heckbert, Susan R A1 - Tsai, Michael Y A1 - Folsom, Aaron R KW - Antigens, CD KW - Case-Control Studies KW - Endothelial Protein C Receptor KW - Female KW - Genotype KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Genetic KW - Prospective Studies KW - Receptors, Cell Surface KW - Risk KW - Venous Thromboembolism AB -

Prior case-control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged > or =45 years. A nested case-control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1.17[0.86-1.59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1.84[1.05-3.22]) and women (OR = 1.51[1.01-2.26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0.93[0.70-1.25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.

VL - 145 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19222470?dopt=Abstract ER - TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. JF - Nat Genet Y1 - 2009 A1 - Ganesh, Santhi K A1 - Zakai, Neil A A1 - van Rooij, Frank J A A1 - Soranzo, Nicole A1 - Smith, Albert V A1 - Nalls, Michael A A1 - Chen, Ming-Huei A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Kuhnel, Brigitte A1 - Aspelund, Thor A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Jaffe, Andrew A1 - Bis, Joshua C M A1 - Verwoert, Germaine C A1 - Teumer, Alexander A1 - Fox, Caroline S A1 - Guralnik, Jack M A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Felix, Janine F A1 - Rendon, Augusto A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Patel, Kushang V A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Sambrook, Jennifer G A1 - Hernandez, Dena G A1 - Zheng, Gang A1 - Bandinelli, Stefania A1 - Singleton, Andrew B A1 - Coresh, Josef A1 - Lumley, Thomas A1 - Uitterlinden, André G A1 - Vangils, Janine M A1 - Launer, Lenore J A1 - Cupples, L Adrienne A1 - Oostra, Ben A A1 - Zwaginga, Jaap-Jan A1 - Ouwehand, Willem H A1 - Thein, Swee-Lay A1 - Meisinger, Christa A1 - Deloukas, Panos A1 - Nauck, Matthias A1 - Spector, Tim D A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Chakravarti, Aravinda A1 - Greinacher, Andreas A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Furth, Susan A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Lin, Jing-Ping KW - Blood Pressure KW - Cell Line KW - Cohort Studies KW - Endothelial Cells KW - Erythrocytes KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

VL - 41 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract ER - TY - JOUR T1 - Predicting risk of dementia in older adults: The late-life dementia risk index. JF - Neurology Y1 - 2009 A1 - Barnes, D E A1 - Covinsky, K E A1 - Whitmer, R A A1 - Kuller, L H A1 - Lopez, O L A1 - Yaffe, K KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Apolipoprotein E4 KW - Body Mass Index KW - Carotid Stenosis KW - Cerebrum KW - Cognition Disorders KW - Cohort Studies KW - Coronary Artery Bypass KW - Dementia KW - Female KW - Genetic Markers KW - Health Status Indicators KW - Humans KW - Logistic Models KW - Male KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Risk Reduction Behavior AB -

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.

METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.

RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores.

CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

VL - 73 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19439724?dopt=Abstract ER - TY - JOUR T1 - Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 2009 A1 - Yanez, N David A1 - Burke, Gregory L A1 - Manolio, Teri A1 - Gardin, Julius M A1 - Polak, Joseph KW - Aged KW - Atherosclerosis KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Male KW - Myocardial Infarction KW - Odds Ratio KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Siblings KW - Stroke KW - United States AB -

PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults.

METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups.

RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile.

CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.

VL - 19 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19944349?dopt=Abstract ER - TY - JOUR T1 - Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. JF - Stat Med Y1 - 2009 A1 - Jackson, Dan A1 - White, Ian A1 - Kostis, J B A1 - Wilson, A C A1 - Folsom, A R A1 - Wu, K A1 - Chambless, L A1 - Benderly, M A1 - Goldbourt, U A1 - Willeit, J A1 - Kiechl, S A1 - Yarnell, J W G A1 - Sweetnam, P M A1 - Elwood, P C A1 - Cushman, M A1 - Psaty, B M A1 - Tracy, R P A1 - Tybjaerg-Hansen, A A1 - Haverkate, F A1 - de Maat, M P M A1 - Thompson, S G A1 - Fowkes, F G R A1 - Lee, A J A1 - Smith, F B A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - D'Agostino, R A1 - Kannel, W B A1 - Wilson, P W F A1 - Tofler, G A1 - Levy, D A1 - Marchioli, R A1 - Valagussa, F A1 - Rosengren, A A1 - Wilhelmsen, L A1 - Lappas, G A1 - Eriksson, H A1 - Cremer, P A1 - Nagel, D A1 - Curb, J D A1 - Rodriguez, B A1 - Yano, K A1 - Salonen, J T A1 - Nyyssönen, K A1 - Tuomainen, T-P A1 - Hedblad, B A1 - Engstrom, G A1 - Berglund, G A1 - Loewel, H A1 - Koenig, W A1 - Hense, H W A1 - Meade, T W A1 - Cooper, J A A1 - De Stavola, B A1 - Knottenbelt, C A1 - Miller, G J A1 - Cooper, J A A1 - Bauer, K A A1 - Rosenberg, R D A1 - Sato, S A1 - Kitamura, A A1 - Naito, Y A1 - Iso, H A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - Palosuo, T A1 - Ducimetiere, P A1 - Amouyel, P A1 - Arveiler, D A1 - Evans, A E A1 - Ferrieres, J A1 - Juhan-Vague, I A1 - Bingham, A A1 - Schulte, H A1 - Assmann, G A1 - Cantin, B A1 - Lamarche, B A1 - Després, J-P A1 - Dagenais, G R A1 - Tunstall-Pedoe, H A1 - Lowe, G D O A1 - Woodward, M A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Palmieri, V A1 - Yeh, J L A1 - Meade, T W A1 - Rudnicka, A A1 - Brennan, P A1 - Knottenbelt, C A1 - Cooper, J A A1 - Ridker, P A1 - Rodeghiero, F A1 - Tosetto, A A1 - Shepherd, J A1 - Lowe, G D O A1 - Ford, I A1 - Robertson, M A1 - Brunner, E A1 - Shipley, M A1 - Feskens, E J M A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Lewington, S A1 - Lowe, G D O A1 - Sarwar, N A1 - Thompson, S G A1 - Walker, M A1 - Watson, S A1 - White, I R A1 - Wood, A M A1 - Danesh, J KW - Cohort Studies KW - Computer Simulation KW - Coronary Disease KW - Data Interpretation, Statistical KW - Female KW - Fibrinogen KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Models, Statistical AB -

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

VL - 28 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19222087?dopt=Abstract ER - TY - JOUR T1 - Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. JF - Nat Genet Y1 - 2010 A1 - Speliotes, Elizabeth K A1 - Willer, Cristen J A1 - Berndt, Sonja I A1 - Monda, Keri L A1 - Thorleifsson, Gudmar A1 - Jackson, Anne U A1 - Lango Allen, Hana A1 - Lindgren, Cecilia M A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Workalemahu, Tsegaselassie A1 - Heid, Iris M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Weedon, Michael N A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Ferreira, Teresa A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Estrada, Karol A1 - Liang, Liming A1 - Nemesh, James A1 - Park, Ju-Hyun A1 - Gustafsson, Stefan A1 - Kilpeläinen, Tuomas O A1 - Yang, Jian A1 - Bouatia-Naji, Nabila A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Raychaudhuri, Soumya A1 - Scherag, Andre A1 - Smith, Albert Vernon A1 - Welch, Ryan A1 - Zhao, Jing Hua A1 - Aben, Katja K A1 - Absher, Devin M A1 - Amin, Najaf A1 - Dixon, Anna L A1 - Fisher, Eva A1 - Glazer, Nicole L A1 - Goddard, Michael E A1 - Heard-Costa, Nancy L A1 - Hoesel, Volker A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Lamina, Claudia A1 - Li, Shengxu A1 - Moffatt, Miriam F A1 - Myers, Richard H A1 - Narisu, Narisu A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan P A1 - van Wingerden, Sophie A1 - Watanabe, Richard M A1 - White, Charles C A1 - Wiklund, Fredrik A1 - Barlassina, Christina A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Prokopenko, Inga A1 - Shi, Jianxin A1 - Thiering, Elisabeth A1 - Alavere, Helene A1 - Alibrandi, Maria T S A1 - Almgren, Peter A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Atwood, Larry D A1 - Balkau, Beverley A1 - Balmforth, Anthony J A1 - Bennett, Amanda J A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Biebermann, Heike A1 - Blakemore, Alexandra I F A1 - Boes, Tanja A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Brown, Morris J A1 - Buchanan, Thomas A A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Cavalcanti-Proença, Christine A1 - Chen, Yii-Der Ida A1 - Chen, Chih-Mei A1 - Chines, Peter S A1 - Clarke, Robert A1 - Coin, Lachlan A1 - Connell, John A1 - Day, Ian N M A1 - den Heijer, Martin A1 - Duan, Jubao A1 - Ebrahim, Shah A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eiriksdottir, Gudny A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Facheris, Maurizio F A1 - Felix, Stephan B A1 - Fischer-Posovszky, Pamela A1 - Folsom, Aaron R A1 - Friedrich, Nele A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Gejman, Pablo V A1 - Geus, Eco J C A1 - Gieger, Christian A1 - Gjesing, Anette P A1 - Goel, Anuj A1 - Goyette, Philippe A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Greenawalt, Danielle M A1 - Groves, Christopher J A1 - Gudnason, Vilmundur A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hall, Alistair S A1 - Havulinna, Aki S A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hinney, Anke A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jacobs, Kevin B A1 - Jarick, Ivonne A1 - Jewell, Elizabeth A1 - John, Ulrich A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kajantie, Eero A1 - Kaplan, Lee M A1 - Kathiresan, Sekar A1 - Kettunen, Johannes A1 - Kinnunen, Leena A1 - Knowles, Joshua W A1 - Kolcic, Ivana A1 - König, Inke R A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kuusisto, Johanna A1 - Kraft, Peter A1 - Kvaløy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lanzani, Chiara A1 - Launer, Lenore J A1 - Lecoeur, Cécile A1 - Lehtimäki, Terho A1 - Lettre, Guillaume A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - Manunta, Paolo A1 - Marek, Diana A1 - Marre, Michel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - McKnight, Barbara A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Meyre, David A1 - Midthjell, Kristian A1 - Montgomery, Grant W A1 - Morken, Mario A A1 - Morris, Andrew P A1 - Mulic, Rosanda A1 - Ngwa, Julius S A1 - Nelis, Mari A1 - Neville, Matt J A1 - Nyholt, Dale R A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Ong, Ken K A1 - Oostra, Ben A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Perola, Markus A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Rafelt, Suzanne A1 - Raitakari, Olli A1 - Rayner, Nigel W A1 - Ridderstråle, Martin A1 - Rief, Winfried A1 - Ruokonen, Aimo A1 - Robertson, Neil R A1 - Rzehak, Peter A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sandhu, Manjinder S A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Savolainen, Markku J A1 - Scherag, Susann A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Silander, Kaisa A1 - Sinisalo, Juha A1 - Siscovick, David S A1 - Smit, Jan H A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Stephens, Jonathan A1 - Surakka, Ida A1 - Swift, Amy J A1 - Tammesoo, Mari-Liis A1 - Tardif, Jean-Claude A1 - Teder-Laving, Maris A1 - Teslovich, Tanya M A1 - Thompson, John R A1 - Thomson, Brian A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Viikari, Jorma A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogel, Carla I G A1 - Voight, Benjamin F A1 - Waite, Lindsay L A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wiegand, Susanna A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Witteman, Jacqueline C A1 - Xu, Jianfeng A1 - Zhang, Qunyuan A1 - Zgaga, Lina A1 - Ziegler, Andreas A1 - Zitting, Paavo A1 - Beilby, John P A1 - Farooqi, I Sadaf A1 - Hebebrand, Johannes A1 - Huikuri, Heikki V A1 - James, Alan L A1 - Kähönen, Mika A1 - Levinson, Douglas F A1 - Macciardi, Fabio A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Beckmann, Jacques S A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Collins, Francis S A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Erdmann, Jeanette A1 - Froguel, Philippe A1 - Grönberg, Henrik A1 - Gyllensten, Ulf A1 - Hall, Per A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayes, Richard B A1 - Heinrich, Joachim A1 - Hu, Frank B A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Kaprio, Jaakko A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Kiemeney, Lambertus A A1 - Krude, Heiko A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Metspalu, Andres A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Pedersen, Oluf A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Reinehr, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Spector, Timothy D A1 - Tuomilehto, Jaakko A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Valle, Timo T A1 - Wabitsch, Martin A1 - Waeber, Gérard A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Chatterjee, Nilanjan A1 - McCarroll, Steven A A1 - Purcell, Shaun A1 - Schadt, Eric E A1 - Visscher, Peter M A1 - Assimes, Themistocles L A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Frayling, Timothy M A1 - Thorsteinsdottir, Unnur A1 - Abecasis, Goncalo R A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Stefansson, Kari A1 - North, Kari E A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Ingelsson, Erik A1 - Loos, Ruth J F KW - Body Height KW - Body Mass Index KW - Body Size KW - Body Weight KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract ER - TY - JOUR T1 - Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables. JF - Stat Med Y1 - 2010 A1 - Burgess, Stephen A1 - Thompson, Simon G A1 - Burgess, S A1 - Thompson, S G A1 - Andrews, G A1 - Samani, N J A1 - Hall, A A1 - Whincup, P A1 - Morris, R A1 - Lawlor, D A A1 - Davey Smith, G A1 - Timpson, N A1 - Ebrahim, S A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Timpson, N A1 - Brown, M A1 - Ricketts, S A1 - Sandhu, M A1 - Reiner, A A1 - Psaty, B A1 - Lange, L A1 - Cushman, M A1 - Hung, J A1 - Thompson, P A1 - Beilby, J A1 - Warrington, N A1 - Palmer, L J A1 - Nordestgaard, B G A1 - Tybjaerg-Hansen, A A1 - Zacho, J A1 - Wu, C A1 - Lowe, G A1 - Tzoulaki, I A1 - Kumari, M A1 - Sandhu, M A1 - Yamamoto, J F A1 - Chiodini, B A1 - Franzosi, M A1 - Hankey, G J A1 - Jamrozik, K A1 - Palmer, L A1 - Rimm, E A1 - Pai, J A1 - Psaty, B A1 - Heckbert, S A1 - Bis, J A1 - Anand, S A1 - Engert, J A1 - Collins, R A1 - Clarke, R A1 - Melander, O A1 - Berglund, G A1 - Ladenvall, P A1 - Johansson, L A1 - Jansson, J-H A1 - Hallmans, G A1 - Hingorani, A A1 - Humphries, S A1 - Rimm, E A1 - Manson, J A1 - Pai, J A1 - Watkins, H A1 - Clarke, R A1 - Hopewell, J A1 - Saleheen, D A1 - Frossard, R A1 - Danesh, J A1 - Sattar, N A1 - Robertson, M A1 - Shepherd, J A1 - Schaefer, E A1 - Hofman, A A1 - Witteman, J C M A1 - Kardys, I A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Timpson, N A1 - de Faire, U A1 - Bennet, A A1 - Sattar, N A1 - Ford, I A1 - Packard, C A1 - Kumari, M A1 - Manson, J A1 - Lawlor, Debbie A A1 - Davey Smith, George A1 - Anand, S A1 - Collins, R A1 - Casas, J P A1 - Danesh, J A1 - Davey Smith, G A1 - Franzosi, M A1 - Hingorani, A A1 - Lawlor, D A A1 - Manson, J A1 - Nordestgaard, B G A1 - Samani, N J A1 - Sandhu, M A1 - Smeeth, L A1 - Wensley, F A1 - Anand, S A1 - Bowden, J A1 - Burgess, S A1 - Casas, J P A1 - Di Angelantonio, E A1 - Engert, J A1 - Gao, P A1 - Shah, T A1 - Smeeth, L A1 - Thompson, S G A1 - Verzilli, C A1 - Walker, M A1 - Whittaker, J A1 - Hingorani, A A1 - Danesh, J KW - Bayes Theorem KW - Biostatistics KW - C-Reactive Protein KW - Fibrinogen KW - Genetic Markers KW - Humans KW - Meta-Analysis as Topic KW - Models, Statistical KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

VL - 29 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20209660?dopt=Abstract ER - TY - JOUR T1 - Biological, clinical and population relevance of 95 loci for blood lipids. JF - Nature Y1 - 2010 A1 - Teslovich, Tanya M A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Ripatti, Samuli A1 - Chasman, Daniel I A1 - Willer, Cristen J A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Isaacs, Aaron A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - Feitosa, Mary F A1 - Chambers, John A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Johnson, Toby A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Li, Mingyao A1 - Shin Cho, Yoon A1 - Jin Go, Min A1 - Jin Kim, Young A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Twee-Hee Ong, Rick A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Song, Kijoung A1 - Hua Zhao, Jing A1 - Yuan, Xin A1 - Luan, Jian'an A1 - Lamina, Claudia A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Wright, Alan F A1 - Witteman, Jacqueline C M A1 - Wilson, James F A1 - Willemsen, Gonneke A1 - Wichmann, H-Erich A1 - Whitfield, John B A1 - Waterworth, Dawn M A1 - Wareham, Nicholas J A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Voight, Benjamin F A1 - Vitart, Veronique A1 - Uitterlinden, André G A1 - Uda, Manuela A1 - Tuomilehto, Jaakko A1 - Thompson, John R A1 - Tanaka, Toshiko A1 - Surakka, Ida A1 - Stringham, Heather M A1 - Spector, Tim D A1 - Soranzo, Nicole A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Silander, Kaisa A1 - Sijbrands, Eric J G A1 - Scuteri, Angelo A1 - Scott, James A1 - Schlessinger, David A1 - Sanna, Serena A1 - Salomaa, Veikko A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Ruokonen, Aimo A1 - Rudan, Igor A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Psaty, Bruce M A1 - Pramstaller, Peter P A1 - Pichler, Irene A1 - Perola, Markus A1 - Penninx, Brenda W J H A1 - Pedersen, Nancy L A1 - Pattaro, Cristian A1 - Parker, Alex N A1 - Paré, Guillaume A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - Meitinger, Thomas A1 - McPherson, Ruth A1 - McCarthy, Mark I A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Mangino, Massimo A1 - Magnusson, Patrik K E A1 - Lucas, Gavin A1 - Luben, Robert A1 - Loos, Ruth J F A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - Kronenberg, Florian A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaprio, Jaakko A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Jarvelin, Marjo-Riitta A1 - Janssens, A Cecile J W A1 - Ingelsson, Erik A1 - Igl, Wilmar A1 - Kees Hovingh, G A1 - Hottenga, Jouke-Jan A1 - Hofman, Albert A1 - Hicks, Andrew A A1 - Hengstenberg, Christian A1 - Heid, Iris M A1 - Hayward, Caroline A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Gyllensten, Ulf A1 - Guiducci, Candace A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Gieger, Christian A1 - Freimer, Nelson B A1 - Ferrucci, Luigi A1 - Erdmann, Jeanette A1 - Elliott, Paul A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Geus, Eco J C A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Collins, Francis S A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Campbell, Harry A1 - Burtt, Noel P A1 - Bonnycastle, Lori L A1 - Boomsma, Dorret I A1 - Boekholdt, S Matthijs A1 - Bergman, Richard N A1 - Barroso, Inês A1 - Bandinelli, Stefania A1 - Ballantyne, Christie M A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Altshuler, David A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Adair, Linda S A1 - Taylor, Herman A A1 - Borecki, Ingrid B A1 - Gabriel, Stacey B A1 - Wilson, James G A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Mohlke, Karen L A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Strachan, David P A1 - Mooser, Vincent A1 - Stefansson, Kari A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Kathiresan, Sekar KW - African Americans KW - Animals KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Male KW - Mice KW - N-Acetylgalactosaminyltransferases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Protein Phosphatase 1 KW - Reproducibility of Results KW - Triglycerides AB -

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

VL - 466 IS - 7307 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Combined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study. JF - Am J Hypertens Y1 - 2010 A1 - Wong, Nathan D A1 - Lopez, Victor A A1 - Roberts, Craig S A1 - Solomon, Henry A A1 - Burke, Gregory L A1 - Kuller, Lewis A1 - Tracy, Russell A1 - Yanez, David A1 - Psaty, Bruce M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus KW - Female KW - Health Surveys KW - Humans KW - Likelihood Functions KW - Lipids KW - Male KW - Proportional Hazards Models KW - Sex Factors KW - Smoking KW - Socioeconomic Factors KW - United States AB -

BACKGROUND: Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events.

METHODS: We studied 4,311 participants aged 65-98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD-including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years.

RESULTS: CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80 mm Hg and LDL-C <100 mg/dl to 94.8 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl, and from 28.9 when BP <120/80 mm Hg and HDL >60 mg/dl to 87.1 for a BP >or=160/100 and HDL-C <40 mg/dl. Compared with those with BP <120/80 mm Hg with either LDL-C <100 mg/dl or HDL-C >60 mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl and 2.1 when BP >or=160/100 and HDL-C <40 mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90 mm Hg, but lower HDL-C also predicted CVD in those with higher BP.

CONCLUSION: Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90 mm Hg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19927131?dopt=Abstract ER - TY - JOUR T1 - Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk. JF - Alzheimers Dement Y1 - 2010 A1 - Barnes, Deborah E A1 - Covinsky, Kenneth E A1 - Whitmer, Rachel A A1 - Kuller, Lewis H A1 - Lopez, Oscar L A1 - Yaffe, Kristine KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Dementia KW - Diagnosis, Differential KW - Disability Evaluation KW - Early Diagnosis KW - Humans KW - National Health Programs KW - Predictive Value of Tests KW - Prognosis KW - Risk Assessment KW - Risk Factors KW - United States VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20298975?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants associate with serum phosphorus concentration. JF - J Am Soc Nephrol Y1 - 2010 A1 - Kestenbaum, Bryan A1 - Glazer, Nicole L A1 - Köttgen, Anna A1 - Felix, Janine F A1 - Hwang, Shih-Jen A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Hausman, Dorothy B A1 - Petersen, Ann-Kristin A1 - Gieger, Christian A1 - Ried, Janina S A1 - Meitinger, Thomas A1 - Strom, Tim M A1 - Wichmann, H Erich A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Rudan, Igor A1 - de Boer, Ian H A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Chen, Yii-Der Ida A1 - Li, Man A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Yang, Qiong A1 - Levy, Daniel A1 - van Rooij, Frank J A A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Shlipak, Michael G A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Siscovick, David S A1 - Fox, Caroline S KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Fibroblast Growth Factors KW - Gene Frequency KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Phosphorus KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing KW - Sex Factors KW - Sodium-Phosphate Cotransporter Proteins, Type IIa AB -

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. JF - Hum Mol Genet Y1 - 2010 A1 - O'Seaghdha, Conall M A1 - Yang, Qiong A1 - Glazer, Nicole L A1 - Leak, Tennille S A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Kao, W H Linda A1 - Lohman, Kurt A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Chen, Yii-Der Ida A1 - Brown, Edward M A1 - Siscovick, David S A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Coresh, Josef A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Liu, Yong Mei A1 - Kestenbaum, Bryan R A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Calcium KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing AB -

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

VL - 19 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract ER - TY - JOUR T1 - CRP gene variation and risk of community-acquired pneumonia. JF - Respirology Y1 - 2010 A1 - Mukamal, Kenneth J A1 - Pai, Jennifer K A1 - O'Meara, Ellen S A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Newman, Anne B A1 - Yende, Sachin A1 - Curhan, Gary C A1 - Siscovick, David S A1 - Rimm, Eric B KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - C-Reactive Protein KW - Cohort Studies KW - Community-Acquired Infections KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Pneumonia KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Smoking AB -

BACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.

METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires.

RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.

CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19947988?dopt=Abstract ER - TY - JOUR T1 - Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. JF - PLoS One Y1 - 2010 A1 - Gkrania-Klotsas, Effrossyni A1 - Ye, Zheng A1 - Cooper, Andrew J A1 - Sharp, Stephen J A1 - Luben, Robert A1 - Biggs, Mary L A1 - Chen, Liang-Kung A1 - Gokulakrishnan, Kuppan A1 - Hanefeld, Markolf A1 - Ingelsson, Erik A1 - Lai, Wen-An A1 - Lin, Shih-Yi A1 - Lind, Lars A1 - Lohsoonthorn, Vitool A1 - Mohan, Viswanathan A1 - Muscari, Antonio A1 - Nilsson, Goran A1 - Ohrvik, John A1 - Chao Qiang, Jiang A1 - Jenny, Nancy Swords A1 - Tamakoshi, Koji A1 - Temelkova-Kurktschiev, Theodora A1 - Wang, Ya-Yu A1 - Yajnik, Chittaranjan Sakerlal A1 - Zoli, Marco A1 - Khaw, Kay-Tee A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Langenberg, Claudia KW - Adult KW - Aged KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Leukocyte Count KW - Male KW - Middle Aged KW - Prospective Studies AB -

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

VL - 5 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract ER - TY - JOUR T1 - Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. JF - PLoS Genet Y1 - 2010 A1 - Ikram, M Kamran A1 - Sim, Xueling A1 - Xueling, Sim A1 - Jensen, Richard A A1 - Cotch, Mary Frances A1 - Hewitt, Alex W A1 - Ikram, M Arfan A1 - Wang, Jie Jin A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Breteler, Monique M B A1 - Cheung, Ning A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - van Duijn, Cornelia M A1 - Kao, Linda A1 - Cheng, Ching-Yu A1 - Smith, Albert Vernon A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Jonasson, Fridbert A1 - Eiriksdottir, Gudny A1 - Aspelund, Thor A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Li, Xiaohui A1 - Iyengar, Sudha K A1 - Xi, Quansheng A1 - Sivakumaran, Theru A A1 - Mackey, David A A1 - Macgregor, Stuart A1 - Martin, Nicholas G A1 - Young, Terri L A1 - Bis, Josh C A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Hammond, Christopher J A1 - Andrew, Toby A1 - Fahy, Samantha A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Islam, F M Amirul A1 - Rotter, Jerome I A1 - McAuley, Annie K A1 - Boerwinkle, Eric A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Vingerling, Johannes R A1 - Wong, Tien Y KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Child KW - Child, Preschool KW - Chromosomes, Human, Pair 12 KW - Chromosomes, Human, Pair 19 KW - Chromosomes, Human, Pair 5 KW - Chromosomes, Human, Pair 6 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Microcirculation KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Retinal Vessels KW - Young Adult AB -

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract ER - TY - JOUR T1 - Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. JF - Hum Mol Genet Y1 - 2010 A1 - McGovern, Dermot P B A1 - Jones, Michelle R A1 - Taylor, Kent D A1 - Marciante, Kristin A1 - Yan, Xiaofei A1 - Dubinsky, Marla A1 - Ippoliti, Andy A1 - Vasiliauskas, Eric A1 - Berel, Dror A1 - Derkowski, Carrie A1 - Dutridge, Deb A1 - Fleshner, Phil A1 - Shih, David Q A1 - Melmed, Gil A1 - Mengesha, Emebet A1 - King, Lily A1 - Pressman, Sheila A1 - Haritunians, Talin A1 - Guo, Xiuqing A1 - Targan, Stephan R A1 - Rotter, Jerome I KW - Adolescent KW - Adult KW - Aged KW - Child KW - Child, Preschool KW - Cohort Studies KW - Crohn Disease KW - Female KW - Fucosyltransferases KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

VL - 19 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20570966?dopt=Abstract ER - TY - JOUR T1 - Genome-wide analysis of genetic loci associated with Alzheimer disease. JF - JAMA Y1 - 2010 A1 - Seshadri, Sudha A1 - Fitzpatrick, Annette L A1 - Ikram, M Arfan A1 - DeStefano, Anita L A1 - Gudnason, Vilmundur A1 - Boada, Merce A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Carassquillo, Minerva M A1 - Lambert, Jean Charles A1 - Harold, Denise A1 - Schrijvers, Elisabeth M C A1 - Ramirez-Lorca, Reposo A1 - Debette, Stephanie A1 - Longstreth, W T A1 - Janssens, A Cecile J W A1 - Pankratz, V Shane A1 - Dartigues, Jean François A1 - Hollingworth, Paul A1 - Aspelund, Thor A1 - Hernandez, Isabel A1 - Beiser, Alexa A1 - Kuller, Lewis H A1 - Koudstaal, Peter J A1 - Dickson, Dennis W A1 - Tzourio, Christophe A1 - Abraham, Richard A1 - Antunez, Carmen A1 - Du, Yangchun A1 - Rotter, Jerome I A1 - Aulchenko, Yurii S A1 - Harris, Tamara B A1 - Petersen, Ronald C A1 - Berr, Claudine A1 - Owen, Michael J A1 - Lopez-Arrieta, Jesus A1 - Varadarajan, Badri N A1 - Becker, James T A1 - Rivadeneira, Fernando A1 - Nalls, Michael A A1 - Graff-Radford, Neill R A1 - Campion, Dominique A1 - Auerbach, Sanford A1 - Rice, Kenneth A1 - Hofman, Albert A1 - Jonsson, Palmi V A1 - Schmidt, Helena A1 - Lathrop, Mark A1 - Mosley, Thomas H A1 - Au, Rhoda A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - Farrer, Lindsay A A1 - Lumley, Thomas A1 - Ruiz, Agustin A1 - Williams, Julie A1 - Amouyel, Philippe A1 - Younkin, Steve G A1 - Wolf, Philip A A1 - Launer, Lenore J A1 - Lopez, Oscar L A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B KW - Age of Onset KW - Aged KW - Alzheimer Disease KW - Case-Control Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

VL - 303 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. JF - PLoS Genet Y1 - 2010 A1 - Meyer, Tamra E A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Glazer, Nicole L A1 - Smith, Albert V A1 - van Rooij, Frank J A A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Felix, Janine F A1 - Leak, Tennille S A1 - Harris, Tamara B A1 - Yang, Qiong A1 - Dehghan, Abbas A1 - Aspelund, Thor A1 - Katz, Ronit A1 - Homuth, Georg A1 - Kocher, Thomas A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Gieger, Christian A1 - Prucha, Hanna A1 - Pfeufer, Arne A1 - Meitinger, Thomas A1 - Coresh, Josef A1 - Hofman, Albert A1 - Sarnak, Mark J A1 - Chen, Yii-Der Ida A1 - Uitterlinden, André G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Magnesium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Potassium KW - Sodium AB -

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract ER - TY - JOUR T1 - Hundreds of variants clustered in genomic loci and biological pathways affect human height. JF - Nature Y1 - 2010 A1 - Lango Allen, Hana A1 - Estrada, Karol A1 - Lettre, Guillaume A1 - Berndt, Sonja I A1 - Weedon, Michael N A1 - Rivadeneira, Fernando A1 - Willer, Cristen J A1 - Jackson, Anne U A1 - Vedantam, Sailaja A1 - Raychaudhuri, Soumya A1 - Ferreira, Teresa A1 - Wood, Andrew R A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Speliotes, Elizabeth K A1 - Wheeler, Eleanor A1 - Soranzo, Nicole A1 - Park, Ju-Hyun A1 - Yang, Jian A1 - Gudbjartsson, Daniel A1 - Heard-Costa, Nancy L A1 - Randall, Joshua C A1 - Qi, Lu A1 - Vernon Smith, Albert A1 - Mägi, Reedik A1 - Pastinen, Tomi A1 - Liang, Liming A1 - Heid, Iris M A1 - Luan, Jian'an A1 - Thorleifsson, Gudmar A1 - Winkler, Thomas W A1 - Goddard, Michael E A1 - Sin Lo, Ken A1 - Palmer, Cameron A1 - Workalemahu, Tsegaselassie A1 - Aulchenko, Yurii S A1 - Johansson, Asa A1 - Zillikens, M Carola A1 - Feitosa, Mary F A1 - Esko, Tõnu A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Kraft, Peter A1 - Mangino, Massimo A1 - Prokopenko, Inga A1 - Absher, Devin A1 - Albrecht, Eva A1 - Ernst, Florian A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Knowles, Joshua W A1 - Kutalik, Zoltán A1 - Monda, Keri L A1 - Polasek, Ozren A1 - Preuss, Michael A1 - Rayner, Nigel W A1 - Robertson, Neil R A1 - Steinthorsdottir, Valgerdur A1 - Tyrer, Jonathan P A1 - Voight, Benjamin F A1 - Wiklund, Fredrik A1 - Xu, Jianfeng A1 - Zhao, Jing Hua A1 - Nyholt, Dale R A1 - Pellikka, Niina A1 - Perola, Markus A1 - Perry, John R B A1 - Surakka, Ida A1 - Tammesoo, Mari-Liis A1 - Altmaier, Elizabeth L A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bhangale, Tushar A1 - Boucher, Gabrielle A1 - Chasman, Daniel I A1 - Chen, Constance A1 - Coin, Lachlan A1 - Cooper, Matthew N A1 - Dixon, Anna L A1 - Gibson, Quince A1 - Grundberg, Elin A1 - Hao, Ke A1 - Juhani Junttila, M A1 - Kaplan, Lee M A1 - Kettunen, Johannes A1 - König, Inke R A1 - Kwan, Tony A1 - Lawrence, Robert W A1 - Levinson, Douglas F A1 - Lorentzon, Mattias A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Müller, Martina A1 - Suh Ngwa, Julius A1 - Purcell, Shaun A1 - Rafelt, Suzanne A1 - Salem, Rany M A1 - Salvi, Erika A1 - Sanna, Serena A1 - Shi, Jianxin A1 - Sovio, Ulla A1 - Thompson, John R A1 - Turchin, Michael C A1 - Vandenput, Liesbeth A1 - Verlaan, Dominique J A1 - Vitart, Veronique A1 - White, Charles C A1 - Ziegler, Andreas A1 - Almgren, Peter A1 - Balmforth, Anthony J A1 - Campbell, Harry A1 - Citterio, Lorena A1 - De Grandi, Alessandro A1 - Dominiczak, Anna A1 - Duan, Jubao A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Geus, Eco J C A1 - Glorioso, Nicola A1 - Haiqing, Shen A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Illig, Thomas A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kilpeläinen, Tuomas O A1 - Koiranen, Markku A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Laitinen, Jaana A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Marusic, Ana A1 - Maschio, Andrea A1 - Meitinger, Thomas A1 - Mulas, Antonella A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Petersmann, Astrid A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Rotter, Jerome I A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Schmidt, Carsten Oliver A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Stringham, Heather M A1 - Bragi Walters, G A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Zagato, Laura A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Alavere, Helene A1 - Farrall, Martin A1 - McArdle, Wendy L A1 - Nelis, Mari A1 - Peters, Marjolein J A1 - Ripatti, Samuli A1 - van Meurs, Joyce B J A1 - Aben, Katja K A1 - Ardlie, Kristin G A1 - Beckmann, Jacques S A1 - Beilby, John P A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Collins, Francis S A1 - Cusi, Daniele A1 - den Heijer, Martin A1 - Eiriksdottir, Gudny A1 - Gejman, Pablo V A1 - Hall, Alistair S A1 - Hamsten, Anders A1 - Huikuri, Heikki V A1 - Iribarren, Carlos A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kathiresan, Sekar A1 - Kiemeney, Lambertus A1 - Kocher, Thomas A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Melander, Olle A1 - Mosley, Tom H A1 - Musk, Arthur W A1 - Nieminen, Markku S A1 - O'Donnell, Christopher J A1 - Ohlsson, Claes A1 - Oostra, Ben A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Rioux, John D A1 - Rissanen, Aila A1 - Rivolta, Carlo A1 - Schunkert, Heribert A1 - Shuldiner, Alan R A1 - Siscovick, David S A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - van Ommen, Gert-Jan A1 - Viikari, Jorma A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Province, Michael A A1 - Kayser, Manfred A1 - Arnold, Alice M A1 - Atwood, Larry D A1 - Boerwinkle, Eric A1 - Chanock, Stephen J A1 - Deloukas, Panos A1 - Gieger, Christian A1 - Grönberg, Henrik A1 - Hall, Per A1 - Hattersley, Andrew T A1 - Hengstenberg, Christian A1 - Hoffman, Wolfgang A1 - Lathrop, G Mark A1 - Salomaa, Veikko A1 - Schreiber, Stefan A1 - Uda, Manuela A1 - Waterworth, Dawn A1 - Wright, Alan F A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Hofman, Albert A1 - Mohlke, Karen L A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Cupples, L Adrienne A1 - Erdmann, Jeanette A1 - Fox, Caroline S A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hayes, Richard B A1 - Jarvelin, Marjo-Riitta A1 - Mooser, Vincent A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Wilson, James F A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hu, Frank B A1 - Kaplan, Robert C A1 - Metspalu, Andres A1 - North, Kari E A1 - Schlessinger, David A1 - Wareham, Nicholas J A1 - Hunter, David J A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Wichmann, H-Erich A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Schadt, Eric E A1 - Thorsteinsdottir, Unnur A1 - Peltonen, Leena A1 - Uitterlinden, André G A1 - Visscher, Peter M A1 - Chatterjee, Nilanjan A1 - Loos, Ruth J F A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Lindgren, Cecilia M A1 - Abecasis, Goncalo R A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N KW - Body Height KW - Chromosomes, Human, Pair 3 KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Metabolic Networks and Pathways KW - Multifactorial Inheritance KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

VL - 467 IS - 7317 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract ER - TY - JOUR T1 - Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. JF - Diabetes Care Y1 - 2010 A1 - Nettleton, Jennifer A A1 - McKeown, Nicola M A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Hivert, Marie-France A1 - Ngwa, Julius A1 - van Rooij, Frank J A A1 - Sonestedt, Emily A1 - Wojczynski, Mary K A1 - Ye, Zheng A1 - Tanaka, Tosh A1 - Garcia, Melissa A1 - Anderson, Jennifer S A1 - Follis, Jack L A1 - Djoussé, Luc A1 - Mukamal, Kenneth A1 - Papoutsakis, Constantina A1 - Mozaffarian, Dariush A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Bennett, Amanda J A1 - Borecki, Ingrid B A1 - Feitosa, Mary F A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Harris, Tamara A1 - Hofman, Albert A1 - Houston, Denise K A1 - Hu, Frank B A1 - Johansson, Ingegerd A1 - Kritchevsky, Stephen B A1 - Langenberg, Claudia A1 - Launer, Lenore A1 - Liu, Yongmei A1 - Loos, Ruth J A1 - Nalls, Michael A1 - Orho-Melander, Marju A1 - Renstrom, Frida A1 - Rice, Kenneth A1 - Riserus, Ulf A1 - Rolandsson, Olov A1 - Rotter, Jerome I A1 - Saylor, Georgia A1 - Sijbrands, Eric J G A1 - Sjogren, Per A1 - Smith, Albert A1 - Steingrímsdóttir, Laufey A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Prokopenko, Inga A1 - Pankow, James S A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Witteman, Jacqueline C M A1 - Dupuis, Josée A1 - Dedoussis, George V A1 - Ordovas, Jose M A1 - Ingelsson, Erik A1 - Cupples, L Adrienne A1 - Siscovick, David S A1 - Franks, Paul W A1 - Meigs, James B KW - Adult KW - Aged KW - Blood Glucose KW - Edible Grain KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. JF - Hum Mol Genet Y1 - 2010 A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Hoogeveen, Ron C A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Bretler, Monique A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Lu, Chen A1 - Tracy, Russell P A1 - Aleksic, Nena A1 - Heeriga, Jan A1 - Keaney, John F A1 - Rice, Kenneth A1 - Lip, Gregory Y H A1 - Vasan, Ramachandran S A1 - Glazer, Nicole L A1 - Larson, Martin G A1 - Uitterlinden, André G A1 - Yamamoto, Jennifer A1 - Durda, Peter A1 - Haritunians, Talin A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Hofman, Albert A1 - Koenig, Wolfgang A1 - Jenny, Nancy S A1 - Witteman, Jacqueline C A1 - Ballantyne, Christie A1 - Benjamin, Emelia J KW - ABO Blood-Group System KW - Blood Platelets KW - Enzyme-Linked Immunosorbent Assay KW - European Continental Ancestry Group KW - Fluorescence KW - Genome-Wide Association Study KW - Humans KW - Intercellular Adhesion Molecule-1 KW - P-Selectin AB -

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

VL - 19 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. JF - Nat Genet Y1 - 2010 A1 - Heid, Iris M A1 - Jackson, Anne U A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Zillikens, M Carola A1 - Speliotes, Elizabeth K A1 - Mägi, Reedik A1 - Workalemahu, Tsegaselassie A1 - White, Charles C A1 - Bouatia-Naji, Nabila A1 - Harris, Tamara B A1 - Berndt, Sonja I A1 - Ingelsson, Erik A1 - Willer, Cristen J A1 - Weedon, Michael N A1 - Luan, Jian'an A1 - Vedantam, Sailaja A1 - Esko, Tõnu A1 - Kilpeläinen, Tuomas O A1 - Kutalik, Zoltán A1 - Li, Shengxu A1 - Monda, Keri L A1 - Dixon, Anna L A1 - Holmes, Christopher C A1 - Kaplan, Lee M A1 - Liang, Liming A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Molony, Cliona A1 - Nicholson, George A1 - Schadt, Eric E A1 - Zondervan, Krina T A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Lango Allen, Hana A1 - Weyant, Robert J A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Estrada, Karol A1 - Goddard, Michael E A1 - Lettre, Guillaume A1 - Mangino, Massimo A1 - Nyholt, Dale R A1 - Purcell, Shaun A1 - Smith, Albert Vernon A1 - Visscher, Peter M A1 - Yang, Jian A1 - McCarroll, Steven A A1 - Nemesh, James A1 - Voight, Benjamin F A1 - Absher, Devin A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Coin, Lachlan A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kapur, Karen A1 - Ketkar, Shamika A1 - Knowles, Joshua W A1 - Kraft, Peter A1 - Kraja, Aldi T A1 - Lamina, Claudia A1 - Leitzmann, Michael F A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Ong, Ken K A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Rayner, Nigel W A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robertson, Neil R A1 - Sanna, Serena A1 - Sovio, Ulla A1 - Surakka, Ida A1 - Teumer, Alexander A1 - van Wingerden, Sophie A1 - Vitart, Veronique A1 - Zhao, Jing Hua A1 - Cavalcanti-Proença, Christine A1 - Chines, Peter S A1 - Fisher, Eva A1 - Kulzer, Jennifer R A1 - Lecoeur, Cécile A1 - Narisu, Narisu A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Silander, Kaisa A1 - Stark, Klaus A1 - Tammesoo, Mari-Liis A1 - Teslovich, Tanya M A1 - Timpson, Nicholas John A1 - Watanabe, Richard M A1 - Welch, Ryan A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Kettunen, Johannes A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Perola, Markus A1 - Vandenput, Liesbeth A1 - Alavere, Helene A1 - Almgren, Peter A1 - Atwood, Larry D A1 - Bennett, Amanda J A1 - Biffar, Reiner A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Buchanan, Thomas A A1 - Campbell, Harry A1 - Day, Ian N M A1 - Dei, Mariano A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Geus, Eco J C A1 - Gjesing, Anette P A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Havulinna, Aki S A1 - Herzig, Karl-Heinz A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kinnunen, Leena A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kroemer, Heyo K A1 - Krzelj, Vjekoslav A1 - Kuusisto, Johanna A1 - Kvaloy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lathrop, G Mark A1 - Lokki, Marja-Liisa A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - Morken, Mario A A1 - Nelis, Mari A1 - Neville, Matt J A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Strawbridge, Rona J A1 - Stringham, Heather M A1 - Swift, Amy J A1 - Teder-Laving, Maris A1 - Thomson, Brian A1 - Usala, Gianluca A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Volpato, Claudia B A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Beilby, John P A1 - James, Alan L A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Viikari, Jorma A1 - Balkau, Beverley A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Boeing, Heiner A1 - Smith, George Davey A1 - Ebrahim, Shah A1 - Froguel, Philippe A1 - Hansen, Torben A1 - Hengstenberg, Christian A1 - Hveem, Kristian A1 - Isomaa, Bo A1 - Jørgensen, Torben A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Midthjell, Kristian A1 - Pedersen, Oluf A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Wareham, Nicholas J A1 - Arnold, Alice M A1 - Beckmann, Jacques S A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Collins, Francis S A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Hattersley, Andrew T A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Kao, W H Linda A1 - Kaprio, Jaakko A1 - Launer, Lenore J A1 - Munroe, Patricia B A1 - Oostra, Ben A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Völzke, Henry A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Wright, Alan F A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - Hirschhorn, Joel N A1 - Assimes, Themistocles L A1 - Wichmann, H-Erich A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Barroso, Inês A1 - McCarthy, Mark I A1 - Fox, Caroline S A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M KW - Adipose Tissue KW - Age Factors KW - Chromosome Mapping KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist-Hip Ratio AB -

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract ER - TY - JOUR T1 - Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Yang, Qiong A1 - Köttgen, Anna A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Glazer, Nicole L A1 - Chen, Ming-Huei A1 - Chasman, Daniel I A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore A1 - Nalls, Michael A1 - Hernandez, Dena A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Li, Man A1 - Linda Kao, W H A1 - Chonchol, Michel A1 - Haritunians, Talin A1 - Li, Guo A1 - Lumley, Thomas A1 - Psaty, Bruce M A1 - Shlipak, Michael A1 - Hwang, Shih-Jen A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Upadhyay, Ashish A1 - van Duijn, Cornelia M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Stricker, Bruno A1 - Uitterlinden, André G A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Ridker, Paul M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Fox, Caroline S A1 - Coresh, Josef KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Gout KW - Humans KW - Male KW - Risk Factors KW - Uric Acid AB -

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract ER - TY - JOUR T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. JF - Circulation Y1 - 2010 A1 - Smith, Nicholas L A1 - Chen, Ming-Huei A1 - Dehghan, Abbas A1 - Strachan, David P A1 - Basu, Saonli A1 - Soranzo, Nicole A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Sabater-Lleal, Maria A1 - Bis, Joshua C A1 - de Maat, Moniek P M A1 - Rumley, Ann A1 - Kong, Xiaoxiao A1 - Yang, Qiong A1 - Williams, Frances M K A1 - Vitart, Veronique A1 - Campbell, Harry A1 - Mälarstig, Anders A1 - Wiggins, Kerri L A1 - van Duijn, Cornelia M A1 - McArdle, Wendy L A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Silveira, Angela A1 - McKnight, Barbara A1 - Uitterlinden, André G A1 - Aleksic, Nena A1 - Meigs, James B A1 - Peters, Annette A1 - Koenig, Wolfgang A1 - Cushman, Mary A1 - Kathiresan, Sekar A1 - Rotter, Jerome I A1 - Bovill, Edwin G A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Tofler, Geoffrey H A1 - Peden, John F A1 - Psaty, Bruce M A1 - Leebeek, Frank A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Spector, Timothy D A1 - Wright, Alan F A1 - Wilson, James F A1 - Hamsten, Anders A1 - Lumley, Thomas A1 - Witteman, Jacqueline C M A1 - Tang, Weihong A1 - O'Donnell, Christopher J KW - Adult KW - Factor VII KW - Factor VIII KW - Female KW - Genome-Wide Association Study KW - Hemostasis KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Thrombosis KW - von Willebrand Factor AB -

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

VL - 121 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract ER - TY - JOUR T1 - Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. JF - Am J Respir Crit Care Med Y1 - 2010 A1 - Redline, Susan A1 - Yenokyan, Gayane A1 - Gottlieb, Daniel J A1 - Shahar, Eyal A1 - O'Connor, George T A1 - Resnick, Helaine E A1 - Diener-West, Marie A1 - Sanders, Mark H A1 - Wolf, Philip A A1 - Geraghty, Estella M A1 - Ali, Tauqeer A1 - Lebowitz, Michael A1 - Punjabi, Naresh M KW - Aged KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Proportional Hazards Models KW - Prospective Studies KW - Severity of Illness Index KW - Sex Factors KW - Sleep Apnea, Obstructive KW - Stroke AB -

RATIONALE: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.

OBJECTIVES: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.

METHODS: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke.

MEASUREMENTS AND MAIN RESULTS: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.

CONCLUSIONS: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.

VL - 182 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20339144?dopt=Abstract ER - TY - JOUR T1 - Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. JF - Circulation Y1 - 2010 A1 - Gottlieb, Daniel J A1 - Yenokyan, Gayane A1 - Newman, Anne B A1 - O'Connor, George T A1 - Punjabi, Naresh M A1 - Quan, Stuart F A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Tong, Elisa K A1 - Diener-West, Marie A1 - Shahar, Eyal KW - Adult KW - Aged KW - Coronary Disease KW - Female KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Proportional Hazards Models KW - Prospective Studies KW - Sleep Apnea, Obstructive KW - Survival Analysis AB -

BACKGROUND: Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women.

METHODS AND RESULTS: A total of 1927 men and 2495 women > or =40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men < or =70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI > or =30 were 68% more likely to develop coronary heart disease than those with AHI <5. Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI > or =30 were 58% more likely to develop heart failure than those with AHI <5.

CONCLUSIONS: Obstructive sleep apnea is associated with an increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.

VL - 122 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20625114?dopt=Abstract ER - TY - JOUR T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. JF - PLoS Genet Y1 - 2011 A1 - Böger, Carsten A A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M A1 - Kutalik, Zoltán A1 - Wichmann, H-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Beckmann, Jacques S A1 - Krämer, Bernhard K A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Kao, W H KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Chronic Disease KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptor, Epidermal Growth Factor KW - Uromodulin AB -

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Franceschini, Nora A1 - Carty, Cara A1 - Bůzková, Petra A1 - Reiner, Alex P A1 - Garrett, Tiana A1 - Lin, Yi A1 - Vöckler, Jens-S A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Boerwinkle, Eric A1 - Lin, Dan-Yu A1 - Bookman, Ebony A1 - Best, Lyle G A1 - Bella, Jonathan N A1 - Eaton, Charles A1 - Greenland, Philip A1 - Jenny, Nancy A1 - North, Kari E A1 - Taverna, Darin A1 - Young, Alicia M A1 - Deelman, Ewa A1 - Kooperberg, Charles A1 - Psaty, Bruce A1 - Heiss, Gerardo KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Coronary Disease KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

VL - 4 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

VL - 20 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract ER - TY - JOUR T1 - Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). JF - Blood Y1 - 2011 A1 - Wassel, Christina L A1 - Lange, Leslie A A1 - Keating, Brendan J A1 - Taylor, Kira C A1 - Johnson, Andrew D A1 - Palmer, Cameron A1 - Ho, Lindsey A A1 - Smith, Nicholas L A1 - Lange, Ethan M A1 - Li, Yun A1 - Yang, Qiong A1 - Delaney, Joseph A A1 - Tang, Weihong A1 - Tofler, Geoffrey A1 - Redline, Susan A1 - Taylor, Herman A A1 - Wilson, James G A1 - Tracy, Russell P A1 - Jacobs, David R A1 - Folsom, Aaron R A1 - Green, David A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. JF - Diabetes Y1 - 2011 A1 - Kraja, Aldi T A1 - Vaidya, Dhananjay A1 - Pankow, James S A1 - Goodarzi, Mark O A1 - Assimes, Themistocles L A1 - Kullo, Iftikhar J A1 - Sovio, Ulla A1 - Mathias, Rasika A A1 - Sun, Yan V A1 - Franceschini, Nora A1 - Absher, Devin A1 - Li, Guo A1 - Zhang, Qunyuan A1 - Feitosa, Mary F A1 - Glazer, Nicole L A1 - Haritunians, Talin A1 - Hartikainen, Anna-Liisa A1 - Knowles, Joshua W A1 - North, Kari E A1 - Iribarren, Carlos A1 - Kral, Brian A1 - Yanek, Lisa A1 - O'Reilly, Paul F A1 - McCarthy, Mark I A1 - Jaquish, Cashell A1 - Couper, David J A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - Becker, Lewis C A1 - Province, Michael A A1 - Boerwinkle, Eric A1 - Quertermous, Thomas A1 - Palotie, Leena A1 - Jarvelin, Marjo-Riitta A1 - Becker, Diane M A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - Chen, Yii-Der Ida A1 - Borecki, Ingrid B KW - Adult KW - Aged KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Metabolic Syndrome KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

VL - 60 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21386085?dopt=Abstract ER - TY - JOUR T1 - Carotid intima-media thickness, electrocardiographic left ventricular hypertrophy, and incidence of intracerebral hemorrhage. JF - Stroke Y1 - 2011 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Shahar, Eyal A1 - Longstreth, W T KW - Carotid Intima-Media Thickness KW - Cerebral Hemorrhage KW - Cohort Studies KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertrophy, Left Ventricular KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND AND PURPOSE: Carotid intima-media thickness and electrocardiographic left ventricular hypertrophy are 2 subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased intima-media thickness and electrocardiographic left ventricular hypertrophy also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid intima-media thickness and the presence of electrocardiographic left ventricular hypertrophy would be independently associated with increased ICH incidence.

METHODS: Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid intima-media thickness, carotid plaque, and electrocardiographic left ventricular hypertrophy. Over a median of 18 years of follow-up, 162 incident ICH events occurred.

RESULTS: After adjustment for other ICH risk factors, carotid intima-media thickness was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific Quartile 1, elevated 1.6- to 2.6-fold in Quartiles 2 to 3, and elevated 2.5 to 3.7-fold in Quartile 4 (P<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI, 1.1-3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI, 0.76-2.0) greater ICH risk in ARIC. Electrocardiographic left ventricular hypertrophy carried a hazard ratio of ICH of 1.7 (95% CI, 0.77-3.7) in CHS and 2.8 (95% CI, 1.2-6.4) in ARIC.

CONCLUSIONS: Our data suggest that people with carotid atherosclerosis and possibly left ventricular hypertrophy are at increased risk not only of ischemic stroke, but also of ICH.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21940954?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. JF - PLoS Genet Y1 - 2011 A1 - Pasaniuc, Bogdan A1 - Zaitlen, Noah A1 - Lettre, Guillaume A1 - Chen, Gary K A1 - Tandon, Arti A1 - Kao, W H Linda A1 - Ruczinski, Ingo A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Zhu, Xiaofeng A1 - Larkin, Emma A1 - Lange, Leslie A A1 - Cupples, L Adrienne A1 - Yang, Qiong A1 - Akylbekova, Ermeg L A1 - Musani, Solomon K A1 - Divers, Jasmin A1 - Mychaleckyj, Joe A1 - Li, Mingyao A1 - Papanicolaou, George J A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - John, Esther M A1 - Bernstein, Leslie A1 - Zheng, Wei A1 - Hu, Jennifer J A1 - Ziegler, Regina G A1 - Nyante, Sarah J A1 - Bandera, Elisa V A1 - Ingles, Sue A A1 - Press, Michael F A1 - Chanock, Stephen J A1 - Deming, Sandra L A1 - Rodriguez-Gil, Jorge L A1 - Palmer, Cameron D A1 - Buxbaum, Sarah A1 - Ekunwe, Lynette A1 - Hirschhorn, Joel N A1 - Henderson, Brian E A1 - Myers, Simon A1 - Haiman, Christopher A A1 - Reich, David A1 - Patterson, Nick A1 - Wilson, James G A1 - Price, Alkes L KW - African Americans KW - Algorithms KW - Breast Neoplasms KW - Chromosome Mapping KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Receptor, Fibroblast Growth Factor, Type 2 KW - Software AB -

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of fibrin D-dimer levels in healthy adults. JF - Circulation Y1 - 2011 A1 - Smith, Nicholas L A1 - Huffman, Jennifer E A1 - Strachan, David P A1 - Huang, Jie A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Shin, So-Youn A1 - Baumert, Jens A1 - Vitart, Veronique A1 - Bis, Joshua C A1 - Wild, Sarah H A1 - Rumley, Ann A1 - Yang, Qiong A1 - Uitterlinden, André G A1 - Stott, David J A1 - Davies, Gail A1 - Carter, Angela M A1 - Thorand, Barbara A1 - Polasek, Ozren A1 - McKnight, Barbara A1 - Campbell, Harry A1 - Rudnicka, Alicja R A1 - Chen, Ming-Huei A1 - Buckley, Brendan M A1 - Harris, Sarah E A1 - Peters, Annette A1 - Pulanic, Drazen A1 - Lumley, Thomas A1 - de Craen, Anton J M A1 - Liewald, David C A1 - Gieger, Christian A1 - Campbell, Susan A1 - Ford, Ian A1 - Gow, Alan J A1 - Luciano, Michelle A1 - Porteous, David J A1 - Guo, Xiuqing A1 - Sattar, Naveed A1 - Tenesa, Albert A1 - Cushman, Mary A1 - Slagboom, P Eline A1 - Visscher, Peter M A1 - Spector, Tim D A1 - Illig, Thomas A1 - Rudan, Igor A1 - Bovill, Edwin G A1 - Wright, Alan F A1 - McArdle, Wendy L A1 - Tofler, Geoffrey A1 - Hofman, Albert A1 - Westendorp, Rudi G J A1 - Starr, John M A1 - Grant, Peter J A1 - Karakas, Mahir A1 - Hastie, Nicholas D A1 - Psaty, Bruce M A1 - Wilson, James F A1 - Lowe, Gordon D O A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Jukema, J Wouter A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Koenig, Wolfgang A1 - Hayward, Caroline KW - Adult KW - Aged KW - Blood Coagulation KW - European Continental Ancestry Group KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Testing KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Reference Values KW - Thromboplastin AB -

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

VL - 123 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. JF - Nature Y1 - 2011 A1 - Ehret, Georg B A1 - Munroe, Patricia B A1 - Rice, Kenneth M A1 - Bochud, Murielle A1 - Johnson, Andrew D A1 - Chasman, Daniel I A1 - Smith, Albert V A1 - Tobin, Martin D A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Pihur, Vasyl A1 - Vollenweider, Peter A1 - O'Reilly, Paul F A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Launer, Lenore A1 - Zhao, Jing Hua A1 - Aulchenko, Yurii A1 - Heath, Simon A1 - Sõber, Siim A1 - Parsa, Afshin A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Dehghan, Abbas A1 - Zhang, Feng A1 - Lucas, Gavin A1 - Hicks, Andrew A A1 - Jackson, Anne U A1 - Peden, John F A1 - Tanaka, Toshiko A1 - Wild, Sarah H A1 - Rudan, Igor A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Parker, Alex N A1 - Fava, Cristiano A1 - Chambers, John C A1 - Fox, Ervin R A1 - Kumari, Meena A1 - Go, Min Jin A1 - van der Harst, Pim A1 - Kao, Wen Hong Linda A1 - Sjögren, Marketa A1 - Vinay, D G A1 - Alexander, Myriam A1 - Tabara, Yasuharu A1 - Shaw-Hawkins, Sue A1 - Whincup, Peter H A1 - Liu, Yongmei A1 - Shi, Gang A1 - Kuusisto, Johanna A1 - Tayo, Bamidele A1 - Seielstad, Mark A1 - Sim, Xueling A1 - Nguyen, Khanh-Dung Hoang A1 - Lehtimäki, Terho A1 - Matullo, Giuseppe A1 - Wu, Ying A1 - Gaunt, Tom R A1 - Onland-Moret, N Charlotte A1 - Cooper, Matthew N A1 - Platou, Carl G P A1 - Org, Elin A1 - Hardy, Rebecca A1 - Dahgam, Santosh A1 - Palmen, Jutta A1 - Vitart, Veronique A1 - Braund, Peter S A1 - Kuznetsova, Tatiana A1 - Uiterwaal, Cuno S P M A1 - Adeyemo, Adebowale A1 - Palmas, Walter A1 - Campbell, Harry A1 - Ludwig, Barbara A1 - Tomaszewski, Maciej A1 - Tzoulaki, Ioanna A1 - Palmer, Nicholette D A1 - Aspelund, Thor A1 - Garcia, Melissa A1 - Chang, Yen-Pei C A1 - O'Connell, Jeffrey R A1 - Steinle, Nanette I A1 - Grobbee, Diederick E A1 - Arking, Dan E A1 - Kardia, Sharon L A1 - Morrison, Alanna C A1 - Hernandez, Dena A1 - Najjar, Samer A1 - McArdle, Wendy L A1 - Hadley, David A1 - Brown, Morris J A1 - Connell, John M A1 - Hingorani, Aroon D A1 - Day, Ian N M A1 - Lawlor, Debbie A A1 - Beilby, John P A1 - Lawrence, Robert W A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Dreisbach, Albert W A1 - Li, Yali A1 - Young, J Hunter A1 - Bis, Joshua C A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Adair, Linda S A1 - Lee, Nanette R A1 - Chen, Ming-Huei A1 - Olden, Matthias A1 - Pattaro, Cristian A1 - Bolton, Judith A Hoffman A1 - Köttgen, Anna A1 - Bergmann, Sven A1 - Mooser, Vincent A1 - Chaturvedi, Nish A1 - Frayling, Timothy M A1 - Islam, Muhammad A1 - Jafar, Tazeen H A1 - Erdmann, Jeanette A1 - Kulkarni, Smita R A1 - Bornstein, Stefan R A1 - Grässler, Jürgen A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Kettunen, Johannes A1 - Howard, Philip A1 - Taylor, Andrew A1 - Guarrera, Simonetta A1 - Ricceri, Fulvio A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Weder, Alan B A1 - Hunt, Steven C A1 - Sun, Yan V A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Bonnycastle, Lori L A1 - Scott, Laura J A1 - Stringham, Heather M A1 - Peltonen, Leena A1 - Perola, Markus A1 - Vartiainen, Erkki A1 - Brand, Stefan-Martin A1 - Staessen, Jan A A1 - Wang, Thomas J A1 - Burton, Paul R A1 - Soler Artigas, Maria A1 - Dong, Yanbin A1 - Snieder, Harold A1 - Wang, Xiaoling A1 - Zhu, Haidong A1 - Lohman, Kurt K A1 - Rudock, Megan E A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Doumatey, Ayo A1 - Shriner, Daniel A1 - Veldre, Gudrun A1 - Viigimaa, Margus A1 - Kinra, Sanjay A1 - Prabhakaran, Dorairaj A1 - Tripathy, Vikal A1 - Langefeld, Carl D A1 - Rosengren, Annika A1 - Thelle, Dag S A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - Forrester, Terrence A1 - Hilton, Gina A1 - McKenzie, Colin A A1 - Salako, Tunde A1 - Iwai, Naoharu A1 - Kita, Yoshikuni A1 - Ogihara, Toshio A1 - Ohkubo, Takayoshi A1 - Okamura, Tomonori A1 - Ueshima, Hirotsugu A1 - Umemura, Satoshi A1 - Eyheramendy, Susana A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Cho, Yoon Shin A1 - Kim, Hyung-Lae A1 - Lee, Jong-Young A1 - Scott, James A1 - Sehmi, Joban S A1 - Zhang, Weihua A1 - Hedblad, Bo A1 - Nilsson, Peter A1 - Smith, George Davey A1 - Wong, Andrew A1 - Narisu, Narisu A1 - Stančáková, Alena A1 - Raffel, Leslie J A1 - Yao, Jie A1 - Kathiresan, Sekar A1 - O'Donnell, Christopher J A1 - Schwartz, Stephen M A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Shrine, Nick R G A1 - Wain, Louise V A1 - Morken, Mario A A1 - Swift, Amy J A1 - Laitinen, Jaana A1 - Prokopenko, Inga A1 - Zitting, Paavo A1 - Cooper, Jackie A A1 - Humphries, Steve E A1 - Danesh, John A1 - Rasheed, Asif A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Bakker, Stephan J L A1 - van Gilst, Wiek H A1 - Janipalli, Charles S A1 - Mani, K Radha A1 - Yajnik, Chittaranjan S A1 - Hofman, Albert A1 - Mattace-Raso, Francesco U S A1 - Oostra, Ben A A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Rivadeneira, Fernando A1 - Lakatta, Edward G A1 - Orrù, Marco A1 - Scuteri, Angelo A1 - Ala-Korpela, Mika A1 - Kangas, Antti J A1 - Lyytikäinen, Leo-Pekka A1 - Soininen, Pasi A1 - Tukiainen, Taru A1 - Würtz, Peter A1 - Ong, Rick Twee-Hee A1 - Dörr, Marcus A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Zelenika, Diana A1 - Deloukas, Panos A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Zhai, Guangju A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Terzic, Janos A1 - Kumar, M V Kranthi A1 - Denniff, Matthew A1 - Zukowska-Szczechowska, Ewa A1 - Wagenknecht, Lynne E A1 - Fowkes, F Gerald R A1 - Charchar, Fadi J A1 - Schwarz, Peter E H A1 - Hayward, Caroline A1 - Guo, Xiuqing A1 - Rotimi, Charles A1 - Bots, Michiel L A1 - Brand, Eva A1 - Samani, Nilesh J A1 - Polasek, Ozren A1 - Talmud, Philippa J A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Laan, Maris A1 - Hveem, Kristian A1 - Palmer, Lyle J A1 - van der Schouw, Yvonne T A1 - Casas, Juan P A1 - Mohlke, Karen L A1 - Vineis, Paolo A1 - Raitakari, Olli A1 - Ganesh, Santhi K A1 - Wong, Tien Y A1 - Tai, E Shyong A1 - Cooper, Richard S A1 - Laakso, Markku A1 - Rao, Dabeeru C A1 - Harris, Tamara B A1 - Morris, Richard W A1 - Dominiczak, Anna F A1 - Kivimaki, Mika A1 - Marmot, Michael G A1 - Miki, Tetsuro A1 - Saleheen, Danish A1 - Chandak, Giriraj R A1 - Coresh, Josef A1 - Navis, Gerjan A1 - Salomaa, Veikko A1 - Han, Bok-Ghee A1 - Zhu, Xiaofeng A1 - Kooner, Jaspal S A1 - Melander, Olle A1 - Ridker, Paul M A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wright, Alan F A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Farrall, Martin A1 - Tuomilehto, Jaakko A1 - Pramstaller, Peter P A1 - Elosua, Roberto A1 - Soranzo, Nicole A1 - Sijbrands, Eric J G A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Shuldiner, Alan R A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Rettig, Rainer A1 - Uda, Manuela A1 - Strachan, David P A1 - Witteman, Jacqueline C M A1 - Hartikainen, Anna-Liisa A1 - Beckmann, Jacques S A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Boehnke, Michael A1 - Larson, Martin G A1 - Jarvelin, Marjo-Riitta A1 - Psaty, Bruce M A1 - Abecasis, Goncalo R A1 - Chakravarti, Aravinda A1 - Elliott, Paul A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Caulfield, Mark J A1 - Johnson, Toby KW - Africa KW - Asia KW - Blood Pressure KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - Europe KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Kidney Diseases KW - Polymorphism, Single Nucleotide KW - Stroke AB -

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

VL - 478 IS - 7367 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. JF - Ann Neurol Y1 - 2011 A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Dufouil, Carole A1 - Sigurdsson, Sigurdur A1 - Lumley, Thomas A1 - DeStefano, Anita L A1 - Fazekas, Franz A1 - Vrooman, Henri A A1 - Shibata, Dean K A1 - Maillard, Pauline A1 - Zijdenbos, Alex A1 - Smith, Albert V A1 - Gudnason, Haukur A1 - de Boer, Renske A1 - Cushman, Mary A1 - Mazoyer, Bernard A1 - Heiss, Gerardo A1 - Vernooij, Meike W A1 - Enzinger, Christian A1 - Glazer, Nicole L A1 - Beiser, Alexa A1 - Knopman, David S A1 - Cavalieri, Margherita A1 - Niessen, Wiro J A1 - Harris, Tamara B A1 - Petrovic, Katja A1 - Lopez, Oscar L A1 - Au, Rhoda A1 - Lambert, Jean-Charles A1 - Hofman, Albert A1 - Gottesman, Rebecca F A1 - Garcia, Melissa A1 - Heckbert, Susan R A1 - Atwood, Larry D A1 - Catellier, Diane J A1 - Uitterlinden, André G A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Aspelund, Thor A1 - Romero, Jose R A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Nalls, Michael A A1 - Rotter, Jerome I A1 - Sharrett, Richey A1 - van Duijn, Cornelia M A1 - Amouyel, Philippe A1 - Wolf, Philip A A1 - Gudnason, Vilmundur A1 - van der Lugt, Aad A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tzourio, Christophe A1 - Breteler, Monique M B A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Longstreth, W T A1 - DeCarli, Charles A1 - Launer, Lenore J KW - Aged KW - Aged, 80 and over KW - Cerebral Cortex KW - Chromosomes, Human, Pair 17 KW - Cognition Disorders KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukoencephalopathies KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Movement Disorders KW - Nerve Fibers, Myelinated KW - Polymorphism, Single Nucleotide KW - Residence Characteristics KW - RNA, Messenger AB -

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. JF - Hum Mol Genet Y1 - 2011 A1 - Tin, Adrienne A1 - Woodward, Owen M A1 - Kao, Wen Hong Linda A1 - Liu, Ching-Ti A1 - Lu, Xiaoning A1 - Nalls, Michael A A1 - Shriner, Daniel A1 - Semmo, Mariam A1 - Akylbekova, Ermeg L A1 - Wyatt, Sharon B A1 - Hwang, Shih-Jen A1 - Yang, Qiong A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A A1 - Palmer, Cameron A1 - Meng, Yan A1 - Reilly, Muredach A1 - Shlipak, Michael G A1 - Siscovick, David A1 - Evans, Michele K A1 - Rotimi, Charles N A1 - Flessner, Michael F A1 - Köttgen, Michael A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - African Americans KW - Aged KW - Animals KW - CHO Cells KW - Cricetinae KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Gout KW - Humans KW - Loss of Heterozygosity KW - Male KW - Middle Aged KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Polymorphism, Single Nucleotide KW - Uric Acid KW - Young Adult AB -

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

VL - 20 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JF - Hum Mol Genet Y1 - 2011 A1 - Kaplan, Robert C A1 - Petersen, Ann-Kristin A1 - Chen, Ming-Huei A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Döring, Angela A1 - Lam, Carolyn S P A1 - Friedrich, Nele A1 - Newman, Anne A1 - Müller, Martina A1 - Yang, Qiong A1 - Homuth, Georg A1 - Cappola, Anne A1 - Klopp, Norman A1 - Smith, Holly A1 - Ernst, Florian A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Sawyer, Douglas B A1 - Biffar, Reiner A1 - Rotter, Jerome I A1 - Gieger, Christian A1 - Sullivan, Lisa S A1 - Völzke, Henry A1 - Rice, Kenneth A1 - Spyroglou, Ariadni A1 - Kroemer, Heyo K A1 - Ida Chen, Y-D A1 - Manolopoulou, Jenny A1 - Nauck, Matthias A1 - Strickler, Howard D A1 - Goodarzi, Mark O A1 - Reincke, Martin A1 - Pollak, Michael N A1 - Bidlingmaier, Martin A1 - Vasan, Ramachandran S A1 - Wallaschofski, Henri KW - Aged KW - Chromosomes, Human, Pair 7 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Polymorphism, Single Nucleotide AB -

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of aging. JF - Neurobiol Aging Y1 - 2011 A1 - Walter, Stefan A1 - Atzmon, Gil A1 - Demerath, Ellen W A1 - Garcia, Melissa E A1 - Kaplan, Robert C A1 - Kumari, Meena A1 - Lunetta, Kathryn L A1 - Milaneschi, Yuri A1 - Tanaka, Toshiko A1 - Tranah, Gregory J A1 - Völker, Uwe A1 - Yu, Lei A1 - Arnold, Alice A1 - Benjamin, Emelia J A1 - Biffar, Reiner A1 - Buchman, Aron S A1 - Boerwinkle, Eric A1 - Couper, David A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Harris, Tamara B A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Karasik, David A1 - Kiel, Douglas P A1 - Kocher, Thomas A1 - Kuningas, Maris A1 - Launer, Lenore J A1 - Lohman, Kurt K A1 - Lutsey, Pamela L A1 - Mackenbach, Johan A1 - Marciante, Kristin A1 - Psaty, Bruce M A1 - Reiman, Eric M A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Shardell, Michelle D A1 - Smith, Albert V A1 - van Duijn, Cornelia A1 - Walston, Jeremy A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Baumeister, Sebastian E A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Liu, Yongmei A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Franceschini, Nora KW - Aging KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity AB -

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

VL - 32 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract ER - TY - JOUR T1 - Health and function of participants in the Long Life Family Study: A comparison with other cohorts. JF - Aging (Albany NY) Y1 - 2011 A1 - Newman, Anne B A1 - Glynn, Nancy W A1 - Taylor, Christopher A A1 - Sebastiani, Paola A1 - Perls, Thomas T A1 - Mayeux, Richard A1 - Christensen, Kaare A1 - Zmuda, Joseph M A1 - Barral, Sandra A1 - Lee, Joseph H A1 - Simonsick, Eleanor M A1 - Walston, Jeremy D A1 - Yashin, Anatoli I A1 - Hadley, Evan KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Gait KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Psychomotor Performance KW - Research Design AB -

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

VL - 3 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21258136?dopt=Abstract ER - TY - JOUR T1 - Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study. JF - Circulation Y1 - 2011 A1 - Hajjar, Ihab A1 - Quach, Lien A1 - Yang, Frances A1 - Chaves, Paulo H M A1 - Newman, Anne B A1 - Mukamal, Kenneth A1 - Longstreth, Will A1 - Inzitari, Marco A1 - Lipsitz, Lewis A KW - Aged KW - Aged, 80 and over KW - Brain KW - Cognition Disorders KW - Female KW - Humans KW - Hypertension KW - Kaplan-Meier Estimate KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Microcirculation KW - Mobility Limitation KW - Mood Disorders KW - Nerve Fibers, Myelinated KW - Retrospective Studies KW - Risk Factors AB -

BACKGROUND: Our objective was to investigate the association between hypertension and concurrent impairments in mobility, cognition, and mood; the role of brain white matter hyperintensities in mediating this association; and the impact of these impairments on disability and mortality in elderly hypertensive individuals.

METHODS AND RESULTS: -Blood pressure, gait speed, digit symbol substitution test, and the Center for Epidemiological Studies Depression Scale were measured yearly (1992-1999) on 4700 participants in the Cardiovascular Health Study (age: 74.7, 58% women, 17% blacks, 68% hypertension, 3600 had brain magnetic resonance imaging in 1992-1993, survival data 1992-2005). Using latent profile analysis at baseline, we found that 498 (11%) subjects had concurrent impairments and 3086 (66%) were intact on all 3 measures. Between 1992 and 1999, 651 (21%) became impaired in all 3 domains. Hypertensive individuals were more likely to be impaired at baseline (odds ratio 1.23, 95% confidence interval 1.04 to 1.42, P=0.01) and become impaired during the follow-up (hazard ratio=1.3, 95% confidence interval 1.02 to 1.66, P=0.037). A greater degree of white matter hyperintensities was associated with impairments in the 3 domains (P=0.007) and mediated the association with hypertension (P=0.19 for hypertension after adjusting for white matter hyperintensities in the model, 21% hazard ratio change). Impairments in the 3 domains increased subsequent disability with hypertension (P<0.0001). Hypertension mortality also was increased in those impaired (compared with unimpaired hypertensive individuals: HR=1.10, 95% confidence interval 1.04 to 1.17, P=0.004).

CONCLUSIONS: Hypertension increases the risk of concurrent impairments in mobility, cognition, and mood, which increases disability and mortality. This association is mediated in part by microvascular brain injury.

VL - 123 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21321150?dopt=Abstract ER - TY - JOUR T1 - Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Schnabel, Renate B A1 - Kerr, Kathleen F A1 - Lubitz, Steven A A1 - Alkylbekova, Ermeg L A1 - Marcus, Gregory M A1 - Sinner, Moritz F A1 - Magnani, Jared W A1 - Wolf, Philip A A1 - Deo, Rajat A1 - Lloyd-Jones, Donald M A1 - Lunetta, Kathryn L A1 - Mehra, Reena A1 - Levy, Daniel A1 - Fox, Ervin R A1 - Arking, Dan E A1 - Mosley, Thomas H A1 - Müller-Nurasyid, Martina A1 - Young, Taylor R A1 - Wichmann, H-Erich A1 - Seshadri, Sudha A1 - Farlow, Deborah N A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Glazer, Nicole L A1 - Wilson, James G A1 - Breteler, Monique M B A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Alleles KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. JF - Circulation Y1 - 2011 A1 - Dehghan, Abbas A1 - Dupuis, Josée A1 - Barbalic, Maja A1 - Bis, Joshua C A1 - Eiriksdottir, Gudny A1 - Lu, Chen A1 - Pellikka, Niina A1 - Wallaschofski, Henri A1 - Kettunen, Johannes A1 - Henneman, Peter A1 - Baumert, Jens A1 - Strachan, David P A1 - Fuchsberger, Christian A1 - Vitart, Veronique A1 - Wilson, James F A1 - Paré, Guillaume A1 - Naitza, Silvia A1 - Rudock, Megan E A1 - Surakka, Ida A1 - de Geus, Eco J C A1 - Alizadeh, Behrooz Z A1 - Guralnik, Jack A1 - Shuldiner, Alan A1 - Tanaka, Toshiko A1 - Zee, Robert Y L A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Kavousi, Maryam A1 - Ripatti, Samuli A1 - Nauck, Matthias A1 - Smith, Nicholas L A1 - Smith, Albert V A1 - Sundvall, Jouko A1 - Scheet, Paul A1 - Liu, Yongmei A1 - Ruokonen, Aimo A1 - Rose, Lynda M A1 - Larson, Martin G A1 - Hoogeveen, Ron C A1 - Freimer, Nelson B A1 - Teumer, Alexander A1 - Tracy, Russell P A1 - Launer, Lenore J A1 - Buring, Julie E A1 - Yamamoto, Jennifer F A1 - Folsom, Aaron R A1 - Sijbrands, Eric J G A1 - Pankow, James A1 - Elliott, Paul A1 - Keaney, John F A1 - Sun, Wei A1 - Sarin, Antti-Pekka A1 - Fontes, João D A1 - Badola, Sunita A1 - Astor, Brad C A1 - Hofman, Albert A1 - Pouta, Anneli A1 - Werdan, Karl A1 - Greiser, Karin H A1 - Kuss, Oliver A1 - Meyer zu Schwabedissen, Henriette E A1 - Thiery, Joachim A1 - Jamshidi, Yalda A1 - Nolte, Ilja M A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Parker, Alexander N A1 - Aspelund, Thor A1 - Bates, David A1 - Young, Lauren A1 - Tsui, Kim A1 - Siscovick, David S A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Uda, Manuela A1 - Schlessinger, David A1 - Rudan, Igor A1 - Hicks, Andrew A A1 - Penninx, Brenda W A1 - Thorand, Barbara A1 - Gieger, Christian A1 - Coresh, Joe A1 - Willemsen, Gonneke A1 - Harris, Tamara B A1 - Uitterlinden, André G A1 - Jarvelin, Marjo-Riitta A1 - Rice, Kenneth A1 - Radke, Dörte A1 - Salomaa, Veikko A1 - Willems van Dijk, Ko A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Ferrucci, Luigi A1 - Gibson, Quince D A1 - Bandinelli, Stefania A1 - Snieder, Harold A1 - Boomsma, Dorret I A1 - Xiao, Xiangjun A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Ridker, Paul M A1 - Homuth, Georg A1 - Koenig, Wolfgang A1 - Ballantyne, Christie M A1 - Witteman, Jacqueline C M A1 - Benjamin, Emelia J A1 - Perola, Markus A1 - Chasman, Daniel I KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Vasculitis AB -

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

VL - 123 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract ER - TY - JOUR T1 - Neighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS). JF - Stroke Y1 - 2011 A1 - Brown, Arleen F A1 - Liang, Li-Jung A1 - Vassar, Stefanie D A1 - Stein-Merkin, Sharon A1 - Longstreth, W T A1 - Ovbiagele, Bruce A1 - Yan, Tingjian A1 - Escarce, José J KW - Aged KW - Aged, 80 and over KW - Brain Ischemia KW - Female KW - Health Status Disparities KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Poverty KW - Residence Characteristics KW - Risk KW - Risk Factors KW - Social Class KW - Social Environment KW - Socioeconomic Factors KW - Stroke KW - Urban Population AB -

BACKGROUND AND PURPOSE: Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations.

METHODS: We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages≥65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors.

RESULTS: Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke.

CONCLUSIONS: Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21940966?dopt=Abstract ER - TY - JOUR T1 - New gene functions in megakaryopoiesis and platelet formation. JF - Nature Y1 - 2011 A1 - Gieger, Christian A1 - Radhakrishnan, Aparna A1 - Cvejic, Ana A1 - Tang, Weihong A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Serbanovic-Canic, Jovana A1 - Elling, Ulrich A1 - Goodall, Alison H A1 - Labrune, Yann A1 - Lopez, Lorna M A1 - Mägi, Reedik A1 - Meacham, Stuart A1 - Okada, Yukinori A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Teumer, Alexander A1 - Voss, Katrin A1 - Zhang, Weihua A1 - Ramirez-Solis, Ramiro A1 - Bis, Joshua C A1 - Ellinghaus, David A1 - Gögele, Martin A1 - Hottenga, Jouke-Jan A1 - Langenberg, Claudia A1 - Kovacs, Peter A1 - O'Reilly, Paul F A1 - Shin, So-Youn A1 - Esko, Tõnu A1 - Hartiala, Jaana A1 - Kanoni, Stavroula A1 - Murgia, Federico A1 - Parsa, Afshin A1 - Stephens, Jonathan A1 - van der Harst, Pim A1 - Ellen van der Schoot, C A1 - Allayee, Hooman A1 - Attwood, Antony A1 - Balkau, Beverley A1 - Bastardot, François A1 - Basu, Saonli A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bomba, Lorenzo A1 - Bonnefond, Amélie A1 - Cambien, Francois A1 - Chambers, John C A1 - Cucca, Francesco A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Boer, Rudolf A A1 - de Geus, Eco J C A1 - Döring, Angela A1 - Elliott, Paul A1 - Erdmann, Jeanette A1 - Evans, David M A1 - Falchi, Mario A1 - Feng, Wei A1 - Folsom, Aaron R A1 - Frazer, Ian H A1 - Gibson, Quince D A1 - Glazer, Nicole L A1 - Hammond, Chris A1 - Hartikainen, Anna-Liisa A1 - Heckbert, Susan R A1 - Hengstenberg, Christian A1 - Hersch, Micha A1 - Illig, Thomas A1 - Loos, Ruth J F A1 - Jolley, Jennifer A1 - Khaw, Kay Tee A1 - Kuhnel, Brigitte A1 - Kyrtsonis, Marie-Christine A1 - Lagou, Vasiliki A1 - Lloyd-Jones, Heather A1 - Lumley, Thomas A1 - Mangino, Massimo A1 - Maschio, Andrea A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Memari, Yasin A1 - Mitchell, Braxton D A1 - Montgomery, Grant W A1 - Nakamura, Yusuke A1 - Nauck, Matthias A1 - Navis, Gerjan A1 - Nöthlings, Ute A1 - Nolte, Ilja M A1 - Porteous, David J A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Pullat, Janne A1 - Ring, Susan M A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ruokonen, Aimo A1 - Sala, Cinzia A1 - Samani, Nilesh J A1 - Sambrook, Jennifer A1 - Schlessinger, David A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Scott, James A1 - Smith, Nicholas L A1 - Snieder, Harold A1 - Starr, John M A1 - Stumvoll, Michael A1 - Takahashi, Atsushi A1 - Tang, W H Wilson A1 - Taylor, Kent A1 - Tenesa, Albert A1 - Lay Thein, Swee A1 - Tönjes, Anke A1 - Uda, Manuela A1 - Ulivi, Sheila A1 - van Veldhuisen, Dirk J A1 - Visscher, Peter M A1 - Völker, Uwe A1 - Wichmann, H-Erich A1 - Wiggins, Kerri L A1 - Willemsen, Gonneke A1 - Yang, Tsun-Po A1 - Hua Zhao, Jing A1 - Zitting, Paavo A1 - Bradley, John R A1 - Dedoussis, George V A1 - Gasparini, Paolo A1 - Hazen, Stanley L A1 - Metspalu, Andres A1 - Pirastu, Mario A1 - Shuldiner, Alan R A1 - Joost van Pelt, L A1 - Zwaginga, Jaap-Jan A1 - Boomsma, Dorret I A1 - Deary, Ian J A1 - Franke, Andre A1 - Froguel, Philippe A1 - Ganesh, Santhi K A1 - Jarvelin, Marjo-Riitta A1 - Martin, Nicholas G A1 - Meisinger, Christa A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Wareham, Nicholas J A1 - Akkerman, Jan-Willem N A1 - Ciullo, Marina A1 - Deloukas, Panos A1 - Greinacher, Andreas A1 - Jupe, Steve A1 - Kamatani, Naoyuki A1 - Khadake, Jyoti A1 - Kooner, Jaspal S A1 - Penninger, Josef A1 - Prokopenko, Inga A1 - Stemple, Derek A1 - Toniolo, Daniela A1 - Wernisch, Lorenz A1 - Sanna, Serena A1 - Hicks, Andrew A A1 - Rendon, Augusto A1 - Ferreira, Manuel A A1 - Ouwehand, Willem H A1 - Soranzo, Nicole KW - Animals KW - Blood Platelets KW - Cell Size KW - Drosophila melanogaster KW - Drosophila Proteins KW - Europe KW - Gene Expression Profiling KW - Gene Silencing KW - Genome, Human KW - Genome-Wide Association Study KW - Hematopoiesis KW - Humans KW - Megakaryocytes KW - Platelet Count KW - Protein Interaction Maps KW - Transcription, Genetic KW - Zebrafish KW - Zebrafish Proteins AB -

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

VL - 480 IS - 7376 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract ER - TY - JOUR T1 - The risk of Parkinson disease associated with urate in a community-based cohort of older adults. JF - Neuroepidemiology Y1 - 2011 A1 - Jain, S A1 - Ton, T G A1 - Boudreau, R M A1 - Yang, M A1 - Thacker, E L A1 - Studenski, S A1 - Longstreth, W T A1 - Strotmeyer, E S A1 - Newman, A B KW - Aged KW - California KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Maryland KW - North Carolina KW - Parkinson Disease KW - Pennsylvania KW - Prospective Studies KW - Risk Factors KW - Sex Distribution KW - Sex Factors KW - Uric Acid AB -

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.

METHODS: The association of baseline urate (µmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 µmol/l), middle (300-500 µmol/l), and high (>500 µmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.

RESULTS: Women had significantly lower urate concentrations than did men [316.8 µmol/l (SD 88.0) vs. 367.4 µmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 µmol/l (OR 1.69, 95% CI 1.03-2.78) but not for urate >500 µmol/l (OR 1.55, 95% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 µmol/l, and across the entire range a convex quadratic term was significant.

CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21677446?dopt=Abstract ER - TY - JOUR T1 - Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. JF - Diabetes Y1 - 2011 A1 - Kanoni, Stavroula A1 - Nettleton, Jennifer A A1 - Hivert, Marie-France A1 - Ye, Zheng A1 - van Rooij, Frank J A A1 - Shungin, Dmitry A1 - Sonestedt, Emily A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Lemaitre, Rozenn N A1 - Gustafsson, Stefan A1 - Anderson, Jennifer S A1 - Tanaka, Toshiko A1 - Hindy, George A1 - Saylor, Georgia A1 - Renstrom, Frida A1 - Bennett, Amanda J A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Fox, Caroline S A1 - Hofman, Albert A1 - Hoogeveen, Ron C A1 - Houston, Denise K A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Johansson, Ingegerd A1 - Lind, Lars A1 - Liu, Yongmei A1 - McKeown, Nicola A1 - Ordovas, Jose A1 - Pankow, James S A1 - Sijbrands, Eric J G A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Wareham, Nick J A1 - Prokopenko, Inga A1 - Bandinelli, Stefania A1 - Forouhi, Nita G A1 - Cupples, L Adrienne A1 - Loos, Ruth J A1 - Hallmans, Göran A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Ferrucci, Luigi A1 - Kritchevsky, Stephen B A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Borecki, Ingrid B A1 - Witteman, Jacqueline C M A1 - Orho-Melander, Marju A1 - Siscovick, David S A1 - Meigs, James B A1 - Franks, Paul W A1 - Dedoussis, George V KW - Blood Glucose KW - Cation Transport Proteins KW - Cohort Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Zinc KW - Zinc Transporter 8 AB -

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

VL - 60 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21810599?dopt=Abstract ER - TY - JOUR T1 - Assessment of gene-by-sex interaction effect on bone mineral density. JF - J Bone Miner Res Y1 - 2012 A1 - Liu, Ching-Ti A1 - Estrada, Karol A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Evangelou, Evangelos A1 - Li, Guo A1 - Minster, Ryan L A1 - Carless, Melanie A A1 - Kammerer, Candace M A1 - Oei, Ling A1 - Zhou, Yanhua A1 - Alonso, Nerea A1 - Dailiana, Zoe A1 - Eriksson, Joel A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Husted, Lise Bjerre A1 - Khusainova, Rita I A1 - Koromila, Theodora A1 - Kung, Annie Waichee A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Richards, J Brent A1 - Sham, Pak Chung A1 - Spector, Timothy A1 - Vandenput, Liesbeth A1 - Xiao, Su-Mei A1 - Zheng, Hou-Feng A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza K A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Marc, Janja A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Olmos, José M A1 - Ralston, Stuart H A1 - Riancho, José A A1 - Rousseau, François A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Zarrabeitia, María T A1 - Castano-Betancourt, Martha A1 - Demissie, Serkalem A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Kwan, Tony A1 - Medina-Gómez, Carolina A1 - Pastinen, Tomi A1 - Sigurdsson, Gunnar A1 - Thorleifsson, Gudmar A1 - Vanmeurs, Joyce Bj A1 - Blangero, John A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Mitchell, Braxton D A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Rotter, Jerome I A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Thorsteinsdottir, Unnur A1 - Tylavsky, Frances A A1 - Uitterlinden, Andre A1 - Cauley, Jane A A1 - Harris, Tamara B A1 - Ioannidis, John Pa A1 - Psaty, Bruce M A1 - Robbins, John A A1 - Zillikens, M Carola A1 - Vanduijn, Cornelia M A1 - Prince, Richard L A1 - Karasik, David A1 - Rivadeneira, Fernando A1 - Kiel, Douglas P A1 - Cupples, L Adrienne A1 - Hsu, Yi-Hsiang KW - Bone Density KW - Cohort Studies KW - Female KW - Genes KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Sex Characteristics AB -

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

VL - 27 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract ER - TY - JOUR T1 - Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. JF - Lancet Y1 - 2012 A1 - Fox, Caroline S A1 - Matsushita, Kunihiro A1 - Woodward, Mark A1 - Bilo, Henk J G A1 - Chalmers, John A1 - Heerspink, Hiddo J Lambers A1 - Lee, Brian J A1 - Perkins, Robert M A1 - Rossing, Peter A1 - Sairenchi, Toshimi A1 - Tonelli, Marcello A1 - Vassalotti, Joseph A A1 - Yamagishi, Kazumasa A1 - Coresh, Josef A1 - de Jong, Paul E A1 - Wen, Chi-Pang A1 - Nelson, Robert G KW - Aged KW - Albuminuria KW - Cardiovascular Diseases KW - Cause of Death KW - Diabetic Nephropathies KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.

METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.

FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.

INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.

FUNDING: US National Kidney Foundation.

VL - 380 IS - 9854 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23013602?dopt=Abstract ER - TY - JOUR T1 - Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. JF - Eur Heart J Y1 - 2012 A1 - Grallert, Harald A1 - Dupuis, Josée A1 - Bis, Joshua C A1 - Dehghan, Abbas A1 - Barbalic, Maja A1 - Baumert, Jens A1 - Lu, Chen A1 - Smith, Nicholas L A1 - Uitterlinden, André G A1 - Roberts, Robert A1 - Khuseyinova, Natalie A1 - Schnabel, Renate B A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Hoogeveen, Ron C A1 - Fontes, João Daniel A1 - Meisinger, Christa A1 - Keaney, John F A1 - Lemaitre, Rozenn A1 - Aulchenko, Yurii S A1 - Vasan, Ramachandran S A1 - Ellis, Stephen A1 - Hazen, Stanley L A1 - van Duijn, Cornelia M A1 - Nelson, Jeanenne J A1 - März, Winfried A1 - Schunkert, Heribert A1 - McPherson, Ruth M A1 - Stirnadel-Farrant, Heide A A1 - Psaty, Bruce M A1 - Gieger, Christian A1 - Siscovick, David A1 - Hofman, Albert A1 - Illig, Thomas A1 - Cushman, Mary A1 - Yamamoto, Jennifer F A1 - Rotter, Jerome I A1 - Larson, Martin G A1 - Stewart, Alexandre F R A1 - Boerwinkle, Eric A1 - Witteman, Jacqueline C M A1 - Tracy, Russell P A1 - Koenig, Wolfgang A1 - Benjamin, Emelia J A1 - Ballantyne, Christie M KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Coronary Artery Disease KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Phospholipases A2 KW - Polymorphism, Single Nucleotide AB -

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

VL - 33 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract ER - TY - JOUR T1 - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. JF - PLoS One Y1 - 2012 A1 - Buyske, Steven A1 - Wu, Ying A1 - Carty, Cara L A1 - Cheng, Iona A1 - Assimes, Themistocles L A1 - Dumitrescu, Logan A1 - Hindorff, Lucia A A1 - Mitchell, Sabrina A1 - Ambite, Jose Luis A1 - Boerwinkle, Eric A1 - Bůzková, Petra A1 - Carlson, Chris S A1 - Cochran, Barbara A1 - Duggan, David A1 - Eaton, Charles B A1 - Fesinmeyer, Megan D A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Jenny, Nancy A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Lin, Yi A1 - Le Marchand, Loïc A1 - Matise, Tara C A1 - Robinson, Jennifer G A1 - Rodriguez, Carlos A1 - Schumacher, Fredrick R A1 - Voight, Benjamin F A1 - Young, Alicia A1 - Manolio, Teri A A1 - Mohlke, Karen L A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - North, Kari E KW - African Americans KW - Cardiovascular Diseases KW - Cholesterol Ester Transfer Proteins KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Chromosomes, Human KW - Cohort Studies KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Metabolic Diseases KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping and initial characterization of QT interval loci in African Americans. JF - PLoS Genet Y1 - 2012 A1 - Avery, Christy L A1 - Sethupathy, Praveen A1 - Buyske, Steven A1 - He, Qianchuan A1 - Lin, Dan-Yu A1 - Arking, Dan E A1 - Carty, Cara L A1 - Duggan, David A1 - Fesinmeyer, Megan D A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Klein, Liviu A1 - Patton, Kristen K A1 - Peters, Ulrike A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Young, Alicia M A1 - Kooperberg, Charles A1 - Haiman, Christopher A A1 - Mohlke, Karen L A1 - Whitsel, Eric A A1 - North, Kari E KW - African Americans KW - Aged KW - Computational Biology KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors KW - Tachycardia KW - United States AB -

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract ER - TY - JOUR T1 - FTO genotype is associated with phenotypic variability of body mass index. JF - Nature Y1 - 2012 A1 - Yang, Jian A1 - Loos, Ruth J F A1 - Powell, Joseph E A1 - Medland, Sarah E A1 - Speliotes, Elizabeth K A1 - Chasman, Daniel I A1 - Rose, Lynda M A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Mägi, Reedik A1 - Waite, Lindsay A1 - Smith, Albert Vernon A1 - Yerges-Armstrong, Laura M A1 - Monda, Keri L A1 - Hadley, David A1 - Mahajan, Anubha A1 - Li, Guo A1 - Kapur, Karen A1 - Vitart, Veronique A1 - Huffman, Jennifer E A1 - Wang, Sophie R A1 - Palmer, Cameron A1 - Esko, Tõnu A1 - Fischer, Krista A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Feitosa, Mary F A1 - Luan, Jian'an A1 - Heard-Costa, Nancy L A1 - White, Charles A1 - Jackson, Anne U A1 - Preuss, Michael A1 - Ziegler, Andreas A1 - Eriksson, Joel A1 - Kutalik, Zoltán A1 - Frau, Francesca A1 - Nolte, Ilja M A1 - van Vliet-Ostaptchouk, Jana V A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Verweij, Niek A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Estrada, Karol A1 - Bragg-Gresham, Jennifer Lynn A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Prokopenko, Inga A1 - Mangino, Massimo A1 - Lindgren, Cecilia M A1 - Assimes, Themistocles L A1 - Shuldiner, Alan R A1 - Hui, Jennie A1 - Beilby, John P A1 - McArdle, Wendy L A1 - Hall, Per A1 - Haritunians, Talin A1 - Zgaga, Lina A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Oostra, Ben A A1 - Junttila, M Juhani A1 - Grönberg, Henrik A1 - Schreiber, Stefan A1 - Peters, Annette A1 - Hicks, Andrew A A1 - Stephens, Jonathan A1 - Foad, Nicola S A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Kaakinen, Marika A1 - Willemsen, Gonneke A1 - Vink, Jacqueline M A1 - Wild, Sarah H A1 - Navis, Gerjan A1 - Asselbergs, Folkert W A1 - Homuth, Georg A1 - John, Ulrich A1 - Iribarren, Carlos A1 - Harris, Tamara A1 - Launer, Lenore A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Boerwinkle, Eric A1 - Cadby, Gemma A1 - Palmer, Lyle J A1 - James, Alan L A1 - Musk, Arthur W A1 - Ingelsson, Erik A1 - Psaty, Bruce M A1 - Beckmann, Jacques S A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Hayward, Caroline A1 - Wright, Alan F A1 - Rudan, Igor A1 - Groop, Leif C A1 - Metspalu, Andres A1 - Khaw, Kay Tee A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Wareham, Nicholas J A1 - Tardif, Jean-Claude A1 - Huikuri, Heikki V A1 - Cupples, L Adrienne A1 - Atwood, Larry D A1 - Fox, Caroline S A1 - Boehnke, Michael A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Erdmann, Jeanette A1 - Schunkert, Heribert A1 - Hengstenberg, Christian A1 - Stark, Klaus A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Cusi, Daniele A1 - Staessen, Jan A A1 - van der Klauw, Melanie M A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Jolley, Jennifer D A1 - Ripatti, Samuli A1 - Jarvelin, Marjo-Riitta A1 - de Geus, Eco J C A1 - Boomsma, Dorret I A1 - Penninx, Brenda A1 - Wilson, James F A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Hofman, Albert A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Zillikens, M Carola A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Abecasis, Goncalo R A1 - Schlessinger, David A1 - Schipf, Sabine A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Spector, Tim D A1 - North, Kari E A1 - Lettre, Guillaume A1 - McCarthy, Mark I A1 - Berndt, Sonja I A1 - Heath, Andrew C A1 - Madden, Pamela A F A1 - Nyholt, Dale R A1 - Montgomery, Grant W A1 - Martin, Nicholas G A1 - McKnight, Barbara A1 - Strachan, David P A1 - Hill, William G A1 - Snieder, Harold A1 - Ridker, Paul M A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Goddard, Michael E A1 - Visscher, Peter M KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Body Height KW - Body Mass Index KW - Co-Repressor Proteins KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proteins KW - Repressor Proteins AB -

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

VL - 490 IS - 7419 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. JF - Atherosclerosis Y1 - 2012 A1 - Wassel, Christina L A1 - Lamina, Claudia A1 - Nambi, Vijay A1 - Coassin, Stefan A1 - Mukamal, Kenneth J A1 - Ganesh, Santhi K A1 - Jacobs, David R A1 - Franceschini, Nora A1 - Papanicolaou, George J A1 - Gibson, Quince A1 - Yanek, Lisa R A1 - van der Harst, Pim A1 - Ferguson, Jane F A1 - Crawford, Dana C A1 - Waite, Lindsay L A1 - Allison, Matthew A A1 - Criqui, Michael H A1 - McDermott, Mary M A1 - Mehra, Reena A1 - Cupples, L Adrienne A1 - Hwang, Shih-Jen A1 - Redline, Susan A1 - Kaplan, Robert C A1 - Heiss, Gerardo A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Taylor, Herman A A1 - Eraso, Luis H A1 - Haun, Margot A1 - Li, Mingyao A1 - Meisinger, Christa A1 - O'Connell, Jeffrey R A1 - Shuldiner, Alan R A1 - Tybjærg-Hansen, Anne A1 - Frikke-Schmidt, Ruth A1 - Kollerits, Barbara A1 - Rantner, Barbara A1 - Dieplinger, Benjamin A1 - Stadler, Marietta A1 - Mueller, Thomas A1 - Haltmayer, Meinhard A1 - Klein-Weigel, Peter A1 - Summerer, Monika A1 - Wichmann, H-Erich A1 - Asselbergs, Folkert W A1 - Navis, Gerjan A1 - Mateo Leach, Irene A1 - Brown-Gentry, Kristin A1 - Goodloe, Robert A1 - Assimes, Themistocles L A1 - Becker, Diane M A1 - Cooke, John P A1 - Absher, Devin M A1 - Olin, Jeffrey W A1 - Mitchell, Braxton D A1 - Reilly, Muredach P A1 - Mohler, Emile R A1 - North, Kari E A1 - Reiner, Alexander P A1 - Kronenberg, Florian A1 - Murabito, Joanne M KW - Adult KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Aryl Hydrocarbon Hydroxylases KW - Cytochrome P-450 CYP2B6 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxidoreductases, N-Demethylating KW - Peripheral Arterial Disease KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.

METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.

RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.

CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

VL - 222 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analyses of smoking behaviors in African Americans. JF - Transl Psychiatry Y1 - 2012 A1 - David, S P A1 - Hamidovic, A A1 - Chen, G K A1 - Bergen, A W A1 - Wessel, J A1 - Kasberger, J L A1 - Brown, W M A1 - Petruzella, S A1 - Thacker, E L A1 - Kim, Y A1 - Nalls, M A A1 - Tranah, G J A1 - Sung, Y J A1 - Ambrosone, C B A1 - Arnett, D A1 - Bandera, E V A1 - Becker, D M A1 - Becker, L A1 - Berndt, S I A1 - Bernstein, L A1 - Blot, W J A1 - Broeckel, U A1 - Buxbaum, S G A1 - Caporaso, N A1 - Casey, G A1 - Chanock, S J A1 - Deming, S L A1 - Diver, W R A1 - Eaton, C B A1 - Evans, D S A1 - Evans, M K A1 - Fornage, M A1 - Franceschini, N A1 - Harris, T B A1 - Henderson, B E A1 - Hernandez, D G A1 - Hitsman, B A1 - Hu, J J A1 - Hunt, S C A1 - Ingles, S A A1 - John, E M A1 - Kittles, R A1 - Kolb, S A1 - Kolonel, L N A1 - Le Marchand, L A1 - Liu, Y A1 - Lohman, K K A1 - McKnight, B A1 - Millikan, R C A1 - Murphy, A A1 - Neslund-Dudas, C A1 - Nyante, S A1 - Press, M A1 - Psaty, B M A1 - Rao, D C A1 - Redline, S A1 - Rodriguez-Gil, J L A1 - Rybicki, B A A1 - Signorello, L B A1 - Singleton, A B A1 - Smoller, J A1 - Snively, B A1 - Spring, B A1 - Stanford, J L A1 - Strom, S S A1 - Swan, G E A1 - Taylor, K D A1 - Thun, M J A1 - Wilson, A F A1 - Witte, J S A1 - Yamamura, Y A1 - Yanek, L R A1 - Yu, K A1 - Zheng, W A1 - Ziegler, R G A1 - Zonderman, A B A1 - Jorgenson, E A1 - Haiman, C A A1 - Furberg, H KW - Adult KW - African Americans KW - Aged KW - Chromosomes, Human, Pair 10 KW - Chromosomes, Human, Pair 15 KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proteoglycans KW - Receptors, Nicotinic KW - Smoking KW - Statistics as Topic AB -

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

VL - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22832964?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

VL - 44 IS - 5 ER - TY - JOUR T1 - Impact of ancestry and common genetic variants on QT interval in African Americans. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Smith, J Gustav A1 - Avery, Christy L A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Meng, Yan A A1 - Smith, Erin N A1 - Palmer, Cameron A1 - Tanaka, Toshiko A1 - Mehra, Reena A1 - Butler, Anne M A1 - Young, Taylor A1 - Buxbaum, Sarah G A1 - Kerr, Kathleen F A1 - Berenson, Gerald S A1 - Schnabel, Renate B A1 - Li, Guo A1 - Ellinor, Patrick T A1 - Magnani, Jared W A1 - Chen, Wei A1 - Bis, Joshua C A1 - Curb, J David A1 - Hsueh, Wen-Chi A1 - Rotter, Jerome I A1 - Liu, Yongmei A1 - Newman, Anne B A1 - Limacher, Marian C A1 - North, Kari E A1 - Reiner, Alexander P A1 - Quibrera, P Miguel A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Solomon, Allen J A1 - Srinivasan, Sathanur R A1 - Alonso, Alvaro A1 - Wallace, Robert A1 - Redline, Susan A1 - Zhang, Zhu-Ming A1 - Post, Wendy S A1 - Zonderman, Alan B A1 - Taylor, Herman A A1 - Murray, Sarah S A1 - Ferrucci, Luigi A1 - Arking, Dan E A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - Newton-Cheh, Christopher KW - Adult KW - African Americans KW - Aged KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genealogy and Heraldry KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract ER - TY - JOUR T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. JF - Nat Genet Y1 - 2012 A1 - Scott, Robert A A1 - Lagou, Vasiliki A1 - Welch, Ryan P A1 - Wheeler, Eleanor A1 - Montasser, May E A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Rehnberg, Emil A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Rasmussen-Torvik, Laura J A1 - Yengo, Loic A1 - Lecoeur, Cécile A1 - Shungin, Dmitry A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Johnson, Paul C D A1 - Jukema, J Wouter A1 - Johnson, Toby A1 - Mahajan, Anubha A1 - Verweij, Niek A1 - Thorleifsson, Gudmar A1 - Hottenga, Jouke-Jan A1 - Shah, Sonia A1 - Smith, Albert V A1 - Sennblad, Bengt A1 - Gieger, Christian A1 - Salo, Perttu A1 - Perola, Markus A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Pourcain, Beate St A1 - Wu, Ying A1 - Andrews, Jeanette S A1 - Hui, Jennie A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Horikoshi, Momoko A1 - Navarro, Pau A1 - Isaacs, Aaron A1 - O'Connell, Jeffrey R A1 - Stirrups, Kathleen A1 - Vitart, Veronique A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - Mihailov, Evelin A1 - Fraser, Ross M A1 - Fall, Tove A1 - Voight, Benjamin F A1 - Raychaudhuri, Soumya A1 - Chen, Han A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Rayner, Nigel W A1 - Robertson, Neil A1 - Rybin, Denis A1 - Liu, Ching-Ti A1 - Beckmann, Jacques S A1 - Willems, Sara M A1 - Chines, Peter S A1 - Jackson, Anne U A1 - Kang, Hyun Min A1 - Stringham, Heather M A1 - Song, Kijoung A1 - Tanaka, Toshiko A1 - Peden, John F A1 - Goel, Anuj A1 - Hicks, Andrew A A1 - An, Ping A1 - Müller-Nurasyid, Martina A1 - Franco-Cereceda, Anders A1 - Folkersen, Lasse A1 - Marullo, Letizia A1 - Jansen, Hanneke A1 - Oldehinkel, Albertine J A1 - Bruinenberg, Marcel A1 - Pankow, James S A1 - North, Kari E A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Edkins, Sarah A1 - Varga, Tibor V A1 - Hallmans, Göran A1 - Oksa, Heikki A1 - Antonella, Mulas A1 - Nagaraja, Ramaiah A1 - Trompet, Stella A1 - Ford, Ian A1 - Bakker, Stephan J L A1 - Kong, Augustine A1 - Kumari, Meena A1 - Gigante, Bruna A1 - Herder, Christian A1 - Munroe, Patricia B A1 - Caulfield, Mark A1 - Antti, Jula A1 - Mangino, Massimo A1 - Small, Kerrin A1 - Miljkovic, Iva A1 - Liu, Yongmei A1 - Atalay, Mustafa A1 - Kiess, Wieland A1 - James, Alan L A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Palmer, Colin N A A1 - Doney, Alex S F A1 - Willemsen, Gonneke A1 - Smit, Johannes H A1 - Campbell, Susan A1 - Polasek, Ozren A1 - Bonnycastle, Lori L A1 - Hercberg, Serge A1 - Dimitriou, Maria A1 - Bolton, Jennifer L A1 - Fowkes, Gerard R A1 - Kovacs, Peter A1 - Lindström, Jaana A1 - Zemunik, Tatijana A1 - Bandinelli, Stefania A1 - Wild, Sarah H A1 - Basart, Hanneke V A1 - Rathmann, Wolfgang A1 - Grallert, Harald A1 - Maerz, Winfried A1 - Kleber, Marcus E A1 - Boehm, Bernhard O A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Hastie, Nicholas D A1 - Rudan, Igor A1 - Campbell, Harry A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Stumvoll, Michael A1 - Ferrucci, Luigi A1 - Waterworth, Dawn M A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Tuomilehto, Jaakko A1 - Watanabe, Richard M A1 - de Geus, Eco J C A1 - Penninx, Brenda W A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Wright, Alan F A1 - Hovingh, G Kees A1 - Metspalu, Andres A1 - Uusitupa, Matti A1 - Magnusson, Patrik K E A1 - Kyvik, Kirsten O A1 - Kaprio, Jaakko A1 - Price, Jackie F A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Meneton, Pierre A1 - Lind, Lars A1 - Boehnke, Michael A1 - Shuldiner, Alan R A1 - van Duijn, Cornelia M A1 - Morris, Andrew D A1 - Toenjes, Anke A1 - Peyser, Patricia A A1 - Beilby, John P A1 - Körner, Antje A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Adair, Linda S A1 - Smith, George Davey A1 - Spector, Tim D A1 - Illig, Thomas A1 - de Faire, Ulf A1 - Hamsten, Anders A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Hingorani, Aroon A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Boomsma, Dorret I A1 - Stefansson, Kari A1 - van der Harst, Pim A1 - Dupuis, Josée A1 - Pedersen, Nancy L A1 - Sattar, Naveed A1 - Harris, Tamara B A1 - Cucca, Francesco A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Mohlke, Karen L A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Pouta, Anneli A1 - Jarvelin, Marjo-Riitta A1 - Wareham, Nicholas J A1 - Bouatia-Naji, Nabila A1 - McCarthy, Mark I A1 - Franks, Paul W A1 - Meigs, James B A1 - Teslovich, Tanya M A1 - Florez, Jose C A1 - Langenberg, Claudia A1 - Ingelsson, Erik A1 - Prokopenko, Inga A1 - Barroso, Inês KW - Adult KW - Animals KW - Blood Glucose KW - Fasting KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Osmolar Concentration KW - Quantitative Trait Loci AB -

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

VL - 44 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Butler, Anne M A1 - Yin, Xiaoyan A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Buxbaum, Sarah G A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Berenson, Gerald S A1 - Bis, Josh C A1 - Chen, Wei A1 - Deo, Rajat A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hsueh, Wen-Chi A1 - Keating, Brendan J A1 - Kerr, Kathleen F A1 - Li, Yun A1 - Limacher, Marian C A1 - Liu, Yongmei A1 - Lubitz, Steven A A1 - Marciante, Kristin D A1 - Mehra, Reena A1 - Meng, Yan A A1 - Newman, Anne B A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Palmer, Cameron D A1 - Psaty, Bruce M A1 - Quibrera, P Miguel A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Evans, Michele K A1 - Sotoodehnia, Nona A1 - Magnani, Jared W A1 - Avery, Christy L KW - Adult KW - African Americans KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. JF - Ann Neurol Y1 - 2012 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Longstreth, W T KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Intracranial Hemorrhages KW - Leukoaraiosis KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Risk Factors AB -

OBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.

METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.

RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or ≥3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).

INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.

VL - 71 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22522444?dopt=Abstract ER - TY - JOUR T1 - Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Yu, Bing A1 - Barbalic, Maja A1 - Brautbar, Ariel A1 - Nambi, Vijay A1 - Hoogeveen, Ron C A1 - Tang, Weihong A1 - Mosley, Thomas H A1 - Rotter, Jerome I A1 - deFilippi, Christopher R A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Rice, Ken A1 - Heckbert, Susan R A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric KW - African Continental Ancestry Group KW - Atherosclerosis KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nuclear Receptor Coactivator 2 KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Residence Characteristics KW - Risk Factors KW - Troponin T AB -

BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.

METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).

CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract ER - TY - JOUR T1 - Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. JF - JAMA Intern Med Y1 - 2013 A1 - Chen, Lin Y A1 - Sotoodehnia, Nona A1 - Bůzková, Petra A1 - Lopez, Faye L A1 - Yee, Laura M A1 - Heckbert, Susan R A1 - Prineas, Ronald A1 - Soliman, Elsayed Z A1 - Adabag, Selcuk A1 - Konety, Suma A1 - Folsom, Aaron R A1 - Siscovick, David A1 - Alonso, Alvaro KW - Aged KW - Atrial Fibrillation KW - Cardiovascular Diseases KW - Death, Sudden, Cardiac KW - Demography KW - Ethnic Groups KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - United States AB -

BACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.

METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.

RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.

CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

VL - 173 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23404043?dopt=Abstract ER - TY - JOUR T1 - Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. JF - PLoS One Y1 - 2013 A1 - Grove, Megan L A1 - Yu, Bing A1 - Cochran, Barbara J A1 - Haritunians, Talin A1 - Bis, Joshua C A1 - Taylor, Kent D A1 - Hansen, Mark A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Kathiresan, Sekar A1 - Kraaij, Robert A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Mosley, Thomas A1 - Peloso, Gina M A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Siscovick, David S A1 - Smith, Albert V A1 - Uitterlinden, Andre A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Boerwinkle, Eric KW - Aging KW - Alleles KW - Cluster Analysis KW - Cohort Studies KW - Continental Population Groups KW - Exome KW - Female KW - Gene Frequency KW - Genomics KW - Genotype KW - Heart KW - Humans KW - Male KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Sample Size KW - Self Report KW - Sequence Analysis, DNA AB -

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract ER - TY - JOUR T1 - Bidirectional relationship between cognitive function and pneumonia. JF - Am J Respir Crit Care Med Y1 - 2013 A1 - Shah, Faraaz Ali A1 - Pike, Francis A1 - Alvarez, Karina A1 - Angus, Derek A1 - Newman, Anne B A1 - Lopez, Oscar A1 - Tate, Judith A1 - Kapur, Vishesh A1 - Wilsdon, Anthony A1 - Krishnan, Jerry A A1 - Hansel, Nadia A1 - Au, David A1 - Avdalovic, Mark A1 - Fan, Vincent S A1 - Barr, R Graham A1 - Yende, Sachin KW - Aged KW - Cognition Disorders KW - Dementia KW - Female KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Pneumonia KW - Proportional Hazards Models KW - Risk Factors AB -

RATIONALE: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems.

OBJECTIVES: To determine bidirectional relationships between cognition and pneumonia.

METHODS: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate.

MEASUREMENTS AND MAIN RESULTS: Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections.

CONCLUSIONS: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.

VL - 188 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23848267?dopt=Abstract ER - TY - JOUR T1 - Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. JF - Am J Clin Nutr Y1 - 2013 A1 - van Meurs, Joyce B J A1 - Paré, Guillaume A1 - Schwartz, Stephen M A1 - Hazra, Aditi A1 - Tanaka, Toshiko A1 - Vermeulen, Sita H A1 - Cotlarciuc, Ioana A1 - Yuan, Xin A1 - Mälarstig, Anders A1 - Bandinelli, Stefania A1 - Bis, Joshua C A1 - Blom, Henk A1 - Brown, Morris J A1 - Chen, Constance A1 - Chen, Yii-Der A1 - Clarke, Robert J A1 - Dehghan, Abbas A1 - Erdmann, Jeanette A1 - Ferrucci, Luigi A1 - Hamsten, Anders A1 - Hofman, Albert A1 - Hunter, David J A1 - Goel, Anuj A1 - Johnson, Andrew D A1 - Kathiresan, Sekar A1 - Kampman, Ellen A1 - Kiel, Douglas P A1 - Kiemeney, Lambertus A L M A1 - Chambers, John C A1 - Kraft, Peter A1 - Lindemans, Jan A1 - McKnight, Barbara A1 - Nelson, Christopher P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Seedorf, Udo A1 - Siscovick, David S A1 - Schunkert, Heribert A1 - Selhub, Jacob A1 - Ueland, Per M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waterworth, Dawn M A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - den Heijer, Martin A1 - Jacques, Paul A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Rader, Dan J A1 - Reilly, Muredach P A1 - Mooser, Vincent A1 - Chasman, Daniel I A1 - Samani, Nilesh J A1 - Ahmadi, Kourosh R KW - Coronary Artery Disease KW - Genes KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Homocysteine KW - Humans KW - Polymorphism, Genetic KW - Risk Factors AB -

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.

OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.

DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.

RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).

CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

VL - 98 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23824729?dopt=Abstract ER - TY - JOUR T1 - Common variants associated with plasma triglycerides and risk for coronary artery disease. JF - Nat Genet Y1 - 2013 A1 - Do, Ron A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Gao, Chi A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Eyjolfsson, Gudmundur Ingi A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Altshuler, David A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R A1 - Daly, Mark J A1 - Neale, Benjamin M A1 - Kathiresan, Sekar KW - Biological Transport KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Triglycerides AB -

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

VL - 45 IS - 11 ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

VL - 45 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract ER - TY - JOUR T1 - Epidemiology and long-term clinical and biologic risk factors for pneumonia in community-dwelling older Americans: analysis of three cohorts. JF - Chest Y1 - 2013 A1 - Yende, Sachin A1 - Alvarez, Karina A1 - Loehr, Laura A1 - Folsom, Aaron R A1 - Newman, Anne B A1 - Weissfeld, Lisa A A1 - Wunderink, Richard G A1 - Kritchevsky, Stephen B A1 - Mukamal, Kenneth J A1 - London, Stephanie J A1 - Harris, Tamara B A1 - Bauer, Doug C A1 - Angus, Derek C KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Community-Acquired Infections KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Hospitalization KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Pneumonia KW - Prognosis KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Survival Rate KW - Time Factors AB -

BACKGROUND: Preventing pneumonia requires better understanding of incidence, mortality, and long-term clinical and biologic risk factors, particularly in younger individuals.

METHODS: This was a cohort study in three population-based cohorts of community-dwelling individuals. A derivation cohort (n = 16,260) was used to determine incidence and survival and develop a risk prediction model. The prediction model was validated in two cohorts (n = 8,495). The primary outcome was 10-year risk of pneumonia hospitalization.

RESULTS: The crude and age-adjusted incidences of pneumonia were 6.71 and 9.43 cases/1,000 person-years (10-year risk was 6.15%). The 30-day and 1-year mortality were 16.5% and 31.5%. Although age was the most important risk factor (range of crude incidence rates, 1.69-39.13 cases/1,000 person-years for each 5-year increment from 45-85 years), 38% of pneumonia cases occurred in adults < 65 years of age. The 30-day and 1-year mortality were 12.5% and 25.7% in those < 65 years of age. Although most comorbidities were associated with higher risk of pneumonia, reduced lung function was the most important risk factor (relative risk = 6.61 for severe reduction based on FEV1 by spirometry). A clinical risk prediction model based on age, smoking, and lung function predicted 10-year risk (area under curve [AUC] = 0.77 and Hosmer-Lemeshow [HL] C statistic = 0.12). Model discrimination and calibration were similar in the internal validation cohort (AUC = 0.77; HL C statistic, 0.65) but lower in the external validation cohort (AUC = 0.62; HL C statistic, 0.45). The model also calibrated well in blacks and younger adults. C-reactive protein and IL-6 were associated with higher pneumonia risk but did not improve model performance.

CONCLUSIONS: Pneumonia hospitalization is common and associated with high mortality, even in younger healthy adults. Long-term risk of pneumonia can be predicted in community-dwelling adults with a simple clinical risk prediction model.

VL - 144 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23744106?dopt=Abstract ER - TY - JOUR T1 - Exploring psychosocial pathways between neighbourhood characteristics and stroke in older adults: the cardiovascular health study. JF - Age Ageing Y1 - 2013 A1 - Yan, Tingjian A1 - Escarce, José J A1 - Liang, Li-Jung A1 - Longstreth, W T A1 - Merkin, Sharon Stein A1 - Ovbiagele, Bruce A1 - Vassar, Stefanie D A1 - Seeman, Teresa A1 - Sarkisian, Catherine A1 - Brown, Arleen F KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Brain Ischemia KW - Depression KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Linear Models KW - Logistic Models KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Residence Characteristics KW - Risk Assessment KW - Risk Factors KW - Social Support KW - Socioeconomic Factors KW - Stroke KW - Time Factors KW - United States KW - Vulnerable Populations AB -

OBJECTIVES: to investigate whether psychosocial pathways mediate the association between neighbourhood socioeconomic disadvantage and stroke.

METHODS: prospective cohort study with a follow-up of 11.5 years.

SETTING: the Cardiovascular Health Study, a longitudinal population-based cohort study of older adults ≥65 years.

MEASUREMENTS: the primary outcome was adjudicated incident ischaemic stroke. Neighbourhood socioeconomic status (NSES) was measured using a composite of six census-tract variables. Psychosocial factors were assessed with standard measures for depression, social support and social networks.

RESULTS: of the 3,834 white participants with no prior stroke, 548 had an incident ischaemic stroke over the 11.5-year follow-up. Among whites, the incident stroke hazard ratio (HR) associated with living in the lowest relative to highest NSES quartile was 1.32 (95% CI = 1.01-1.73), in models adjusted for individual SES. Additional adjustment for psychosocial factors had a minimal effect on hazard of incident stroke (HR = 1.31, CI = 1.00-1.71). Associations between NSES and stroke incidence were not found among African-Americans (n = 785) in either partially or fully adjusted models.

CONCLUSIONS: psychosocial factors played a minimal role in mediating the effect of NSES on stroke incidence among white older adults.

VL - 42 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23264005?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

VL - 11 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract ER - TY - JOUR T1 - Genetic analysis of a population heavy drinking phenotype identifies risk variants in whites. JF - J Clin Psychopharmacol Y1 - 2013 A1 - Hamidovic, Ajna A1 - Goodloe, Robert J A1 - Young, Taylor R A1 - Styn, Mindi A A1 - Mukamal, Kenneth J A1 - Choquet, Helene A1 - Kasberger, Jay L A1 - Buxbaum, Sarah G A1 - Papanicolaou, George J A1 - White, Wendy A1 - Volcik, Kelly A1 - Spring, Bonnie A1 - Hitsman, Brian A1 - Levy, Daniel A1 - Jorgenson, Eric KW - Aged KW - Alcohol Drinking KW - Alcoholism KW - Case-Control Studies KW - European Continental Ancestry Group KW - Feasibility Studies KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk AB -

Genetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk. We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals--Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)--and in a separate cohort of related individuals--Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 × 10(-05)) with a P value in FHS of 0.042. The top variants in FHS were rs12249562 in cubulin (P = 3.03 × 10(-05)) and rs9839267 near cholecystokinin (P = 3.05 × 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses.

VL - 33 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23422394?dopt=Abstract ER - TY - JOUR T1 - Genetic loci for retinal arteriolar microcirculation. JF - PLoS One Y1 - 2013 A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Ikram, M Kamran A1 - Cotch, Mary Frances A1 - Li, Xiaohui A1 - Macgregor, Stuart A1 - Xie, Jing A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Mitchell, Paul A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - de Jong, Paulus T V M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Launer, Lenore J A1 - Attia, John A1 - Baird, Paul N A1 - Harrap, Stephen A1 - Holliday, Elizabeth G A1 - Inouye, Michael A1 - Rochtchina, Elena A1 - Scott, Rodney J A1 - Viswanathan, Ananth A1 - Li, Guo A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - Taylor, Kent D A1 - Hewitt, Alex W A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Sun, Cong A1 - Young, Terri L A1 - Mackey, David A A1 - van Zuydam, Natalie R A1 - Doney, Alex S F A1 - Palmer, Colin N A A1 - Morris, Andrew D A1 - Rotter, Jerome I A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Vingerling, Johannes R A1 - Siscovick, David S A1 - Wang, Jie Jin A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Arterioles KW - Chromosomes, Human, Pair 5 KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - MEF2 Transcription Factors KW - Microcirculation KW - Middle Aged KW - Models, Genetic KW - Retinal Vessels AB -

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

VL - 8 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Asa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - D'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association of body fat distribution in African ancestry populations suggests new loci. JF - PLoS Genet Y1 - 2013 A1 - Liu, Ching-Ti A1 - Monda, Keri L A1 - Taylor, Kira C A1 - Lange, Leslie A1 - Demerath, Ellen W A1 - Palmas, Walter A1 - Wojczynski, Mary K A1 - Ellis, Jaclyn C A1 - Vitolins, Mara Z A1 - Liu, Simin A1 - Papanicolaou, George J A1 - Irvin, Marguerite R A1 - Xue, Luting A1 - Griffin, Paula J A1 - Nalls, Michael A A1 - Adeyemo, Adebowale A1 - Liu, Jiankang A1 - Li, Guo A1 - Ruiz-Narvaez, Edward A A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Henderson, Brian E A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - Strom, Sara S A1 - Guo, Xiuqing A1 - Andrews, Jeanette S A1 - Sun, Yan V A1 - Mosley, Thomas H A1 - Yanek, Lisa R A1 - Shriner, Daniel A1 - Haritunians, Talin A1 - Rotter, Jerome I A1 - Speliotes, Elizabeth K A1 - Smith, Megan A1 - Rosenberg, Lynn A1 - Mychaleckyj, Josyf A1 - Nayak, Uma A1 - Spruill, Ida A1 - Garvey, W Timothy A1 - Pettaway, Curtis A1 - Nyante, Sarah A1 - Bandera, Elisa V A1 - Britton, Angela F A1 - Zonderman, Alan B A1 - Rasmussen-Torvik, Laura J A1 - Chen, Yii-Der Ida A1 - Ding, Jingzhong A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Zhao, Wei A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Kabagambe, Edmond A1 - Broeckel, Ulrich A1 - Chen, Guanjie A1 - Zhou, Jie A1 - Wassertheil-Smoller, Sylvia A1 - Neuhouser, Marian L A1 - Rampersaud, Evadnie A1 - Psaty, Bruce A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Kuller, Lewis H A1 - Ochs-Balcom, Heather M A1 - Johnson, Karen C A1 - Sucheston, Lara A1 - Ordovas, Jose M A1 - Palmer, Julie R A1 - Haiman, Christopher A A1 - McKnight, Barbara A1 - Howard, Barbara V A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Liu, Yongmei A1 - Allison, Matthew A A1 - Grant, Struan F A A1 - Burke, Gregory L A1 - Patel, Sanjay R A1 - Schreiner, Pamela J A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Taylor, Herman A1 - Sale, Michèle M A1 - Howard, Virginia A1 - Carlson, Christopher S A1 - Rotimi, Charles N A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Reiner, Alexander P A1 - Cupples, L Adrienne A1 - North, Kari E A1 - Fox, Caroline S KW - Adiposity KW - African Continental Ancestry Group KW - Body Fat Distribution KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

VL - 9 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Fox, Ervin R A1 - Musani, Solomon K A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Yu, Bing A1 - Ogunyankin, Kofo O A1 - Smith, Nicholas L A1 - Kutlar, Abdullah A1 - Glazer, Nicole L A1 - Post, Wendy S A1 - Paltoo, Dina N A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Duarte, Christine W A1 - Kardia, Sharon L A1 - Meyers, Kristin J A1 - Sun, Yan V A1 - Arnett, Donna K A1 - Patki, Amit A A1 - Sha, Jin A1 - Cui, Xiangqui A1 - Samdarshi, Tandaw E A1 - Penman, Alan D A1 - Bibbins-Domingo, Kirsten A1 - Bůzková, Petra A1 - Benjamin, Emelia J A1 - Bluemke, David A A1 - Morrison, Alanna C A1 - Heiss, Gerardo A1 - Carr, J Jeffrey A1 - Tracy, Russell P A1 - Mosley, Thomas H A1 - Taylor, Herman A A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cappola, Thomas P A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Cohort Studies KW - Diastole KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of depressive symptoms. JF - Biol Psychiatry Y1 - 2013 A1 - Hek, Karin A1 - Demirkan, Ayse A1 - Lahti, Jari A1 - Terracciano, Antonio A1 - Teumer, Alexander A1 - Cornelis, Marilyn C A1 - Amin, Najaf A1 - Bakshis, Erin A1 - Baumert, Jens A1 - Ding, Jingzhong A1 - Liu, Yongmei A1 - Marciante, Kristin A1 - Meirelles, Osorio A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Vogelzangs, Nicole A1 - Yu, Lei A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Bennett, David A A1 - Boomsma, Dorret A1 - Cannas, Alessandra A1 - Coker, Laura H A1 - de Geus, Eco A1 - De Jager, Philip L A1 - Diez-Roux, Ana V A1 - Purcell, Shaun A1 - Hu, Frank B A1 - Rimma, Eric B A1 - Hunter, David J A1 - Jensen, Majken K A1 - Curhan, Gary A1 - Rice, Kenneth A1 - Penman, Alan D A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Emeny, Rebecca A1 - Eriksson, Johan G A1 - Evans, Denis A A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Illig, Thomas A1 - Kardia, Sharon A1 - Kelly-Hayes, Margaret A1 - Koenen, Karestan A1 - Kraft, Peter A1 - Kuningas, Maris A1 - Massaro, Joseph M A1 - Melzer, David A1 - Mulas, Antonella A1 - Mulder, Cornelis L A1 - Murray, Anna A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Penninx, Brenda A1 - Petersmann, Astrid A1 - Pilling, Luke C A1 - Psaty, Bruce A1 - Rawal, Rajesh A1 - Reiman, Eric M A1 - Schulz, Andrea A1 - Shulman, Joshua M A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Sutin, Angelina R A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Widen, Elisabeth A1 - Yaffe, Kristine A1 - Zonderman, Alan B A1 - Cucca, Francesco A1 - Harris, Tamara A1 - Ladwig, Karl-Heinz A1 - Llewellyn, David J A1 - Räikkönen, Katri A1 - Tanaka, Toshiko A1 - van Duijn, Cornelia M A1 - Grabe, Hans J A1 - Launer, Lenore J A1 - Lunetta, Kathryn L A1 - Mosley, Thomas H A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Murabito, Joanne KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human, Pair 5 KW - Depression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

VL - 73 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. JF - Nat Genet Y1 - 2013 A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Mägi, Reedik A1 - Ganna, Andrea A1 - Wheeler, Eleanor A1 - Feitosa, Mary F A1 - Justice, Anne E A1 - Monda, Keri L A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gentilini, Davide A1 - Jackson, Anne U A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Willer, Cristen J A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Hu, Yi-Juan A1 - Lee, Sang Hong A1 - Liang, Liming A1 - Lin, Dan-Yu A1 - Min, Josine L A1 - Neale, Benjamin M A1 - Thorleifsson, Gudmar A1 - Yang, Jian A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - den Heijer, Martin A1 - Eklund, Niina A1 - Fischer, Krista A1 - Goel, Anuj A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Jarick, Ivonne A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - König, Inke R A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lamina, Claudia A1 - Lecoeur, Cécile A1 - Li, Guo A1 - Mangino, Massimo A1 - McArdle, Wendy L A1 - Medina-Gómez, Carolina A1 - Müller-Nurasyid, Martina A1 - Ngwa, Julius S A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Pechlivanis, Sonali A1 - Perola, Markus A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Rose, Lynda M A1 - Shi, Jianxin A1 - Shungin, Dmitry A1 - Smith, Albert Vernon A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Trip, Mieke D A1 - Tyrer, Jonathan A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Waite, Lindsay L A1 - Zhao, Jing Hua A1 - Absher, Devin A1 - Asselbergs, Folkert W A1 - Atalay, Mustafa A1 - Attwood, Antony P A1 - Balmforth, Anthony J A1 - Basart, Hanneke A1 - Beilby, John A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Connell, John M A1 - Cookson, William O A1 - de Faire, Ulf A1 - de Vegt, Femmie A1 - Dei, Mariano A1 - Dimitriou, Maria A1 - Edkins, Sarah A1 - Estrada, Karol A1 - Evans, David M A1 - Farrall, Martin A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Franke, Lude A1 - Frau, Francesca A1 - Gejman, Pablo V A1 - Grallert, Harald A1 - Grönberg, Henrik A1 - Gudnason, Vilmundur A1 - Hall, Alistair S A1 - Hall, Per A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Hebebrand, Johannes A1 - Homuth, Georg A1 - Hu, Frank B A1 - Hunt, Sarah E A1 - Hyppönen, Elina A1 - Iribarren, Carlos A1 - Jacobs, Kevin B A1 - Jansson, John-Olov A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Khaw, Kay-Tee A1 - Kivimaki, Mika A1 - Koenig, Wolfgang A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laitinen, Jaana H A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lind, Lars A1 - Lindström, Jaana A1 - Liu, Jianjun A1 - Liuzzi, Antonio A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Madden, Pamela A A1 - Magnusson, Patrik K A1 - Manunta, Paolo A1 - Marek, Diana A1 - März, Winfried A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Mooser, Vincent A1 - Mühleisen, Thomas W A1 - Munroe, Patricia B A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Navis, Gerjan A1 - Nicholson, George A1 - Nohr, Ellen A A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Palotie, Aarno A1 - Peden, John F A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Pütter, Carolin A1 - Radhakrishnan, Aparna A1 - Raitakari, Olli A1 - Rendon, Augusto A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Saaristo, Timo E A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Shin, So-Youn A1 - Signorini, Stefano A1 - Sinisalo, Juha A1 - Skrobek, Boris A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Stark, Klaus A1 - Stephens, Jonathan C A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Stumvoll, Michael A1 - Swift, Amy J A1 - Theodoraki, Eirini V A1 - Thorand, Barbara A1 - Trégouët, David-Alexandre A1 - Tremoli, Elena A1 - van der Klauw, Melanie M A1 - van Meurs, Joyce B J A1 - Vermeulen, Sita H A1 - Viikari, Jorma A1 - Virtamo, Jarmo A1 - Vitart, Veronique A1 - Waeber, Gérard A1 - Wang, Zhaoming A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Winkelmann, Bernhard R A1 - Witteman, Jacqueline C M A1 - Wolffenbuttel, Bruce H R A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Amouyel, Philippe A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Dedoussis, George V A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hingorani, Aroon A1 - Hinney, Anke A1 - Hofman, Albert A1 - Hovingh, Kees G A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Kuh, Diana A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Levinson, Douglas F A1 - Martin, Nicholas G A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nieminen, Markku S A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ouwehand, Willem H A1 - Palmer, Lyle J A1 - Penninx, Brenda A1 - Power, Chris A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Rauramaa, Rainer A1 - Ridker, Paul M A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Vollenweider, Peter A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunian, Talin A1 - Heid, Iris M A1 - Hunter, David A1 - Kaplan, Robert C A1 - Karpe, Fredrik A1 - Moffatt, Miriam F A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Pawitan, Yudi A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Steinthorsdottir, Valgerdur A1 - Strachan, David P A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Visscher, Peter M A1 - Di Blasio, Anna Maria A1 - Hirschhorn, Joel N A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Meyre, David A1 - Scherag, Andre A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Loos, Ruth J F A1 - Ingelsson, Erik KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Meta-Analysis as Topic KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Waist-Hip Ratio AB -

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. JF - Am J Clin Nutr Y1 - 2013 A1 - Tanaka, Toshiko A1 - Ngwa, Julius S A1 - van Rooij, Frank J A A1 - Zillikens, M Carola A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Luan, Jian'an A1 - Mikkilä, Vera A1 - Renstrom, Frida A1 - Sonestedt, Emily A1 - Zhao, Jing Hua A1 - Chu, Audrey Y A1 - Qi, Lu A1 - Chasman, Daniel I A1 - de Oliveira Otto, Marcia C A1 - Dhurandhar, Emily J A1 - Feitosa, Mary F A1 - Johansson, Ingegerd A1 - Khaw, Kay-Tee A1 - Lohman, Kurt K A1 - Manichaikul, Ani A1 - McKeown, Nicola M A1 - Mozaffarian, Dariush A1 - Singleton, Andrew A1 - Stirrups, Kathleen A1 - Viikari, Jorma A1 - Ye, Zheng A1 - Bandinelli, Stefania A1 - Barroso, Inês A1 - Deloukas, Panos A1 - Forouhi, Nita G A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - North, Kari E A1 - Dimitriou, Maria A1 - Hallmans, Göran A1 - Kähönen, Mika A1 - Langenberg, Claudia A1 - Ordovas, Jose M A1 - Uitterlinden, André G A1 - Hu, Frank B A1 - Kalafati, Ioanna-Panagiota A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Johnson, Andrew A1 - Emilsson, Valur A1 - Schrack, Jennifer A A1 - Semba, Richard D A1 - Siscovick, David S A1 - Arnett, Donna K A1 - Borecki, Ingrid B A1 - Franks, Paul W A1 - Kritchevsky, Stephen B A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Orho-Melander, Marju A1 - Rotter, Jerome I A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Ferrucci, Luigi A1 - Dedoussis, George A1 - Cupples, L Adrienne A1 - Nettleton, Jennifer A KW - Alleles KW - Atherosclerosis KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fibroblast Growth Factors KW - Follow-Up Studies KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Life Style KW - Obesity KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Quantitative Trait Loci KW - Surveys and Questionnaires AB -

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract ER - TY - JOUR T1 - Height and risk of incident intraparenchymal hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health study cohorts. JF - J Stroke Cerebrovasc Dis Y1 - 2013 A1 - Smith, Lindsay G A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Folsom, Aaron R KW - African Americans KW - Aged KW - Body Height KW - Cerebral Hemorrhage KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States AB -

BACKGROUND: Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage (IPH). We hypothesized that height would be inversely associated with incident IPH in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.

METHODS: Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident IPH verified by clinician review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.

RESULTS: A total of 20,983 participants initially free of stroke (11,788 women and 9195 men) were followed for an average of 15.9 years (standard deviation [SD] 5.1 years). Incident IPH occurred in 115 women and 73 men. Sex, but not age, race, study, or blood pressure, modified the association (P = .03). After adjustment for risk factors (age, systolic blood pressure, triglycerides, low-density lipoprotein cholesterol, fibrinogen, and race), among women, height was significantly inversely associated with incident IPH (hazard ratio [HR] per SD [6.3 cm] was 0.81; 95% confidence interval [CI] 0.66-0.99; P = .04). The HR for tertile 3 vs 1 in women was 0.63 (95% CI 0.37-1.08). Among men, height was not linearly associated with incident IPH (HR per SD [6.7 cm] was 1.09; 95% CI 0.84-1.40; P = .52).

CONCLUSIONS: This large prospective study provides evidence that shorter height may be a risk factor for incident IPH in women.

VL - 22 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22177930?dopt=Abstract ER - TY - JOUR T1 - Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. JF - J Nutr Y1 - 2013 A1 - Hruby, Adela A1 - Ngwa, Julius S A1 - Renstrom, Frida A1 - Wojczynski, Mary K A1 - Ganna, Andrea A1 - Hallmans, Göran A1 - Houston, Denise K A1 - Jacques, Paul F A1 - Kanoni, Stavroula A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Sonestedt, Emily A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Bandinelli, Stefania A1 - Djoussé, Luc A1 - Grigoriou, Efi A1 - Johansson, Ingegerd A1 - Lohman, Kurt K A1 - Pankow, James S A1 - Raitakari, Olli T A1 - Riserus, Ulf A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Hassanali, Neelam A1 - Liu, Yongmei A1 - Mozaffarian, Dariush A1 - Papoutsakis, Constantina A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Groves, Christopher J A1 - Hofman, Albert A1 - Lind, Lars A1 - McCarthy, Mark I A1 - Mikkilä, Vera A1 - Mukamal, Kenneth A1 - Franco, Oscar H A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Dedoussis, George V A1 - Ferrucci, Luigi A1 - Hu, Frank B A1 - Ingelsson, Erik A1 - Kähönen, Mika A1 - Kao, W H Linda A1 - Kritchevsky, Stephen B A1 - Orho-Melander, Marju A1 - Prokopenko, Inga A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Witteman, Jacqueline C M A1 - Franks, Paul W A1 - Meigs, James B A1 - McKeown, Nicola M A1 - Nettleton, Jennifer A KW - Blood Glucose KW - Female KW - Genetic Loci KW - Humans KW - Insulin KW - Magnesium KW - Male KW - Polymorphism, Single Nucleotide KW - Trace Elements KW - TRPM Cation Channels AB -

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

VL - 143 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23343670?dopt=Abstract ER - TY - JOUR T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. JF - Nat Genet Y1 - 2013 A1 - den Hoed, Marcel A1 - Eijgelsheim, Mark A1 - Esko, Tõnu A1 - Brundel, Bianca J J M A1 - Peal, David S A1 - Evans, David M A1 - Nolte, Ilja M A1 - Segrè, Ayellet V A1 - Holm, Hilma A1 - Handsaker, Robert E A1 - Westra, Harm-Jan A1 - Johnson, Toby A1 - Isaacs, Aaron A1 - Yang, Jian A1 - Lundby, Alicia A1 - Zhao, Jing Hua A1 - Kim, Young Jin A1 - Go, Min Jin A1 - Almgren, Peter A1 - Bochud, Murielle A1 - Boucher, Gabrielle A1 - Cornelis, Marilyn C A1 - Gudbjartsson, Daniel A1 - Hadley, David A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - den Heijer, Martin A1 - Igl, Wilmar A1 - Jackson, Anne U A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Kemp, John P A1 - Kristiansson, Kati A1 - Ladenvall, Claes A1 - Lorentzon, Mattias A1 - Montasser, May E A1 - Njajou, Omer T A1 - O'Reilly, Paul F A1 - Padmanabhan, Sandosh A1 - St Pourcain, Beate A1 - Rankinen, Tuomo A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - Timpson, Nicholas J A1 - Vitart, Veronique A1 - Waite, Lindsay A1 - Wheeler, William A1 - Zhang, Weihua A1 - Draisma, Harmen H M A1 - Feitosa, Mary F A1 - Kerr, Kathleen F A1 - Lind, Penelope A A1 - Mihailov, Evelin A1 - Onland-Moret, N Charlotte A1 - Song, Ci A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Yengo, Loic A1 - Absher, Devin A1 - Albert, Christine M A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - de Bakker, Paul I W A1 - Balkau, Beverley A1 - Barlassina, Cristina A1 - Benaglio, Paola A1 - Bis, Joshua C A1 - Bouatia-Naji, Nabila A1 - Brage, Søren A1 - Chanock, Stephen J A1 - Chines, Peter S A1 - Chung, Mina A1 - Darbar, Dawood A1 - Dina, Christian A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Felix, Stephan B A1 - Fischer, Krista A1 - Fuchsberger, Christian A1 - de Geus, Eco J C A1 - Goyette, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Hoogstra-Berends, Femke A1 - Hottenga, Jouke-Jan A1 - Jensen, Majken K A1 - Johansson, Asa A1 - Junttila, Juhani A1 - Kääb, Stefan A1 - Kanon, Bart A1 - Ketkar, Shamika A1 - Khaw, Kay-Tee A1 - Knowles, Joshua W A1 - Kooner, Angrad S A1 - Kors, Jan A A1 - Kumari, Meena A1 - Milani, Lili A1 - Laiho, Päivi A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Leusink, Maarten A1 - Liu, Yongmei A1 - Luben, Robert N A1 - Lunetta, Kathryn L A1 - Lynch, Stacey N A1 - Markus, Marcello R P A1 - Marques-Vidal, Pedro A1 - Mateo Leach, Irene A1 - McArdle, Wendy L A1 - McCarroll, Steven A A1 - Medland, Sarah E A1 - Miller, Kathryn A A1 - Montgomery, Grant W A1 - Morrison, Alanna C A1 - Müller-Nurasyid, Martina A1 - Navarro, Pau A1 - Nelis, Mari A1 - O'Connell, Jeffrey R A1 - O'Donnell, Christopher J A1 - Ong, Ken K A1 - Newman, Anne B A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Ring, Susan M A1 - Rossin, Elizabeth J A1 - Rudan, Diana A1 - Sanna, Serena A1 - Scott, Robert A A1 - Sehmi, Jaban S A1 - Sharp, Stephen A1 - Shin, Jordan T A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Stewart, Chip A1 - Stringham, Heather M A1 - Tarasov, Kirill V A1 - Uitterlinden, André G A1 - Vandenput, Liesbeth A1 - Hwang, Shih-Jen A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Wong, Andrew A1 - Wong, Quenna A1 - Jamshidi, Yalda A1 - Zitting, Paavo A1 - Boer, Jolanda M A A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Ekelund, Ulf A1 - Forouhi, Nita G A1 - Froguel, Philippe A1 - Hingorani, Aroon A1 - Ingelsson, Erik A1 - Kivimaki, Mika A1 - Kronmal, Richard A A1 - Kuh, Diana A1 - Lind, Lars A1 - Martin, Nicholas G A1 - Oostra, Ben A A1 - Pedersen, Nancy L A1 - Quertermous, Thomas A1 - Rotter, Jerome I A1 - van der Schouw, Yvonne T A1 - Verschuren, W M Monique A1 - Walker, Mark A1 - Albanes, Demetrius A1 - Arnar, David O A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Boehnke, Michael A1 - de Boer, Rudolf A A1 - Bouchard, Claude A1 - Caulfield, W L Mark A1 - Chambers, John C A1 - Curhan, Gary A1 - Cusi, Daniele A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - van Gilst, Wiek H A1 - Glorioso, Nicola A1 - de Graaf, Jacqueline A1 - Groop, Leif A1 - Gyllensten, Ulf A1 - Hsueh, Wen-Chi A1 - Hu, Frank B A1 - Huikuri, Heikki V A1 - Hunter, David J A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kiemeney, Lambertus A A1 - van der Klauw, Melanie M A1 - Kooner, Jaspal S A1 - Kraft, Peter A1 - Iacoviello, Licia A1 - Lehtimäki, Terho A1 - Lokki, Marja-Liisa L A1 - Mitchell, Braxton D A1 - Navis, Gerjan A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Poulter, Neil R A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rimm, Eric B A1 - Rioux, John D A1 - Rizzi, Federica A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Sever, Peter S A1 - Shields, Denis C A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stanton, Alice V A1 - Stolk, Ronald P A1 - Strachan, David P A1 - Tardif, Jean-Claude A1 - Thorsteinsdottir, Unnur A1 - Tuomilehto, Jaako A1 - van Veldhuisen, Dirk J A1 - Virtamo, Jarmo A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Cho, Yoon Shin A1 - Olsen, Jesper V A1 - Visscher, Peter M A1 - Willer, Cristen A1 - Franke, Lude A1 - Erdmann, Jeanette A1 - Thompson, John R A1 - Pfeufer, Arne A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Ellinor, Patrick T A1 - Stricker, Bruno H Ch A1 - Metspalu, Andres A1 - Perola, Markus A1 - Beckmann, Jacques S A1 - Smith, George Davey A1 - Stefansson, Kari A1 - Wareham, Nicholas J A1 - Munroe, Patricia B A1 - Sibon, Ody C M A1 - Milan, David J A1 - Snieder, Harold A1 - Samani, Nilesh J A1 - Loos, Ruth J F KW - Animals KW - Arrhythmias, Cardiac KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Heart Rate KW - Humans KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

VL - 45 IS - 6 ER - TY - JOUR T1 - Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study. JF - Atherosclerosis Y1 - 2013 A1 - Tehrani, David M A1 - Gardin, Julius M A1 - Yanez, David A1 - Hirsch, Calvin H A1 - Lloyd-Jones, Donald M A1 - Stein, Phyllis K A1 - Wong, Nathan D KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Inflammation KW - Interleukin-6 KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers' individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA₂) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA₂ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA₂ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA₂ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

VL - 231 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24267235?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies. JF - Int J Obes (Lond) Y1 - 2013 A1 - Smith, C E A1 - Ngwa, J A1 - Tanaka, T A1 - Qi, Q A1 - Wojczynski, M K A1 - Lemaitre, R N A1 - Anderson, J S A1 - Manichaikul, A A1 - Mikkilä, V A1 - van Rooij, F J A A1 - Ye, Z A1 - Bandinelli, S A1 - Frazier-Wood, A C A1 - Houston, D K A1 - Hu, F A1 - Langenberg, C A1 - McKeown, N M A1 - Mozaffarian, D A1 - North, K E A1 - Viikari, J A1 - Zillikens, M C A1 - Djoussé, L A1 - Hofman, A A1 - Kähönen, M A1 - Kabagambe, E K A1 - Loos, R J F A1 - Saylor, G B A1 - Forouhi, N G A1 - Liu, Y A1 - Mukamal, K J A1 - Chen, Y-D I A1 - Tsai, M Y A1 - Uitterlinden, A G A1 - Raitakari, O A1 - van Duijn, C M A1 - Arnett, D K A1 - Borecki, I B A1 - Cupples, L A A1 - Ferrucci, L A1 - Kritchevsky, S B A1 - Lehtimäki, T A1 - Qi, Lu A1 - Rotter, J I A1 - Siscovick, D S A1 - Wareham, N J A1 - Witteman, J C M A1 - Ordovás, J M A1 - Nettleton, J A KW - Adipose Tissue KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Europe KW - European Continental Ancestry Group KW - Fatty Acids KW - Female KW - Gene Frequency KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-1 KW - Male KW - Middle Aged KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prevalence KW - United States AB -

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.

DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).

RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.

CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

VL - 37 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23357958?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. JF - Nat Genet Y1 - 2013 A1 - Monda, Keri L A1 - Chen, Gary K A1 - Taylor, Kira C A1 - Palmer, Cameron A1 - Edwards, Todd L A1 - Lange, Leslie A A1 - Ng, Maggie C Y A1 - Adeyemo, Adebowale A A1 - Allison, Matthew A A1 - Bielak, Lawrence F A1 - Chen, Guanjie A1 - Graff, Mariaelisa A1 - Irvin, Marguerite R A1 - Rhie, Suhn K A1 - Li, Guo A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Lu, Yingchang A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Aldrich, Melinda C A1 - Ademola, Adeyinka A1 - Amos, Christopher I A1 - Bandera, Elisa V A1 - Bock, Cathryn H A1 - Britton, Angela A1 - Broeckel, Ulrich A1 - Cai, Quiyin A1 - Caporaso, Neil E A1 - Carlson, Chris S A1 - Carpten, John A1 - Casey, Graham A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Chen, Yii-der I A1 - Chiang, Charleston W K A1 - Coetzee, Gerhard A A1 - Demerath, Ellen A1 - Deming-Halverson, Sandra L A1 - Driver, Ryan W A1 - Dubbert, Patricia A1 - Feitosa, Mary F A1 - Feng, Ye A1 - Freedman, Barry I A1 - Gillanders, Elizabeth M A1 - Gottesman, Omri A1 - Guo, Xiuqing A1 - Haritunians, Talin A1 - Harris, Tamara A1 - Harris, Curtis C A1 - Hennis, Anselm J M A1 - Hernandez, Dena G A1 - McNeill, Lorna H A1 - Howard, Timothy D A1 - Howard, Barbara V A1 - Howard, Virginia J A1 - Johnson, Karen C A1 - Kang, Sun J A1 - Keating, Brendan J A1 - Kolb, Suzanne A1 - Kuller, Lewis H A1 - Kutlar, Abdullah A1 - Langefeld, Carl D A1 - Lettre, Guillaume A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lyon, Helen A1 - Manson, JoAnn E A1 - Maixner, William A1 - Meng, Yan A A1 - Monroe, Kristine R A1 - Morhason-Bello, Imran A1 - Murphy, Adam B A1 - Mychaleckyj, Josyf C A1 - Nadukuru, Rajiv A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Wu, Suh-Yuh A1 - Leske, M Cristina A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogunniyi, Adesola A1 - Ogundiran, Temidayo O A1 - Ojengbede, Oladosu A1 - Olopade, Olufunmilayo I A1 - Palmer, Julie R A1 - Ruiz-Narvaez, Edward A A1 - Palmer, Nicholette D A1 - Press, Michael F A1 - Rampersaud, Evandine A1 - Rasmussen-Torvik, Laura J A1 - Rodriguez-Gil, Jorge L A1 - Salako, Babatunde A1 - Schadt, Eric E A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Siscovick, David A1 - Smith, Shad B A1 - Wassertheil-Smoller, Sylvia A1 - Speliotes, Elizabeth K A1 - Spitz, Margaret R A1 - Sucheston, Lara A1 - Taylor, Herman A1 - Tayo, Bamidele O A1 - Tucker, Margaret A A1 - Van Den Berg, David J A1 - Edwards, Digna R Velez A1 - Wang, Zhaoming A1 - Wiencke, John K A1 - Winkler, Thomas W A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yang, James J A1 - Levin, Albert M A1 - Young, Taylor R A1 - Zakai, Neil A A1 - Cushman, Mary A1 - Zanetti, Krista A A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zheng, Yonglan A1 - Zhou, Jie A1 - Ziegler, Regina G A1 - Zmuda, Joseph M A1 - Fernandes, Jyotika K A1 - Gilkeson, Gary S A1 - Kamen, Diane L A1 - Hunt, Kelly J A1 - Spruill, Ida J A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Borecki, Ingrid B A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Burke, Gregory A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - Ding, Jingzhong A1 - Duggan, David A1 - Evans, Michele K A1 - Fox, Caroline A1 - Garvey, W Timothy A1 - Bradfield, Jonathan P A1 - Hakonarson, Hakon A1 - Grant, Struan F A A1 - Hsing, Ann A1 - Chu, Lisa A1 - Hu, Jennifer J A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - John, Esther M A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kardia, Sharon L R A1 - Kittles, Rick A A1 - Goodman, Phyllis J A1 - Klein, Eric A A1 - Kolonel, Laurence N A1 - Le Marchand, Loïc A1 - Liu, Simin A1 - McKnight, Barbara A1 - Millikan, Robert C A1 - Mosley, Thomas H A1 - Padhukasahasram, Badri A1 - Williams, L Keoki A1 - Patel, Sanjay R A1 - Peters, Ulrike A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotimi, Charles N A1 - Rybicki, Benjamin A A1 - Sale, Michèle M A1 - Schreiner, Pamela J A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Stanford, Janet L A1 - Strom, Sara S A1 - Thun, Michael J A1 - Vitolins, Mara A1 - Zheng, Wei A1 - Moore, Jason H A1 - Williams, Scott M A1 - Ketkar, Shamika A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Henderson, Brian E A1 - Reiner, Alex P A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A KW - African Americans KW - Body Mass Index KW - Case-Control Studies KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

VL - 45 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. JF - Nat Genet Y1 - 2013 A1 - Lambert, J C A1 - Ibrahim-Verbaas, C A A1 - Harold, D A1 - Naj, A C A1 - Sims, R A1 - Bellenguez, C A1 - DeStafano, A L A1 - Bis, J C A1 - Beecham, G W A1 - Grenier-Boley, B A1 - Russo, G A1 - Thorton-Wells, T A A1 - Jones, N A1 - Smith, A V A1 - Chouraki, V A1 - Thomas, C A1 - Ikram, M A A1 - Zelenika, D A1 - Vardarajan, B N A1 - Kamatani, Y A1 - Lin, C F A1 - Gerrish, A A1 - Schmidt, H A1 - Kunkle, B A1 - Dunstan, M L A1 - Ruiz, A A1 - Bihoreau, M T A1 - Choi, S H A1 - Reitz, C A1 - Pasquier, F A1 - Cruchaga, C A1 - Craig, D A1 - Amin, N A1 - Berr, C A1 - Lopez, O L A1 - De Jager, P L A1 - Deramecourt, V A1 - Johnston, J A A1 - Evans, D A1 - Lovestone, S A1 - Letenneur, L A1 - Morón, F J A1 - Rubinsztein, D C A1 - Eiriksdottir, G A1 - Sleegers, K A1 - Goate, A M A1 - Fiévet, N A1 - Huentelman, M W A1 - Gill, M A1 - Brown, K A1 - Kamboh, M I A1 - Keller, L A1 - Barberger-Gateau, P A1 - McGuiness, B A1 - Larson, E B A1 - Green, R A1 - Myers, A J A1 - Dufouil, C A1 - Todd, S A1 - Wallon, D A1 - Love, S A1 - Rogaeva, E A1 - Gallacher, J A1 - St George-Hyslop, P A1 - Clarimon, J A1 - Lleo, A A1 - Bayer, A A1 - Tsuang, D W A1 - Yu, L A1 - Tsolaki, M A1 - Bossù, P A1 - Spalletta, G A1 - Proitsi, P A1 - Collinge, J A1 - Sorbi, S A1 - Sanchez-Garcia, F A1 - Fox, N C A1 - Hardy, J A1 - Deniz Naranjo, M C A1 - Bosco, P A1 - Clarke, R A1 - Brayne, C A1 - Galimberti, D A1 - Mancuso, M A1 - Matthews, F A1 - Moebus, S A1 - Mecocci, P A1 - Del Zompo, M A1 - Maier, W A1 - Hampel, H A1 - Pilotto, A A1 - Bullido, M A1 - Panza, F A1 - Caffarra, P A1 - Nacmias, B A1 - Gilbert, J R A1 - Mayhaus, M A1 - Lannefelt, L A1 - Hakonarson, H A1 - Pichler, S A1 - Carrasquillo, M M A1 - Ingelsson, M A1 - Beekly, D A1 - Alvarez, V A1 - Zou, F A1 - Valladares, O A1 - Younkin, S G A1 - Coto, E A1 - Hamilton-Nelson, K L A1 - Gu, W A1 - Razquin, C A1 - Pastor, P A1 - Mateo, I A1 - Owen, M J A1 - Faber, K M A1 - Jonsson, P V A1 - Combarros, O A1 - O'Donovan, M C A1 - Cantwell, L B A1 - Soininen, H A1 - Blacker, D A1 - Mead, S A1 - Mosley, T H A1 - Bennett, D A A1 - Harris, T B A1 - Fratiglioni, L A1 - Holmes, C A1 - de Bruijn, R F A1 - Passmore, P A1 - Montine, T J A1 - Bettens, K A1 - Rotter, J I A1 - Brice, A A1 - Morgan, K A1 - Foroud, T M A1 - Kukull, W A A1 - Hannequin, D A1 - Powell, J F A1 - Nalls, M A A1 - Ritchie, K A1 - Lunetta, K L A1 - Kauwe, J S A1 - Boerwinkle, E A1 - Riemenschneider, M A1 - Boada, M A1 - Hiltuenen, M A1 - Martin, E R A1 - Schmidt, R A1 - Rujescu, D A1 - Wang, L S A1 - Dartigues, J F A1 - Mayeux, R A1 - Tzourio, C A1 - Hofman, A A1 - Nöthen, M M A1 - Graff, C A1 - Psaty, B M A1 - Jones, L A1 - Haines, J L A1 - Holmans, P A A1 - Lathrop, M A1 - Pericak-Vance, M A A1 - Launer, L J A1 - Farrer, L A A1 - van Duijn, C M A1 - Van Broeckhoven, C A1 - Moskvina, V A1 - Seshadri, S A1 - Williams, J A1 - Schellenberg, G D A1 - Amouyel, P KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

VL - 45 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. JF - Circulation Y1 - 2013 A1 - Sabater-Lleal, Maria A1 - Huang, Jie A1 - Chasman, Daniel A1 - Naitza, Silvia A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Teumer, Alexander A1 - Reiner, Alex P A1 - Folkersen, Lasse A1 - Basu, Saonli A1 - Rudnicka, Alicja R A1 - Trompet, Stella A1 - Mälarstig, Anders A1 - Baumert, Jens A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Hottenga, Jouke J A1 - Shin, So-Youn A1 - Lopez, Lorna M A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Oudot-Mellakh, Tiphaine A1 - Wilson, James F A1 - Navarro, Pau A1 - Huffman, Jennifer E A1 - Zemunik, Tatijana A1 - Redline, Susan A1 - Mehra, Reena A1 - Pulanic, Drazen A1 - Rudan, Igor A1 - Wright, Alan F A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Curb, J David A1 - Wallace, Robert A1 - Liu, Simin A1 - Eaton, Charles B A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Bandinelli, Stefania A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Fornage, Myriam A1 - Green, David A1 - Gross, Myron A1 - Davies, Gail A1 - Harris, Sarah E A1 - Liewald, David C A1 - Starr, John M A1 - Williams, Frances M K A1 - Grant, Peter J A1 - Spector, Timothy D A1 - Strawbridge, Rona J A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofman, Albert A1 - van Dongen, Jenny A1 - Willemsen, Gonneke A1 - Boomsma, Dorret I A1 - Yao, Jie A1 - Swords Jenny, Nancy A1 - Haritunians, Talin A1 - McKnight, Barbara A1 - Lumley, Thomas A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Gieger, Christian A1 - Illig, Thomas A1 - Grotevendt, Anne A1 - Homuth, Georg A1 - Völzke, Henry A1 - Kocher, Thomas A1 - Goel, Anuj A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Clarke, Robert A1 - Steri, Maristella A1 - Tarasov, Kirill V A1 - Sanna, Serena A1 - Schlessinger, David A1 - Stott, David J A1 - Sattar, Naveed A1 - Buckley, Brendan M A1 - Rumley, Ann A1 - Lowe, Gordon D A1 - McArdle, Wendy L A1 - Chen, Ming-Huei A1 - Tofler, Geoffrey H A1 - Song, Jaejoon A1 - Boerwinkle, Eric A1 - Folsom, Aaron R A1 - Rose, Lynda M A1 - Franco-Cereceda, Anders A1 - Teichert, Martina A1 - Ikram, M Arfan A1 - Mosley, Thomas H A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M A1 - Sudlow, Cathie L M A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Kooner, Jaspal S A1 - Danesh, John A1 - Nelson, Christopher P A1 - Erdmann, Jeanette A1 - Reilly, Muredach P A1 - Kathiresan, Sekar A1 - Schunkert, Heribert A1 - Morange, Pierre-Emmanuel A1 - Ferrucci, Luigi A1 - Eriksson, Johan G A1 - Jacobs, David A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - de Geus, Eco J C A1 - Tracy, Russell P A1 - Hayward, Caroline A1 - Koenig, Wolfgang A1 - Cucca, Francesco A1 - Jukema, J Wouter A1 - Eriksson, Per A1 - Seshadri, Sudha A1 - Markus, Hugh S A1 - Watkins, Hugh A1 - Samani, Nilesh J A1 - Wallaschofski, Henri A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Ridker, Paul M A1 - Tang, Weihong A1 - Strachan, David P A1 - Hamsten, Anders A1 - O'Donnell, Christopher J KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Venous Thromboembolism KW - Young Adult AB -

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

VL - 128 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract ER - TY - JOUR T1 - Neighborhood socioeconomic disadvantage and mortality after stroke. JF - Neurology Y1 - 2013 A1 - Brown, Arleen F A1 - Liang, Li-Jung A1 - Vassar, Stefanie D A1 - Merkin, Sharon Stein A1 - Longstreth, W T A1 - Ovbiagele, Bruce A1 - Yan, Tingjian A1 - Escarce, José J KW - Aged KW - Female KW - Humans KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Proportional Hazards Models KW - Residence Characteristics KW - Risk Factors KW - Socioeconomic Factors KW - Stroke KW - Vulnerable Populations AB -

OBJECTIVE: Residence in a socioeconomically disadvantaged community is associated with mortality, but the mechanisms are not well understood. We examined whether socioeconomic features of the residential neighborhood contribute to poststroke mortality and whether neighborhood influences are mediated by traditional behavioral and biologic risk factors.

METHODS: We used data from the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ≥65 years. Residential neighborhood disadvantage was measured using neighborhood socioeconomic status (NSES), a composite of 6 census tract variables representing income, education, employment, and wealth. Multilevel Cox proportional hazard models were constructed to determine the association of NSES to mortality after an incident stroke, adjusted for sociodemographic characteristics, stroke type, and behavioral and biologic risk factors.

RESULTS: Among the 3,834 participants with no prior stroke at baseline, 806 had a stroke over a mean 11.5 years of follow-up, with 168 (20%) deaths 30 days after stroke and 276 (34%) deaths at 1 year. In models adjusted for demographic characteristics, stroke type, and behavioral and biologic risk factors, mortality hazard 1 year after stroke was significantly higher among residents of neighborhoods with the lowest NSES than those in the highest NSES neighborhoods (hazard ratio 1.77, 95% confidence interval 1.17-2.68).

CONCLUSION: Living in a socioeconomically disadvantaged neighborhood is associated with higher mortality hazard at 1 year following an incident stroke. Further work is needed to understand the structural and social characteristics of neighborhoods that may contribute to mortality in the year after a stroke and the pathways through which these characteristics operate.

VL - 80 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23284071?dopt=Abstract ER - TY - JOUR T1 - Obesity is associated with a lower resting oxygen saturation in the ambulatory elderly: results from the cardiovascular health study. JF - Respir Care Y1 - 2013 A1 - Kapur, Vishesh K A1 - Wilsdon, Anthony G A1 - Au, David A1 - Avdalovic, Mark A1 - Enright, Paul A1 - Fan, Vincent S A1 - Hansel, Nadia N A1 - Heckbert, Susan R A1 - Jiang, Rui A1 - Krishnan, Jerry A A1 - Mukamal, Kenneth A1 - Yende, Sachin A1 - Barr, R Graham KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Obesity KW - Oximetry KW - Oxygen KW - Smoking KW - Waist Circumference AB -

BACKGROUND: The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population.

METHODS: The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated.

RESULTS: Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = -0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m(2) and ≥ 35 kg/m(2)) was 1.33% (95% CI 0.89-1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2-1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47-1.27, for African Americans).

CONCLUSIONS: We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2.

VL - 58 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23107018?dopt=Abstract ER - TY - JOUR T1 - Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Hum Reprod Y1 - 2013 A1 - Carty, C L A1 - Spencer, K L A1 - Setiawan, V W A1 - Fernandez-Rhodes, L A1 - Malinowski, J A1 - Buyske, S A1 - Young, A A1 - Jorgensen, N W A1 - Cheng, I A1 - Carlson, C S A1 - Brown-Gentry, K A1 - Goodloe, R A1 - Park, A A1 - Parikh, N I A1 - Henderson, B A1 - Le Marchand, L A1 - Wactawski-Wende, J A1 - Fornage, M A1 - Matise, T C A1 - Hindorff, L A A1 - Arnold, A M A1 - Haiman, C A A1 - Franceschini, N A1 - Peters, U A1 - Crawford, D C KW - Age Factors KW - Cross-Sectional Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Menarche KW - Menopause KW - Polymorphism, Single Nucleotide AB -

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?

SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.

WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.

STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.

MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.

MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.

LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.

WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

VL - 28 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23508249?dopt=Abstract ER - TY - JOUR T1 - Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. JF - PLoS Genet Y1 - 2013 A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Kutalik, Zoltán A1 - Berndt, Sonja I A1 - Jackson, Anne U A1 - Monda, Keri L A1 - Kilpeläinen, Tuomas O A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Li, Shengxu A1 - Workalemahu, Tsegaselassie A1 - Feitosa, Mary F A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Locke, Adam E A1 - Mathieson, Iain A1 - Scherag, Andre A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Liang, Liming A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Dermitzakis, Emmanouil T A1 - Dimas, Antigone S A1 - Karpe, Fredrik A1 - Min, Josine L A1 - Nicholson, George A1 - Clegg, Deborah J A1 - Person, Thomas A1 - Krohn, Jon P A1 - Bauer, Sabrina A1 - Buechler, Christa A1 - Eisinger, Kristina A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Hottenga, Jouke-Jan A1 - Prokopenko, Inga A1 - Waite, Lindsay L A1 - Harris, Tamara B A1 - Smith, Albert Vernon A1 - Shuldiner, Alan R A1 - McArdle, Wendy L A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Grönberg, Henrik A1 - Chen, Yii-Der Ida A1 - Li, Guo A1 - Beckmann, Jacques S A1 - Johnson, Toby A1 - Thorsteinsdottir, Unnur A1 - Teder-Laving, Maris A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Oostra, Ben A A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Cupples, L Adrienne A1 - Heard-Costa, Nancy L A1 - Kaprio, Jaakko A1 - Ripatti, Samuli A1 - Surakka, Ida A1 - Collins, Francis S A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Erdmann, Jeanette A1 - Hengstenberg, Christian A1 - Loley, Christina A1 - Schunkert, Heribert A1 - Lamina, Claudia A1 - Wichmann, H Erich A1 - Albrecht, Eva A1 - Gieger, Christian A1 - Hicks, Andrew A A1 - Johansson, Asa A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Speliotes, Elizabeth K A1 - Penninx, Brenda A1 - Hartikainen, Anna-Liisa A1 - Jarvelin, Marjo-Riitta A1 - Gyllensten, Ulf A1 - Boomsma, Dorret I A1 - Campbell, Harry A1 - Wilson, James F A1 - Chanock, Stephen J A1 - Farrall, Martin A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Rivadeneira, Fernando A1 - Estrada, Karol A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Zillikens, M Carola A1 - den Heijer, Martin A1 - Kiemeney, Lambertus A A1 - Maschio, Andrea A1 - Hall, Per A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Tönjes, Anke A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Attwood, Antony Paul A1 - Sambrook, Jennifer G A1 - Hung, Joseph A1 - Palmer, Lyle J A1 - Lokki, Marja-Liisa A1 - Sinisalo, Juha A1 - Boucher, Gabrielle A1 - Huikuri, Heikki A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Eklund, Niina A1 - Eriksson, Johan G A1 - Barlassina, Cristina A1 - Rivolta, Carlo A1 - Nolte, Ilja M A1 - Snieder, Harold A1 - van der Klauw, Melanie M A1 - van Vliet-Ostaptchouk, Jana V A1 - Gejman, Pablo V A1 - Shi, Jianxin A1 - Jacobs, Kevin B A1 - Wang, Zhaoming A1 - Bakker, Stephan J L A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van der Harst, Pim A1 - Martin, Nicholas G A1 - Medland, Sarah E A1 - Montgomery, Grant W A1 - Yang, Jian A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Raitakari, Olli A1 - Absher, Devin A1 - Iribarren, Carlos A1 - Basart, Hanneke A1 - Hovingh, Kees G A1 - Hyppönen, Elina A1 - Power, Chris A1 - Anderson, Denise A1 - Beilby, John P A1 - Hui, Jennie A1 - Jolley, Jennifer A1 - Sager, Hendrik A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Kristiansson, Kati A1 - Perola, Markus A1 - Lindström, Jaana A1 - Swift, Amy J A1 - Uusitupa, Matti A1 - Atalay, Mustafa A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Bolton, Jennifer L A1 - Fowkes, Gerry A1 - Fraser, Ross M A1 - Price, Jackie F A1 - Fischer, Krista A1 - Krjutå Kov, Kaarel A1 - Metspalu, Andres A1 - Mihailov, Evelin A1 - Langenberg, Claudia A1 - Luan, Jian'an A1 - Ong, Ken K A1 - Chines, Peter S A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Edkins, Sarah A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Shungin, Dmitry A1 - Morris, Andrew David A1 - Palmer, Colin N A A1 - Erbel, Raimund A1 - Moebus, Susanne A1 - Nöthen, Markus M A1 - Pechlivanis, Sonali A1 - Hveem, Kristian A1 - Narisu, Narisu A1 - Hamsten, Anders A1 - Humphries, Steve E A1 - Strawbridge, Rona J A1 - Tremoli, Elena A1 - Grallert, Harald A1 - Thorand, Barbara A1 - Illig, Thomas A1 - Koenig, Wolfgang A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Boehm, Bernhard O A1 - Kleber, Marcus E A1 - März, Winfried A1 - Winkelmann, Bernhard R A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Arveiler, Dominique A1 - Cesana, Giancarlo A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Yarnell, John W G A1 - Kuh, Diana A1 - Wong, Andrew A1 - Lind, Lars A1 - de Faire, Ulf A1 - Gigante, Bruna A1 - Magnusson, Patrik K E A1 - Pedersen, Nancy L A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Kolovou, Genovefa A1 - Kanoni, Stavroula A1 - Stirrups, Kathleen A1 - Bonnycastle, Lori L A1 - Njølstad, Inger A1 - Wilsgaard, Tom A1 - Ganna, Andrea A1 - Rehnberg, Emil A1 - Hingorani, Aroon A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David A1 - Ingelsson, Erik A1 - Kaplan, Robert A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Qi, Lu A1 - Loos, Ruth J F A1 - Lindgren, Cecilia M A1 - North, Kari E A1 - Heid, Iris M KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Body Weight KW - Body Weights and Measures KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist Circumference KW - Waist-Hip Ratio AB -

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. JF - PLoS Genet Y1 - 2013 A1 - Wu, Ying A1 - Waite, Lindsay L A1 - Jackson, Anne U A1 - Sheu, Wayne H-H A1 - Buyske, Steven A1 - Absher, Devin A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Carty, Cara L A1 - Cheng, Iona A1 - Cochran, Barbara A1 - Croteau-Chonka, Damien C A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Henderson, Brian E A1 - Hindorff, Lucia A A1 - Kim, Eric A1 - Kinnunen, Leena A1 - Komulainen, Pirjo A1 - Lee, Wen-Jane A1 - Le Marchand, Loïc A1 - Lin, Yi A1 - Lindström, Jaana A1 - Lingaas-Holmen, Oddgeir A1 - Mitchell, Sabrina L A1 - Narisu, Narisu A1 - Robinson, Jennifer G A1 - Schumacher, Fred A1 - Stančáková, Alena A1 - Sundvall, Jouko A1 - Sung, Yun-Ju A1 - Swift, Amy J A1 - Wang, Wen-Chang A1 - Wilkens, Lynne A1 - Wilsgaard, Tom A1 - Young, Alicia M A1 - Adair, Linda S A1 - Ballantyne, Christie M A1 - Bůzková, Petra A1 - Chakravarti, Aravinda A1 - Collins, Francis S A1 - Duggan, David A1 - Feranil, Alan B A1 - Ho, Low-Tone A1 - Hung, Yi-Jen A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Juang, Jyh-Ming J A1 - Kesäniemi, Antero Y A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lee, I-Te A1 - Leppert, Mark F A1 - Matise, Tara C A1 - Moilanen, Leena A1 - Njølstad, Inger A1 - Peters, Ulrike A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rotter, Jerome I A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Wang, Tzung-Dau A1 - Boehnke, Michael A1 - Haiman, Christopher A A1 - Chen, Yii-der I A1 - Kooperberg, Charles A1 - Assimes, Themistocles L A1 - Crawford, Dana C A1 - Hsiung, Chao A A1 - North, Kari E A1 - Mohlke, Karen L KW - African Americans KW - Apolipoproteins A KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Proprotein Convertases KW - Serine Endopeptidases KW - Triglycerides AB -

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract ER - TY - JOUR T1 - Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. JF - Nat Genet Y1 - 2013 A1 - Morrison, Alanna C A1 - Voorman, Arend A1 - Johnson, Andrew D A1 - Liu, Xiaoming A1 - Yu, Jin A1 - Li, Alexander A1 - Muzny, Donna A1 - Yu, Fuli A1 - Rice, Kenneth A1 - Zhu, Chengsong A1 - Bis, Joshua A1 - Heiss, Gerardo A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Gibbs, Richard A1 - Boerwinkle, Eric KW - Cholesterol, HDL KW - Computational Biology KW - Databases, Genetic KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Genomics KW - Heterozygote KW - Humans KW - Open Reading Frames AB -

We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.

VL - 45 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23770607?dopt=Abstract ER - TY - JOUR T1 - Association Between 6-Minute Walk Test and All-Cause Mortality, Coronary Heart Disease-Specific Mortality, and Incident Coronary Heart Disease. JF - J Aging Health Y1 - 2014 A1 - Yazdanyar, Ali A1 - Aziz, Michael M A1 - Enright, Paul L A1 - Edmundowicz, Daniel A1 - Boudreau, Robert A1 - Sutton-Tyrell, Kim A1 - Kuller, Lewis A1 - Newman, Anne B AB -

OBJECTIVE: To examine the association between 6-min walk test (6 MWT) performance and all-cause mortality, coronary heart disease mortality, and incident coronary heart disease in older adults.

METHOD: We conducted a time-to-event analysis of 1,665 Cardiovascular Health Study participants without prevalent cardiovascular disease with a 6 MWT.

RESULTS: During a mean follow-up of 8 years, there were 305 incident coronary heart disease events, and 504 deaths of which 100 were coronary heart disease-related deaths. The 6 MWT performance in the shortest two distance quintiles was associated with increased risk of all-cause mortality (290-338 m: hazard ratio [HR] = 1.7; 95% confidence interval [CI] = [1.2, 2.5]; <290 m: HR = 2.1; 95% CI = [1.4, 3.0]). The adjusted risk of coronary heart disease mortality incident events among those with a 6 MWT < 290 m was not significant.

DISCUSSION: Performance on the 6 MWT is independently associated with all-cause mortality and is of prognostic utility in community-dwelling older adults.

VL - 26 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24695552?dopt=Abstract ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. JF - Am J Kidney Dis Y1 - 2014 A1 - O'Seaghdha, Conall M A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Katz, Ronit A1 - Liu, Yongmei A1 - Harris, Tamara A1 - Astor, Brad A1 - Coresh, Josef A1 - Fox, Caroline S A1 - Kao, W H Linda A1 - Shlipak, Michael G KW - Aged KW - Bias KW - Biomarkers KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Genetic Variation KW - Glomerular Filtration Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic KW - Risk Assessment KW - Risk Factors KW - Severity of Illness Index KW - Statistics as Topic KW - Survival Rate AB -

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

VL - 63 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23932088?dopt=Abstract ER - TY - JOUR T1 - Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts. JF - Stroke Y1 - 2014 A1 - Mahmoodi, Bakhtawar K A1 - Yatsuya, Hiroshi A1 - Matsushita, Kunihiro A1 - Sang, Yinying A1 - Gottesman, Rebecca F A1 - Astor, Brad C A1 - Woodward, Mark A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Shlipak, Michael G A1 - Folsom, Aaron R A1 - Gansevoort, Ron T A1 - Coresh, Josef KW - Aged KW - Albuminuria KW - Brain Ischemia KW - Comorbidity KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Intracranial Hemorrhages KW - Kidney Diseases KW - Male KW - Middle Aged KW - Netherlands KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND AND PURPOSE: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.

METHODS: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.

RESULTS: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.

CONCLUSIONS: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24876078?dopt=Abstract ER - TY - JOUR T1 - Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2014 A1 - Longstreth, W T A1 - Diehr, Paula H A1 - Yee, Laura M A1 - Newman, Anne B A1 - Beauchamp, Norman J KW - Activities of Daily Living KW - Aged KW - Atrophy KW - Brain KW - Brain Infarction KW - Cohort Studies KW - Disability Evaluation KW - Female KW - Health Status KW - Humans KW - Leukoaraiosis KW - Longevity KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prognosis KW - Regression Analysis KW - United States AB -

OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes.

DESIGN: Longitudinal cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses.

MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses.

RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38%) and not able (38%).

CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.

VL - 62 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25333525?dopt=Abstract ER - TY - JOUR T1 - B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. JF - Europace Y1 - 2014 A1 - Sinner, Moritz F A1 - Stepas, Katherine A A1 - Moser, Carlee B A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Franco, Oscar H A1 - Yin, Xiaoyan A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Astor, Brad C A1 - Ballantyne, Christie M A1 - Hoogeveen, Ron C A1 - Arai, Andrew E A1 - Soliman, Elsayed Z A1 - Ellinor, Patrick T A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Pencina, Michael J A1 - Benjamin, Emelia J A1 - Alonso, Alvaro KW - Aged KW - Atrial Fibrillation KW - Biomarkers KW - C-Reactive Protein KW - Europe KW - Female KW - Humans KW - Incidence KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - United States AB -

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

VL - 16 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a brief dementia screening indicator for primary care. JF - Alzheimers Dement Y1 - 2014 A1 - Barnes, Deborah E A1 - Beiser, Alexa S A1 - Lee, Anne A1 - Langa, Kenneth M A1 - Koyama, Alain A1 - Preis, Sarah R A1 - Neuhaus, John A1 - McCammon, Ryan J A1 - Yaffe, Kristine A1 - Seshadri, Sudha A1 - Haan, Mary N A1 - Weir, David R KW - Aged KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Male KW - Mass Screening KW - Predictive Value of Tests KW - Primary Health Care KW - Proportional Hazards Models KW - Risk Assessment AB -

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.

METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.

RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).

CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

VL - 10 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24491321?dopt=Abstract ER - TY - JOUR T1 - Disability and recovery of independent function in obstructive lung disease: the cardiovascular health study. JF - Respiration Y1 - 2014 A1 - Fan, Vincent S A1 - Locke, Emily R A1 - Diehr, Paula A1 - Wilsdon, Anthony A1 - Enright, Paul A1 - Yende, Sachin A1 - Avdalovic, Mark A1 - Barr, Graham A1 - Kapur, Vishesh K A1 - Thomas, Rachel A1 - Krishnan, Jerry A A1 - Lovasi, Gina A1 - Thielke, Stephen KW - Activities of Daily Living KW - Aged KW - Cardiac Rehabilitation KW - Cardiovascular Diseases KW - Disability Evaluation KW - Exercise Test KW - Female KW - Humans KW - Independent Living KW - Longitudinal Studies KW - Male KW - Motor Activity KW - Muscle Strength KW - Outcome Assessment (Health Care) KW - Pulmonary Disease, Chronic Obstructive KW - Recovery of Function KW - Risk Assessment KW - Severity of Illness Index KW - Spirometry KW - United States AB -

BACKGROUND: Chronic obstructive lung disease frequently leads to disability. Older patients may experience transitions between states of disability and independence over time.

OBJECTIVE: To identify factors associated with transition between states of disability and independent function in obstructive lung disease.

METHODS: We analyzed data on 4,394 participants in the Cardiovascular Health Study who completed prebronchodilator spirometry. We calculated the 1-year probability of developing and resolving impairment in ≥1 instrumental activity of daily living (IADL) or ≥1 activity of daily living (ADL) using transition probability analysis. We identified factors associated with resolving disability using relative risk (RR) regression.

RESULTS: The prevalence of IADL impairment was higher with moderate (23.9%) and severe (36.9%) airflow obstruction compared to normal spirometry (22.5%; p < 0.001). Among participants with severe airflow obstruction, 23.5% recovered independence in IADLs and 40.5% recovered independence in ADLs. In the adjusted analyses, airflow obstruction predicted the development of IADL, but not ADL impairment. Participants with severe airflow obstruction were less likely to resolve IADL impairment [RR 0.67 and 95% confidence interval (CI) 0.49-0.94]. Compared to the most active individuals (i.e. who walked ≥28 blocks per week), walking less was associated with a decreased likelihood of resolving IADL impairment (7-27 blocks: RR 0.81 and 95% CI 0.69-0.86 and <7 blocks: RR 0.73 and 95% CI 0.61-0.86). Increased strength (RR 1.16 and 95% CI 1.05-1.29) was associated with resolving IADL impairment.

CONCLUSIONS: Disability is common in older people, especially in those with severe airflow obstruction. Increased physical activity and muscle strength are associated with recovery. Research is needed on interventions to improve these factors among patients with obstructive lung disease and disability.

VL - 88 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25228204?dopt=Abstract ER - TY - JOUR T1 - Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. JF - Am J Hum Genet Y1 - 2014 A1 - Ganesh, Santhi K A1 - Chasman, Daniel I A1 - Larson, Martin G A1 - Guo, Xiuqing A1 - Verwoert, Germain A1 - Bis, Joshua C A1 - Gu, Xiangjun A1 - Smith, Albert V A1 - Yang, Min-Lee A1 - Zhang, Yan A1 - Ehret, Georg A1 - Rose, Lynda M A1 - Hwang, Shih-Jen A1 - Papanicolau, George J A1 - Sijbrands, Eric J A1 - Rice, Kenneth A1 - Eiriksdottir, Gudny A1 - Pihur, Vasyl A1 - Ridker, Paul M A1 - Vasan, Ramachandran S A1 - Newton-Cheh, Christopher A1 - Raffel, Leslie J A1 - Amin, Najaf A1 - Rotter, Jerome I A1 - Liu, Kiang A1 - Launer, Lenore J A1 - Xu, Ming A1 - Caulfield, Mark A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - Vaidya, Dhananjay A1 - Dehghan, Abbas A1 - Li, Guo A1 - Bouchard, Claude A1 - Harris, Tamara B A1 - Zhang, He A1 - Boerwinkle, Eric A1 - Siscovick, David S A1 - Gao, Wei A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Willer, Cristen J A1 - Franco, Oscar H A1 - Huo, Yong A1 - Witteman, Jacqueline C M A1 - Munroe, Patricia B A1 - Gudnason, Vilmundur A1 - Palmas, Walter A1 - van Duijn, Cornelia A1 - Fornage, Myriam A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Chakravarti, Aravinda KW - Blood Pressure KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract ER - TY - JOUR T1 - Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. JF - Epidemiology Y1 - 2014 A1 - Seyerle, Amanda A A1 - Young, Alicia M A1 - Jeff, Janina M A1 - Melton, Phillip E A1 - Jorgensen, Neal W A1 - Lin, Yi A1 - Carty, Cara L A1 - Deelman, Ewa A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Jackson, Rebecca D A1 - Martin, Lisa W A1 - Okin, Peter M A1 - Perez, Marco V A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Whitsel, Eric A A1 - North, Kari E A1 - Laston, Sandra A1 - Kooperberg, Charles A1 - Avery, Christy L KW - Aged KW - Continental Population Groups KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

VL - 25 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract ER - TY - JOUR T1 - Extreme deep white matter hyperintensity volumes are associated with African American race. JF - Cerebrovasc Dis Y1 - 2014 A1 - Nyquist, Paul A A1 - Bilgel, Murat S A1 - Gottesman, Rebecca A1 - Yanek, Lisa R A1 - Moy, Taryn F A1 - Becker, Lewis C A1 - Cuzzocreo, Jennifer A1 - Prince, Jerry A1 - Yousem, David M A1 - Becker, Diane M A1 - Kral, Brian G A1 - Vaidya, Dhananjay KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Cerebrovascular Disorders KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Prevalence KW - Risk Factors KW - White Matter AB -

BACKGROUND: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors.

METHODS: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl.

RESULTS: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26).

CONCLUSIONS: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.

VL - 37 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24686322?dopt=Abstract ER - TY - JOUR T1 - Gender and telomere length: systematic review and meta-analysis. JF - Exp Gerontol Y1 - 2014 A1 - Gardner, Michael A1 - Bann, David A1 - Wiley, Laura A1 - Cooper, Rachel A1 - Hardy, Rebecca A1 - Nitsch, Dorothea A1 - Martin-Ruiz, Carmen A1 - Shiels, Paul A1 - Sayer, Avan Aihie A1 - Barbieri, Michelangela A1 - Bekaert, Sofie A1 - Bischoff, Claus A1 - Brooks-Wilson, Angela A1 - Chen, Wei A1 - Cooper, Cyrus A1 - Christensen, Kaare A1 - De Meyer, Tim A1 - Deary, Ian A1 - Der, Geoff A1 - Diez Roux, Ana A1 - Fitzpatrick, Annette A1 - Hajat, Anjum A1 - Halaschek-Wiener, Julius A1 - Harris, Sarah A1 - Hunt, Steven C A1 - Jagger, Carol A1 - Jeon, Hyo-Sung A1 - Kaplan, Robert A1 - Kimura, Masayuki A1 - Lansdorp, Peter A1 - Li, Changyong A1 - Maeda, Toyoki A1 - Mangino, Massimo A1 - Nawrot, Tim S A1 - Nilsson, Peter A1 - Nordfjall, Katarina A1 - Paolisso, Giuseppe A1 - Ren, Fu A1 - Riabowol, Karl A1 - Robertson, Tony A1 - Roos, Goran A1 - Staessen, Jan A A1 - Spector, Tim A1 - Tang, Nelson A1 - Unryn, Brad A1 - van der Harst, Pim A1 - Woo, Jean A1 - Xing, Chao A1 - Yadegarfar, Mohammad E A1 - Park, Jae Yong A1 - Young, Neal A1 - Kuh, Diana A1 - von Zglinicki, Thomas A1 - Ben-Shlomo, Yoav KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Female KW - Humans KW - Male KW - Middle Aged KW - Sex Factors KW - Telomere AB -

BACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.

METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.

RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.

CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

VL - 51 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24365661?dopt=Abstract ER - TY - JOUR T1 - Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. JF - Am J Hum Genet Y1 - 2014 A1 - Simino, Jeannette A1 - Shi, Gang A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - Ehret, Georg B A1 - Gu, Xiangjun A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric A1 - Smith, Albert V A1 - Verwoert, Germaine C A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - Chen, Peng A1 - Cheng, Ching-Yu A1 - Corre, Tanguy A1 - de Boer, Rudolf A A1 - Goel, Anuj A1 - Johnson, Toby A1 - Khor, Chiea-Chuen A1 - Lluís-Ganella, Carla A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Sim, Xueling A1 - Sõber, Siim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Bouchard, Claude A1 - Dehghan, Abbas A1 - Eiriksdottir, Gudny A1 - Elosua, Roberto A1 - Franco, Oscar H A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hercberg, Serge A1 - Hofman, Albert A1 - James, Alan L A1 - Johnson, Andrew D A1 - Kähönen, Mika A1 - Khaw, Kay-Tee A1 - Kutalik, Zoltán A1 - Larson, Martin G A1 - Launer, Lenore J A1 - Li, Guo A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Navis, Gerjan A1 - Ong, Rick Twee-Hee A1 - Papanicolau, George J A1 - Penninx, Brenda W A1 - Psaty, Bruce M A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scott, Robert A A1 - Siscovick, David S A1 - Stolk, Ronald P A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Klauw, Melanie M A1 - Vasan, Ramachandran S A1 - Vithana, Eranga Nishanthie A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Young, Terri L A1 - Aung, Tin A1 - Bochud, Murielle A1 - Farrall, Martin A1 - Hartman, Catharina A A1 - Laan, Maris A1 - Lakatta, Edward G A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Lucas, Gavin A1 - Meneton, Pierre A1 - Palmer, Lyle J A1 - Rettig, Rainer A1 - Snieder, Harold A1 - Tai, E Shyong A1 - Teo, Yik-Ying A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Wong, Tien Yin A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Levy, Daniel A1 - Palmas, Walter A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - van Duijn, Cornelia M A1 - Witteman, Jacqueline C M A1 - Chakravarti, Aravinda A1 - Rao, Dabeeru C KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Humans KW - Middle Aged KW - Young Adult AB -

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. JF - Hum Mol Genet Y1 - 2014 A1 - Yoneyama, Sachiko A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Barnes, Michael R A1 - Elbers, Clara C A1 - Karczewski, Konrad J A1 - Padmanabhan, Sandosh A1 - Bauer, Florianne A1 - Baumert, Jens A1 - Beitelshees, Amber A1 - Berenson, Gerald S A1 - Boer, Jolanda M A A1 - Burke, Gregory A1 - Cade, Brian A1 - Chen, Wei A1 - Cooper-Dehoff, Rhonda M A1 - Gaunt, Tom R A1 - Gieger, Christian A1 - Gong, Yan A1 - Gorski, Mathias A1 - Heard-Costa, Nancy A1 - Johnson, Toby A1 - Lamonte, Michael J A1 - McDonough, Caitrin A1 - Monda, Keri L A1 - Onland-Moret, N Charlotte A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Ordovas, Jose A1 - Peter, Inga A1 - Peters, Annette A1 - Shaffer, Jonathan A1 - Shen, Haiqinq A1 - Smith, Erin A1 - Speilotes, Liz A1 - Thomas, Fridtjof A1 - Thorand, Barbara A1 - Monique Verschuren, W M A1 - Anand, Sonia S A1 - Dominiczak, Anna A1 - Davidson, Karina W A1 - Hegele, Robert A A1 - Heid, Iris A1 - Hofker, Marten H A1 - Huggins, Gordon S A1 - Illig, Thomas A1 - Johnson, Julie A A1 - Kirkland, Susan A1 - König, Wolfgang A1 - Langaee, Taimour Y A1 - McCaffery, Jeanne A1 - Melander, Olle A1 - Mitchell, Braxton D A1 - Munroe, Patricia A1 - Murray, Sarah S A1 - Papanicolaou, George A1 - Redline, Susan A1 - Reilly, Muredach A1 - Samani, Nilesh J A1 - Schork, Nicholas J A1 - van der Schouw, Yvonne T A1 - Shimbo, Daichi A1 - Shuldiner, Alan R A1 - Tobin, Martin D A1 - Wijmenga, Cisca A1 - Yusuf, Salim A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Demerath, Ellen W A1 - Fox, Caroline S A1 - North, Kari E A1 - Reiner, Alex P A1 - Keating, Brendan A1 - Taylor, Kira C KW - Adiposity KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Waist Circumference KW - Waist-Hip Ratio KW - Young Adult AB -

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract ER - TY - JOUR T1 - A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups. JF - Thromb Res Y1 - 2014 A1 - Weng, Lu-Chen A1 - Tang, Weihong A1 - Rich, Stephen S A1 - Smith, Nicholas L A1 - Redline, Susan A1 - O'Donnell, Christopher J A1 - Basu, Saonli A1 - Reiner, Alexander P A1 - Delaney, Joseph A A1 - Tracy, Russell P A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Yang, Qiong A1 - Folsom, Aaron R A1 - Cushman, Mary KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Ethnic Groups KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Association Studies KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.

CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

VL - 134 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24908450?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - D'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orrù, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Lunetta, Kathryn L A1 - Nalls, Mike A1 - Smith, Jennifer A A1 - Tanaka, Toshiko A1 - Davies, Gail A1 - Yu, Lei A1 - Mirza, Saira Saeed A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Li, Hanyue A1 - Karasik, David A1 - Kiel, Douglas P A1 - Garcia, Melissa A1 - Liu, Yongmei A1 - Faul, Jessica D A1 - Kardia, Sharon Lr A1 - Zhao, Wei A1 - Ferrucci, Luigi A1 - Allerhand, Michael A1 - Liewald, David C A1 - Redmond, Paul A1 - Starr, John M A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Direk, Nese A1 - Ikram, Mohammed Arfan A1 - Uitterlinden, Andre A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Grabe, Hans J A1 - Launer, Lenore A1 - Murabito, Joanne M A1 - Singleton, Andrew B A1 - Weir, David R A1 - Bandinelli, Stefania A1 - Deary, Ian J A1 - Bennett, David A A1 - Tiemeier, Henning A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Arking, Dan E KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

VL - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract ER - TY - JOUR T1 - Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. JF - PLoS One Y1 - 2014 A1 - Escott-Price, Valentina A1 - Bellenguez, Céline A1 - Wang, Li-San A1 - Choi, Seung-Hoan A1 - Harold, Denise A1 - Jones, Lesley A1 - Holmans, Peter A1 - Gerrish, Amy A1 - Vedernikov, Alexey A1 - Richards, Alexander A1 - DeStefano, Anita L A1 - Lambert, Jean-Charles A1 - Ibrahim-Verbaas, Carla A A1 - Naj, Adam C A1 - Sims, Rebecca A1 - Jun, Gyungah A1 - Bis, Joshua C A1 - Beecham, Gary W A1 - Grenier-Boley, Benjamin A1 - Russo, Giancarlo A1 - Thornton-Wells, Tricia A A1 - Denning, Nicola A1 - Smith, Albert V A1 - Chouraki, Vincent A1 - Thomas, Charlene A1 - Ikram, M Arfan A1 - Zelenika, Diana A1 - Vardarajan, Badri N A1 - Kamatani, Yoichiro A1 - Lin, Chiao-Feng A1 - Schmidt, Helena A1 - Kunkle, Brian A1 - Dunstan, Melanie L A1 - Vronskaya, Maria A1 - Johnson, Andrew D A1 - Ruiz, Agustin A1 - Bihoreau, Marie-Thérèse A1 - Reitz, Christiane A1 - Pasquier, Florence A1 - Hollingworth, Paul A1 - Hanon, Olivier A1 - Fitzpatrick, Annette L A1 - Buxbaum, Joseph D A1 - Campion, Dominique A1 - Crane, Paul K A1 - Baldwin, Clinton A1 - Becker, Tim A1 - Gudnason, Vilmundur A1 - Cruchaga, Carlos A1 - Craig, David A1 - Amin, Najaf A1 - Berr, Claudine A1 - Lopez, Oscar L A1 - De Jager, Philip L A1 - Deramecourt, Vincent A1 - Johnston, Janet A A1 - Evans, Denis A1 - Lovestone, Simon A1 - Letenneur, Luc A1 - Hernandez, Isabel A1 - Rubinsztein, David C A1 - Eiriksdottir, Gudny A1 - Sleegers, Kristel A1 - Goate, Alison M A1 - Fiévet, Nathalie A1 - Huentelman, Matthew J A1 - Gill, Michael A1 - Brown, Kristelle A1 - Kamboh, M Ilyas A1 - Keller, Lina A1 - Barberger-Gateau, Pascale A1 - McGuinness, Bernadette A1 - Larson, Eric B A1 - Myers, Amanda J A1 - Dufouil, Carole A1 - Todd, Stephen A1 - Wallon, David A1 - Love, Seth A1 - Rogaeva, Ekaterina A1 - Gallacher, John A1 - George-Hyslop, Peter St A1 - Clarimon, Jordi A1 - Lleo, Alberto A1 - Bayer, Anthony A1 - Tsuang, Debby W A1 - Yu, Lei A1 - Tsolaki, Magda A1 - Bossù, Paola A1 - Spalletta, Gianfranco A1 - Proitsi, Petra A1 - Collinge, John A1 - Sorbi, Sandro A1 - Garcia, Florentino Sanchez A1 - Fox, Nick C A1 - Hardy, John A1 - Naranjo, Maria Candida Deniz A1 - Bosco, Paolo A1 - Clarke, Robert A1 - Brayne, Carol A1 - Galimberti, Daniela A1 - Scarpini, Elio A1 - Bonuccelli, Ubaldo A1 - Mancuso, Michelangelo A1 - Siciliano, Gabriele A1 - Moebus, Susanne A1 - Mecocci, Patrizia A1 - Zompo, Maria Del A1 - Maier, Wolfgang A1 - Hampel, Harald A1 - Pilotto, Alberto A1 - Frank-García, Ana A1 - Panza, Francesco A1 - Solfrizzi, Vincenzo A1 - Caffarra, Paolo A1 - Nacmias, Benedetta A1 - Perry, William A1 - Mayhaus, Manuel A1 - Lannfelt, Lars A1 - Hakonarson, Hakon A1 - Pichler, Sabrina A1 - Carrasquillo, Minerva M A1 - Ingelsson, Martin A1 - Beekly, Duane A1 - Alvarez, Victoria A1 - Zou, Fanggeng A1 - Valladares, Otto A1 - Younkin, Steven G A1 - Coto, Eliecer A1 - Hamilton-Nelson, Kara L A1 - Gu, Wei A1 - Razquin, Cristina A1 - Pastor, Pau A1 - Mateo, Ignacio A1 - Owen, Michael J A1 - Faber, Kelley M A1 - Jonsson, Palmi V A1 - Combarros, Onofre A1 - O'Donovan, Michael C A1 - Cantwell, Laura B A1 - Soininen, Hilkka A1 - Blacker, Deborah A1 - Mead, Simon A1 - Mosley, Thomas H A1 - Bennett, David A A1 - Harris, Tamara B A1 - Fratiglioni, Laura A1 - Holmes, Clive A1 - de Bruijn, Renee F A G A1 - Passmore, Peter A1 - Montine, Thomas J A1 - Bettens, Karolien A1 - Rotter, Jerome I A1 - Brice, Alexis A1 - Morgan, Kevin A1 - Foroud, Tatiana M A1 - Kukull, Walter A A1 - Hannequin, Didier A1 - Powell, John F A1 - Nalls, Michael A A1 - Ritchie, Karen A1 - Lunetta, Kathryn L A1 - Kauwe, John S K A1 - Boerwinkle, Eric A1 - Riemenschneider, Matthias A1 - Boada, Merce A1 - Hiltunen, Mikko A1 - Martin, Eden R A1 - Schmidt, Reinhold A1 - Rujescu, Dan A1 - Dartigues, Jean-François A1 - Mayeux, Richard A1 - Tzourio, Christophe A1 - Hofman, Albert A1 - Nöthen, Markus M A1 - Graff, Caroline A1 - Psaty, Bruce M A1 - Haines, Jonathan L A1 - Lathrop, Mark A1 - Pericak-Vance, Margaret A A1 - Launer, Lenore J A1 - Van Broeckhoven, Christine A1 - Farrer, Lindsay A A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Seshadri, Sudha A1 - Schellenberg, Gerard D A1 - Amouyel, Philippe A1 - Williams, Julie KW - Alzheimer Disease KW - Carrier Proteins KW - Case-Control Studies KW - Genome-Wide Association Study KW - Heat-Shock Proteins KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, Antigen, B-Cell AB -

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Yamakuchi, Munekazu A1 - Yamkauchi, Munekazu A1 - Trompet, Stella A1 - Asselbergs, Folkert W A1 - Sabater-Lleal, Maria A1 - Trégouët, David-Alexandre A1 - Chen, Wei-Min A1 - Smith, Nicholas L A1 - Kleber, Marcus E A1 - Shin, So-Youn A1 - Becker, Diane M A1 - Tang, Weihong A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Truong, Vinh A1 - Folkersen, Lasse A1 - Yang, Qiong A1 - Oudot-Mellkah, Tiphaine A1 - Buckley, Brendan M A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Campbell, Harry A1 - Silbernagel, Günther A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Tofler, Geoffrey H A1 - Navis, Gerjan J A1 - DeStefano, Anita A1 - Wright, Alan F A1 - Chen, Ming-Huei A1 - de Craen, Anton J M A1 - Worrall, Bradford B A1 - Rudnicka, Alicja R A1 - Rumley, Ann A1 - Bookman, Ebony B A1 - Psaty, Bruce M A1 - Chen, Fang A1 - Keene, Keith L A1 - Franco, Oscar H A1 - Böhm, Bernhard O A1 - Uitterlinden, André G A1 - Carter, Angela M A1 - Jukema, J Wouter A1 - Sattar, Naveed A1 - Bis, Joshua C A1 - Ikram, Mohammad A A1 - Sale, Michèle M A1 - McKnight, Barbara A1 - Fornage, Myriam A1 - Ford, Ian A1 - Taylor, Kent A1 - Slagboom, P Eline A1 - McArdle, Wendy L A1 - Hsu, Fang-Chi A1 - Franco-Cereceda, Anders A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Furie, Karen L A1 - Cushman, Mary A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Wilson, James F A1 - Westendorp, Rudi G J A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Tracy, Russell P A1 - Polasek, Ozren A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Cambien, Francois A1 - Stott, David J A1 - Lowe, Gordon D A1 - Spector, Timothy D A1 - Meigs, James B A1 - März, Winfried A1 - Eriksson, Per A1 - Becker, Lewis C A1 - Morange, Pierre-Emmanuel A1 - Soranzo, Nicole A1 - Williams, Scott M A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Lowenstein, Charles J A1 - Strachan, David P A1 - O'Donnell, Christopher J KW - Aged KW - Cells, Cultured KW - Coronary Artery Disease KW - Endothelial Cells KW - Europe KW - Female KW - Gene Expression Regulation KW - Gene Silencing KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - R-SNARE Proteins KW - Risk Factors KW - Stroke KW - Syntaxin 1 KW - Tissue Plasminogen Activator KW - Transfection KW - United States KW - Up-Regulation AB -

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

VL - 34 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract ER - TY - JOUR T1 - Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. JF - Circulation Y1 - 2014 A1 - Sinner, Moritz F A1 - Tucker, Nathan R A1 - Lunetta, Kathryn L A1 - Ozaki, Kouichi A1 - Smith, J Gustav A1 - Trompet, Stella A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Chung, Mina K A1 - Nielsen, Jonas B A1 - Lubitz, Steven A A1 - Krijthe, Bouwe P A1 - Magnani, Jared W A1 - Ye, Jiangchuan A1 - Gollob, Michael H A1 - Tsunoda, Tatsuhiko A1 - Müller-Nurasyid, Martina A1 - Lichtner, Peter A1 - Peters, Annette A1 - Dolmatova, Elena A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Psaty, Bruce M A1 - Smith, Nicholas L A1 - Jukema, J Wouter A1 - Chasman, Daniel I A1 - Albert, Christine M A1 - Ebana, Yusuke A1 - Furukawa, Tetsushi A1 - Macfarlane, Peter W A1 - Harris, Tamara B A1 - Darbar, Dawood A1 - Dörr, Marcus A1 - Holst, Anders G A1 - Svendsen, Jesper H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur A1 - Isobe, Mitsuaki A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Rosand, Jonathan A1 - Van Wagoner, David R A1 - Benjamin, Emelia J A1 - Milan, David J A1 - Melander, Olle A1 - Heckbert, Susan R A1 - Ford, Ian A1 - Liu, Yongmei A1 - Barnard, John A1 - Olesen, Morten S A1 - Stricker, Bruno H C A1 - Tanaka, Toshihiro A1 - Kääb, Stefan A1 - Ellinor, Patrick T KW - Aged KW - Animals KW - Atrial Fibrillation KW - Chromosome Mapping KW - Connexin 43 KW - Europe KW - Female KW - Gene Knockdown Techniques KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Homeodomain Proteins KW - Humans KW - Japan KW - Male KW - Middle Aged KW - Muscle Proteins KW - Nuclear Proteins KW - Quantitative Trait Loci KW - Repressor Proteins KW - T-Box Domain Proteins KW - Transcription Factors KW - Ubiquitin-Protein Ligases KW - Zebrafish KW - Zebrafish Proteins AB -

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

VL - 130 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25124494?dopt=Abstract ER - TY - JOUR T1 - Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. JF - Hum Genet Y1 - 2014 A1 - Ellis, Jaclyn A1 - Lange, Ethan M A1 - Li, Jin A1 - Dupuis, Josée A1 - Baumert, Jens A1 - Walston, Jeremy D A1 - Keating, Brendan J A1 - Durda, Peter A1 - Fox, Ervin R A1 - Palmer, Cameron D A1 - Meng, Yan A A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Schnabel, Renate B A1 - Marzi, Carola S A1 - Larkin, Emma A1 - Martin, Lisa W A1 - Bis, Joshua C A1 - Auer, Paul A1 - Ramachandran, Vasan S A1 - Gabriel, Stacey B A1 - Willis, Monte S A1 - Pankow, James S A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Ballantyne, Christie M A1 - Gross, Myron D A1 - Lettre, Guillaume A1 - Wilson, James G A1 - Peters, Ulrike A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Redline, Susan A1 - Reiner, Alex P A1 - Benjamin, Emelia J A1 - Lange, Leslie A KW - Adult KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - CD36 Antigens KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

VL - 133 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. JF - PLoS Genet Y1 - 2014 A1 - Ng, Maggie C Y A1 - Shriner, Daniel A1 - Chen, Brian H A1 - Li, Jiang A1 - Chen, Wei-Min A1 - Guo, Xiuqing A1 - Liu, Jiankang A1 - Bielinski, Suzette J A1 - Yanek, Lisa R A1 - Nalls, Michael A A1 - Comeau, Mary E A1 - Rasmussen-Torvik, Laura J A1 - Jensen, Richard A A1 - Evans, Daniel S A1 - Sun, Yan V A1 - An, Ping A1 - Patel, Sanjay R A1 - Lu, Yingchang A1 - Long, Jirong A1 - Armstrong, Loren L A1 - Wagenknecht, Lynne A1 - Yang, Lingyao A1 - Snively, Beverly M A1 - Palmer, Nicholette D A1 - Mudgal, Poorva A1 - Langefeld, Carl D A1 - Keene, Keith L A1 - Freedman, Barry I A1 - Mychaleckyj, Josyf C A1 - Nayak, Uma A1 - Raffel, Leslie J A1 - Goodarzi, Mark O A1 - Chen, Y-D Ida A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Sims, Mario A1 - Couper, David A1 - Pankow, James S A1 - Boerwinkle, Eric A1 - Adeyemo, Adebowale A1 - Doumatey, Ayo A1 - Chen, Guanjie A1 - Mathias, Rasika A A1 - Vaidya, Dhananjay A1 - Singleton, Andrew B A1 - Zonderman, Alan B A1 - Igo, Robert P A1 - Sedor, John R A1 - Kabagambe, Edmond K A1 - Siscovick, David S A1 - McKnight, Barbara A1 - Rice, Kenneth A1 - Liu, Yongmei A1 - Hsueh, Wen-Chi A1 - Zhao, Wei A1 - Bielak, Lawrence F A1 - Kraja, Aldi A1 - Province, Michael A A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Cai, Qiuyin A1 - Zheng, Wei A1 - Blot, William J A1 - Lowe, William L A1 - Pacheco, Jennifer A A1 - Crawford, Dana C A1 - Grundberg, Elin A1 - Rich, Stephen S A1 - Hayes, M Geoffrey A1 - Shu, Xiao-Ou A1 - Loos, Ruth J F A1 - Borecki, Ingrid B A1 - Peyser, Patricia A A1 - Cummings, Steven R A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Iyengar, Sudha K A1 - Evans, Michele K A1 - Becker, Diane M A1 - Kao, W H Linda A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Sale, Michèle M A1 - Liu, Simin A1 - Rotimi, Charles N A1 - Bowden, Donald W KW - African Americans KW - Diabetes Mellitus, Type 2 KW - Genome-Wide Association Study KW - HLA-B27 Antigen KW - HMGA2 Protein KW - Humans KW - KCNQ1 Potassium Channel KW - Mutant Chimeric Proteins KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94) VL - 10 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract ER - TY - JOUR T1 - Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Liu, Ching-Ti A1 - Young, Kristin L A1 - Brody, Jennifer A A1 - Olden, Matthias A1 - Wojczynski, Mary K A1 - Heard-Costa, Nancy A1 - Li, Guo A1 - Morrison, Alanna C A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Reid, Jeffrey G A1 - Shao, Yaming A1 - Zhou, Yanhua A1 - Boerwinkle, Eric A1 - Heiss, Gerardo A1 - Wagenknecht, Lynne A1 - McKnight, Barbara A1 - Borecki, Ingrid B A1 - Fox, Caroline S A1 - North, Kari E A1 - Cupples, L Adrienne KW - Adult KW - Aged KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Female KW - Genetic Association Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Male KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Young Adult AB -

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.

CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951660?dopt=Abstract ER - TY - JOUR T1 - Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Magnani, Jared W A1 - Brody, Jennifer A A1 - Prins, Bram P A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Yin, Xiaoyan A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Zhang, Feng A1 - Spector, Tim D A1 - Alonso, Alvaro A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Lubitz, Steven A A1 - Soliman, Elsayed Z A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - O'Donnell, Christopher J A1 - Ellinor, Patrick T A1 - Benjamin, Emelia J A1 - Muzny, Donna M A1 - Gibbs, Richard A A1 - Santibanez, Jireh A1 - Taylor, Herman A A1 - Rotter, Jerome I A1 - Lange, Leslie A A1 - Psaty, Bruce M A1 - Jackson, Rebecca A1 - Rich, Stephen S A1 - Boerwinkle, Eric A1 - Jamshidi, Yalda A1 - Sotoodehnia, Nona KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Conduction System KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract ER - TY - JOUR T1 - Serum carboxymethyl-lysine, disability, and frailty in older persons: the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Whitson, Heather E A1 - Arnold, Alice M A1 - Yee, Laura M A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R A1 - Djoussé, Luc A1 - Ix, Joachim H A1 - Siscovick, David A1 - Tracy, Russell P A1 - Thielke, Stephen M A1 - Hirsch, Calvin A1 - Newman, Anne B A1 - Zieman, Susan KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Aging KW - Biomarkers KW - Cardiac Rehabilitation KW - Cardiovascular Diseases KW - Disabled Persons KW - Female KW - Follow-Up Studies KW - Frail Elderly KW - Health Status KW - Humans KW - Incidence KW - Lysine KW - Male KW - Prevalence KW - Prognosis KW - Retrospective Studies KW - United States AB -

BACKGROUND: Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.

METHODS: In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 ± 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.

RESULTS: Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.

CONCLUSIONS: Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML's value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24127427?dopt=Abstract ER - TY - JOUR T1 - Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Varadhan, Ravi A1 - Yao, Wenliang A1 - Matteini, Amy A1 - Beamer, Brock A A1 - Xue, Qian-Li A1 - Yang, Huanle A1 - Manwani, Bhavish A1 - Reiner, Alexander A1 - Jenny, Nancy A1 - Parekh, Neel A1 - Fallin, M Daniele A1 - Newman, Anne A1 - Bandeen-Roche, Karen A1 - Tracy, Russell A1 - Ferrucci, Luigi A1 - Walston, Jeremy KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Cohort Studies KW - Female KW - Humans KW - Inflammation KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-18 KW - Interleukin-6 KW - Longevity KW - Male KW - Receptors, Tumor Necrosis Factor, Type I KW - Risk Factors AB -

BACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.

METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.

CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

VL - 69 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23689826?dopt=Abstract ER - TY - JOUR T1 - Subclinical vascular disease burden and longer survival. JF - J Am Geriatr Soc Y1 - 2014 A1 - Odden, Michelle C A1 - Yee, Laura M A1 - Arnold, Alice M A1 - Sanders, Jason L A1 - Hirsch, Calvin A1 - DeFilippi, Christopher A1 - Kizer, Jorge R A1 - Inzitari, Marco A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Cystatin C KW - Depression KW - Diabetes Mellitus KW - Electrocardiography KW - Female KW - Humans KW - Inflammation KW - Kidney Diseases KW - Male KW - Smoking KW - Survival Analysis KW - United States KW - Vascular Diseases AB -

OBJECTIVES: To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.

DESIGN: Cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals born between June 30, 1918, and June 30, 1921 (N = 2,082; aged 70-75 at baseline (1992-93)).

MEASUREMENTS: A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.

RESULTS: A 1-point lower SVD score was associated with 1.22 greater odds (95% confidence interval = 1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.

CONCLUSION: A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.

VL - 62 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25243681?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - A variant of sparse partial least squares for variable selection and data exploration. JF - Front Neuroinform Y1 - 2014 A1 - Olson Hunt, Megan J A1 - Weissfeld, Lisa A1 - Boudreau, Robert M A1 - Aizenstein, Howard A1 - Newman, Anne B A1 - Simonsick, Eleanor M A1 - Van Domelen, Dane R A1 - Thomas, Fridtjof A1 - Yaffe, Kristine A1 - Rosano, Caterina AB - When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a "large" number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors. VL - 8 ER - TY - JOUR T1 - Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JF - JAMA Y1 - 2015 A1 - Corrales-Medina, Vicente F A1 - Alvarez, Karina N A1 - Weissfeld, Lisa A A1 - Angus, Derek C A1 - Chirinos, Julio A A1 - Chang, Chung-Chou H A1 - Newman, Anne A1 - Loehr, Laura A1 - Folsom, Aaron R A1 - Elkind, Mitchell S A1 - Lyles, Mary F A1 - Kronmal, Richard A A1 - Yende, Sachin KW - Aged KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Hospitalization KW - Humans KW - Male KW - Middle Aged KW - Pneumonia KW - Risk Factors AB -

IMPORTANCE: The risk of cardiovascular disease (CVD) after infection is poorly understood.

OBJECTIVE: To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD.

DESIGN, SETTINGS, AND PARTICIPANTS: We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989-1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15,792; enrollment age, 45-64 years; enrollment period, 1987-1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status.

EXPOSURES: Hospitalization for pneumonia.

MAIN OUTCOMES AND MEASURES: Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease).

RESULTS: Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant.

CONCLUSIONS AND RELEVANCE: Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.

VL - 313 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25602997?dopt=Abstract ER - TY - JOUR T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. JF - Neurobiol Aging Y1 - 2015 A1 - Chauhan, Ganesh A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Weinstein, Galit A1 - Yu, Lei A1 - Töglhofer, Anna Maria A1 - Smith, Albert Vernon A1 - van der Lee, Sven J A1 - Gottesman, Rebecca F A1 - Thomson, Russell A1 - Wang, Jing A1 - Yang, Qiong A1 - Niessen, Wiro J A1 - Lopez, Oscar L A1 - Becker, James T A1 - Phan, Thanh G A1 - Beare, Richard J A1 - Arfanakis, Konstantinos A1 - Fleischman, Debra A1 - Vernooij, Meike W A1 - Mazoyer, Bernard A1 - Schmidt, Helena A1 - Srikanth, Velandai A1 - Knopman, David S A1 - Jack, Clifford R A1 - Amouyel, Philippe A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Bennett, David A A1 - Schmidt, Reinhold A1 - Longstreth, William T A1 - Mosley, Thomas H A1 - Fornage, Myriam A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Debette, Stephanie KW - Aging KW - Alleles KW - Alzheimer Disease KW - Apolipoproteins E KW - Brain KW - Female KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Organ Size KW - Polymorphism, Single Nucleotide KW - Risk KW - Sialic Acid Binding Ig-like Lectin 3 AB -

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract ER - TY - JOUR T1 - Association of Cardiometabolic Multimorbidity With Mortality. JF - JAMA Y1 - 2015 A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Wormser, David A1 - Willeit, Peter A1 - Butterworth, Adam S A1 - Bansal, Narinder A1 - O'Keeffe, Linda M A1 - Gao, Pei A1 - Wood, Angela M A1 - Burgess, Stephen A1 - Freitag, Daniel F A1 - Pennells, Lisa A1 - Peters, Sanne A A1 - Hart, Carole L A1 - Håheim, Lise Lund A1 - Gillum, Richard F A1 - Nordestgaard, Børge G A1 - Psaty, Bruce M A1 - Yeap, Bu B A1 - Knuiman, Matthew W A1 - Nietert, Paul J A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Kuller, Lewis H A1 - Simons, Leon A A1 - van der Schouw, Yvonne T A1 - Barrett-Connor, Elizabeth A1 - Selmer, Randi A1 - Crespo, Carlos J A1 - Rodriguez, Beatriz A1 - Verschuren, W M Monique A1 - Salomaa, Veikko A1 - Svärdsudd, Kurt A1 - van der Harst, Pim A1 - Björkelund, Cecilia A1 - Wilhelmsen, Lars A1 - Wallace, Robert B A1 - Brenner, Hermann A1 - Amouyel, Philippe A1 - Barr, Elizabeth L M A1 - Iso, Hiroyasu A1 - Onat, Altan A1 - Trevisan, Maurizio A1 - D'Agostino, Ralph B A1 - Cooper, Cyrus A1 - Kavousi, Maryam A1 - Welin, Lennart A1 - Roussel, Ronan A1 - Hu, Frank B A1 - Sato, Shinichi A1 - Davidson, Karina W A1 - Howard, Barbara V A1 - Leening, Maarten J G A1 - Leening, Maarten A1 - Rosengren, Annika A1 - Dörr, Marcus A1 - Deeg, Dorly J H A1 - Kiechl, Stefan A1 - Stehouwer, Coen D A A1 - Nissinen, Aulikki A1 - Giampaoli, Simona A1 - Donfrancesco, Chiara A1 - Kromhout, Daan A1 - Price, Jackie F A1 - Peters, Annette A1 - Meade, Tom W A1 - Casiglia, Edoardo A1 - Lawlor, Debbie A A1 - Gallacher, John A1 - Nagel, Dorothea A1 - Franco, Oscar H A1 - Assmann, Gerd A1 - Dagenais, Gilles R A1 - Jukema, J Wouter A1 - Sundström, Johan A1 - Woodward, Mark A1 - Brunner, Eric J A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Whitsel, Eric A A1 - Njølstad, Inger A1 - Hedblad, Bo A1 - Wassertheil-Smoller, Sylvia A1 - Engström, Gunnar A1 - Rosamond, Wayne D A1 - Selvin, Elizabeth A1 - Sattar, Naveed A1 - Thompson, Simon G A1 - Danesh, John KW - Adult KW - Aged KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality KW - Myocardial Infarction KW - Risk Factors KW - Stroke AB -

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

VL - 314 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract ER - TY - JOUR T1 - Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Yu, Bing A1 - Li, Alexander H A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - de Vries, Paul S A1 - Bis, Joshua C A1 - Musani, Solomon K A1 - Alexander, Danny A1 - Morrison, Alanna C A1 - Franco, Oscar H A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Dehghan, Abbas A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Gibbs, Richard A1 - Wei, Peng A1 - Boerwinkle, Eric KW - Adult KW - African Americans KW - Alleles KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Histidine KW - Histidine Ammonia-Lyase KW - Humans KW - Male KW - Mutation AB -

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25575548?dopt=Abstract ER - TY - JOUR T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. JF - Neurology Y1 - 2015 A1 - Rannikmae, Kristiina A1 - Davies, Gail A1 - Thomson, Pippa A A1 - Bevan, Steve A1 - Devan, William J A1 - Falcone, Guido J A1 - Traylor, Matthew A1 - Anderson, Christopher D A1 - Battey, Thomas W K A1 - Radmanesh, Farid A1 - Deka, Ranjan A1 - Woo, Jessica G A1 - Martin, Lisa J A1 - Jimenez-Conde, Jordi A1 - Selim, Magdy A1 - Brown, Devin L A1 - Silliman, Scott L A1 - Kidwell, Chelsea S A1 - Montaner, Joan A1 - Langefeld, Carl D A1 - Slowik, Agnieszka A1 - Hansen, Bjorn M A1 - Lindgren, Arne G A1 - Meschia, James F A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Debette, Stephanie A1 - Ikram, Mohammad A A1 - Longstreth, Will T A1 - Schmidt, Reinhold A1 - Zhang, Cathy R A1 - Yang, Qiong A1 - Sharma, Pankaj A1 - Kittner, Steven J A1 - Mitchell, Braxton D A1 - Holliday, Elizabeth G A1 - Levi, Christopher R A1 - Attia, John A1 - Rothwell, Peter M A1 - Poole, Deborah L A1 - Boncoraglio, Giorgio B A1 - Psaty, Bruce M A1 - Malik, Rainer A1 - Rost, Natalia A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Van Agtmael, Tom A1 - Woo, Daniel A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Rosand, Jonathan A1 - Sudlow, Cathie L M KW - Cerebral Small Vessel Diseases KW - Collagen Type IV KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide AB -

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

VL - 84 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract ER - TY - JOUR T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. JF - Nature Y1 - 2015 A1 - Do, Ron A1 - Stitziel, Nathan O A1 - Won, Hong-Hee A1 - Jørgensen, Anders Berg A1 - Duga, Stefano A1 - Angelica Merlini, Pier A1 - Kiezun, Adam A1 - Farrall, Martin A1 - Goel, Anuj A1 - Zuk, Or A1 - Guella, Illaria A1 - Asselta, Rosanna A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Farlow, Deborah N A1 - DePristo, Mark A A1 - Roberts, Robert A1 - Stewart, Alexander F R A1 - Saleheen, Danish A1 - Danesh, John A1 - Epstein, Stephen E A1 - Sivapalaratnam, Suthesh A1 - Hovingh, G Kees A1 - Kastelein, John J A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Shah, Svati H A1 - Kraus, William E A1 - Davies, Robert A1 - Nikpay, Majid A1 - Johansen, Christopher T A1 - Wang, Jian A1 - Hegele, Robert A A1 - Hechter, Eliana A1 - März, Winfried A1 - Kleber, Marcus E A1 - Huang, Jie A1 - Johnson, Andrew D A1 - Li, Mingyao A1 - Burke, Greg L A1 - Gross, Myron A1 - Liu, Yongmei A1 - Assimes, Themistocles L A1 - Heiss, Gerardo A1 - Lange, Ethan M A1 - Folsom, Aaron R A1 - Taylor, Herman A A1 - Olivieri, Oliviero A1 - Hamsten, Anders A1 - Clarke, Robert A1 - Reilly, Dermot F A1 - Yin, Wu A1 - Rivas, Manuel A A1 - Donnelly, Peter A1 - Rossouw, Jacques E A1 - Psaty, Bruce M A1 - Herrington, David M A1 - Wilson, James G A1 - Rich, Stephen S A1 - Bamshad, Michael J A1 - Tracy, Russell P A1 - Cupples, L Adrienne A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Spertus, John A A1 - Cresci, Sharon A1 - Hartiala, Jaana A1 - Tang, W H Wilson A1 - Hazen, Stanley L A1 - Allayee, Hooman A1 - Reiner, Alex P A1 - Carlson, Christopher S A1 - Kooperberg, Charles A1 - Jackson, Rebecca D A1 - Boerwinkle, Eric A1 - Lander, Eric S A1 - Schwartz, Stephen M A1 - Siscovick, David S A1 - McPherson, Ruth A1 - Tybjaerg-Hansen, Anne A1 - Abecasis, Goncalo R A1 - Watkins, Hugh A1 - Nickerson, Deborah A A1 - Ardissino, Diego A1 - Sunyaev, Shamil R A1 - O'Donnell, Christopher J A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Kathiresan, Sekar KW - Age Factors KW - Age of Onset KW - Alleles KW - Apolipoproteins A KW - Case-Control Studies KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Receptors, LDL KW - Triglycerides KW - United States AB -

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

VL - 518 IS - 7537 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract ER - TY - JOUR T1 - Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. JF - Am J Hematol Y1 - 2015 A1 - Tang, Weihong A1 - Cushman, Mary A1 - Green, David A1 - Rich, Stephen S A1 - Lange, Leslie A A1 - Yang, Qiong A1 - Tracy, Russell P A1 - Tofler, Geoffrey H A1 - Basu, Saonli A1 - Wilson, James G A1 - Keating, Brendan J A1 - Weng, Lu-Chen A1 - Taylor, Herman A A1 - Jacobs, David R A1 - Delaney, Joseph A A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Pankow, James S A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Reiner, Alexander P A1 - Folsom, Aaron R KW - Adult KW - African Americans KW - Aged KW - European Continental Ancestry Group KW - Factor VIII KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Methionine Adenosyltransferase KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Venous Thromboembolism KW - von Willebrand Factor AB -

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

VL - 90 IS - 6 ER - TY - JOUR T1 - Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. JF - Stroke Y1 - 2015 A1 - Lopez, Lorna M A1 - Hill, W David A1 - Harris, Sarah E A1 - Valdes Hernandez, Maria A1 - Munoz Maniega, Susana A1 - Bastin, Mark E A1 - Bailey, Emma A1 - Smith, Colin A1 - McBride, Martin A1 - McClure, John A1 - Graham, Delyth A1 - Dominiczak, Anna A1 - Yang, Qiong A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Launer, Lenore A1 - Bis, Joshua C A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Porteous, David J A1 - Starr, John A1 - Deary, Ian J A1 - Wardlaw, Joanna M KW - Aged KW - Alzheimer Disease KW - Animals KW - Brain KW - Causality KW - Dementia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Polymorphism, Single Nucleotide KW - Rats KW - Rats, Inbred SHR KW - Rats, Wistar KW - Risk Factors KW - Translational Medical Research KW - White Matter AB -

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.

METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.

RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).

CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.

VL - 46 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract ER - TY - JOUR T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). JF - Mol Psychiatry Y1 - 2015 A1 - Davies, G A1 - Armstrong, N A1 - Bis, J C A1 - Bressler, J A1 - Chouraki, V A1 - Giddaluru, S A1 - Hofer, E A1 - Ibrahim-Verbaas, C A A1 - Kirin, M A1 - Lahti, J A1 - van der Lee, S J A1 - Le Hellard, S A1 - Liu, T A1 - Marioni, R E A1 - Oldmeadow, C A1 - Postmus, I A1 - Smith, A V A1 - Smith, J A A1 - Thalamuthu, A A1 - Thomson, R A1 - Vitart, V A1 - Wang, J A1 - Yu, L A1 - Zgaga, L A1 - Zhao, W A1 - Boxall, R A1 - Harris, S E A1 - Hill, W D A1 - Liewald, D C A1 - Luciano, M A1 - Adams, H A1 - Ames, D A1 - Amin, N A1 - Amouyel, P A1 - Assareh, A A A1 - Au, R A1 - Becker, J T A1 - Beiser, A A1 - Berr, C A1 - Bertram, L A1 - Boerwinkle, E A1 - Buckley, B M A1 - Campbell, H A1 - Corley, J A1 - De Jager, P L A1 - Dufouil, C A1 - Eriksson, J G A1 - Espeseth, T A1 - Faul, J D A1 - Ford, I A1 - Gottesman, R F A1 - Griswold, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heiss, G A1 - Hofman, A A1 - Holliday, E G A1 - Huffman, J A1 - Kardia, S L R A1 - Kochan, N A1 - Knopman, D S A1 - Kwok, J B A1 - Lambert, J-C A1 - Lee, T A1 - Li, G A1 - Li, S-C A1 - Loitfelder, M A1 - Lopez, O L A1 - Lundervold, A J A1 - Lundqvist, A A1 - Mather, K A A1 - Mirza, S S A1 - Nyberg, L A1 - Oostra, B A A1 - Palotie, A A1 - Papenberg, G A1 - Pattie, A A1 - Petrovic, K A1 - Polasek, O A1 - Psaty, B M A1 - Redmond, P A1 - Reppermund, S A1 - Rotter, J I A1 - Schmidt, H A1 - Schuur, M A1 - Schofield, P W A1 - Scott, R J A1 - Steen, V M A1 - Stott, D J A1 - van Swieten, J C A1 - Taylor, K D A1 - Trollor, J A1 - Trompet, S A1 - Uitterlinden, A G A1 - Weinstein, G A1 - Widen, E A1 - Windham, B G A1 - Jukema, J W A1 - Wright, A F A1 - Wright, M J A1 - Yang, Q A1 - Amieva, H A1 - Attia, J R A1 - Bennett, D A A1 - Brodaty, H A1 - de Craen, A J M A1 - Hayward, C A1 - Ikram, M A A1 - Lindenberger, U A1 - Nilsson, L-G A1 - Porteous, D J A1 - Räikkönen, K A1 - Reinvang, I A1 - Rudan, I A1 - Sachdev, P S A1 - Schmidt, R A1 - Schofield, P R A1 - Srikanth, V A1 - Starr, J M A1 - Turner, S T A1 - Weir, D R A1 - Wilson, J F A1 - van Duijn, C A1 - Launer, L A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - Mosley, T H A1 - Deary, I J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cognition KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HMGN1 Protein KW - Humans KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Scotland AB -

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

VL - 20 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. JF - Mol Psychiatry Y1 - 2015 A1 - Cornelis, M C A1 - Byrne, E M A1 - Esko, T A1 - Nalls, M A A1 - Ganna, A A1 - Paynter, N A1 - Monda, K L A1 - Amin, N A1 - Fischer, K A1 - Renstrom, F A1 - Ngwa, J S A1 - Huikari, V A1 - Cavadino, A A1 - Nolte, I M A1 - Teumer, A A1 - Yu, K A1 - Marques-Vidal, P A1 - Rawal, R A1 - Manichaikul, A A1 - Wojczynski, M K A1 - Vink, J M A1 - Zhao, J H A1 - Burlutsky, G A1 - Lahti, J A1 - Mikkilä, V A1 - Lemaitre, R N A1 - Eriksson, J A1 - Musani, S K A1 - Tanaka, T A1 - Geller, F A1 - Luan, J A1 - Hui, J A1 - Mägi, R A1 - Dimitriou, M A1 - Garcia, M E A1 - Ho, W-K A1 - Wright, M J A1 - Rose, L M A1 - Magnusson, P K E A1 - Pedersen, N L A1 - Couper, D A1 - Oostra, B A A1 - Hofman, A A1 - Ikram, M A A1 - Tiemeier, H W A1 - Uitterlinden, A G A1 - van Rooij, F J A A1 - Barroso, I A1 - Johansson, I A1 - Xue, L A1 - Kaakinen, M A1 - Milani, L A1 - Power, C A1 - Snieder, H A1 - Stolk, R P A1 - Baumeister, S E A1 - Biffar, R A1 - Gu, F A1 - Bastardot, F A1 - Kutalik, Z A1 - Jacobs, D R A1 - Forouhi, N G A1 - Mihailov, E A1 - Lind, L A1 - Lindgren, C A1 - Michaëlsson, K A1 - Morris, A A1 - Jensen, M A1 - Khaw, K-T A1 - Luben, R N A1 - Wang, J J A1 - Männistö, S A1 - Perälä, M-M A1 - Kähönen, M A1 - Lehtimäki, T A1 - Viikari, J A1 - Mozaffarian, D A1 - Mukamal, K A1 - Psaty, B M A1 - Döring, A A1 - Heath, A C A1 - Montgomery, G W A1 - Dahmen, N A1 - Carithers, T A1 - Tucker, K L A1 - Ferrucci, L A1 - Boyd, H A A1 - Melbye, M A1 - Treur, J L A1 - Mellström, D A1 - Hottenga, J J A1 - Prokopenko, I A1 - Tönjes, A A1 - Deloukas, P A1 - Kanoni, S A1 - Lorentzon, M A1 - Houston, D K A1 - Liu, Y A1 - Danesh, J A1 - Rasheed, A A1 - Mason, M A A1 - Zonderman, A B A1 - Franke, L A1 - Kristal, B S A1 - Karjalainen, J A1 - Reed, D R A1 - Westra, H-J A1 - Evans, M K A1 - Saleheen, D A1 - Harris, T B A1 - Dedoussis, G A1 - Curhan, G A1 - Stumvoll, M A1 - Beilby, J A1 - Pasquale, L R A1 - Feenstra, B A1 - Bandinelli, S A1 - Ordovás, J M A1 - Chan, A T A1 - Peters, U A1 - Ohlsson, C A1 - Gieger, C A1 - Martin, N G A1 - Waldenberger, M A1 - Siscovick, D S A1 - Raitakari, O A1 - Eriksson, J G A1 - Mitchell, P A1 - Hunter, D J A1 - Kraft, P A1 - Rimm, E B A1 - Boomsma, D I A1 - Borecki, I B A1 - Loos, R J F A1 - Wareham, N J A1 - Vollenweider, P A1 - Caporaso, N A1 - Grabe, H J A1 - Neuhouser, M L A1 - Wolffenbuttel, B H R A1 - Hu, F B A1 - Hypponen, E A1 - Järvelin, M-R A1 - Cupples, L A A1 - Franks, P W A1 - Ridker, P M A1 - van Duijn, C M A1 - Heiss, G A1 - Metspalu, A A1 - North, K E A1 - Ingelsson, E A1 - Nettleton, J A A1 - van Dam, R M A1 - Chasman, D I KW - Adaptor Proteins, Signal Transducing KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors KW - Brain-Derived Neurotrophic Factor KW - Coffea KW - Cytochrome P-450 CYP1A2 KW - Food Habits KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

VL - 20 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25288136?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Buchman, Aron S A1 - Deelen, Joris A1 - Evans, Daniel S A1 - Faul, Jessica D A1 - Lunetta, Kathryn L A1 - Sebastiani, Paola A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Yu, Lei A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Benjamin, Emelia J A1 - De Jager, Philip L A1 - Eirkisdottir, Gudny A1 - Evans, Denis A A1 - Garcia, Melissa E A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kiel, Douglas P A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Singleton, Andrew A1 - Tiemeier, Henning A1 - Uitterlinden, André G A1 - Zhao, Wei A1 - Bandinelli, Stefania A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Karasik, David A1 - Launer, Lenore J A1 - Perls, Thomas T A1 - Slagboom, P Eline A1 - Tranah, Gregory J A1 - Weir, David R A1 - Newman, Anne B A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

VL - 70 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults. JF - Am Heart J Y1 - 2015 A1 - Corrales-Medina, Vicente F A1 - Taljaard, Monica A1 - Yende, Sachin A1 - Kronmal, Richard A1 - Dwivedi, Girish A1 - Newman, Anne B A1 - Elkind, Mitchell S V A1 - Lyles, Mary F A1 - Chirinos, Julio A KW - Aged KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Forecasting KW - Heart Failure KW - Hospitalization KW - Humans KW - Incidence KW - Inpatients KW - Male KW - Patient Readmission KW - Pneumonia KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors AB -

BACKGROUND: Pneumonia is associated with high risk of heart failure (HF) in the short term (30 days) postinfection. Whether this association persists beyond this period is unknown.

METHODS: We studied 5,613 elderly (≥65 years) adults enrolled in the Cardiovascular Health Study between 1989 and 1994 at 4 US communities. Participants had no clinical diagnosis of HF at enrollment, and they were followed up through December 2010. Hospitalizations for pneumonia were identified using validated International Classification of Disease Ninth Revision codes. A centralized committee adjudicated new-onset HF events. Using Cox regression, we estimated adjusted hazard ratios (HRs) of new-onset HF at different time intervals after hospitalization for pneumonia.

RESULTS: A total of 652 participants hospitalized for pneumonia during follow-up were still alive and free of clinical diagnosis of HF by day 30 posthospitalization. Relative to the time of their hospitalization, new-onset HF occurred in 22 cases between 31 and 90 days (HR 6.9, 95% CI 4.46-10.63, P < .001), 14 cases between 91 days and 6 months (HR 3.2, 95% CI 1.88-5.50, P < .001), 20 cases between 6 months and 1 year (HR 2.6, 95% CI 1.64-4.04, P < .001), 76 cases between 1 and 5 years (HR 1.7, 95% CI 1.30-2.12, P < .001), and 71 cases after 5 years (HR 2.0, 95% CI 1.56-2.58, P < .001). Results were robust to sensitivity analyses using stringent definitions of pneumonia and extreme assumptions for potential informative censoring.

CONCLUSION: Hospitalization for pneumonia is associated with increased risk of new-onset HF in the intermediate and long term. Studies should characterize the mechanisms of this association in order to prevent HF in elderly pneumonia survivors.

VL - 170 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26299228?dopt=Abstract ER - TY - JOUR T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. JF - Nat Commun Y1 - 2015 A1 - Wessel, Jennifer A1 - Chu, Audrey Y A1 - Willems, Sara M A1 - Wang, Shuai A1 - Yaghootkar, Hanieh A1 - Brody, Jennifer A A1 - Dauriz, Marco A1 - Hivert, Marie-France A1 - Raghavan, Sridharan A1 - Lipovich, Leonard A1 - Hidalgo, Bertha A1 - Fox, Keolu A1 - Huffman, Jennifer E A1 - An, Ping A1 - Lu, Yingchang A1 - Rasmussen-Torvik, Laura J A1 - Grarup, Niels A1 - Ehm, Margaret G A1 - Li, Li A1 - Baldridge, Abigail S A1 - Stančáková, Alena A1 - Abrol, Ravinder A1 - Besse, Céline A1 - Boland, Anne A1 - Bork-Jensen, Jette A1 - Fornage, Myriam A1 - Freitag, Daniel F A1 - Garcia, Melissa E A1 - Guo, Xiuqing A1 - Hara, Kazuo A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Lange, Leslie A A1 - Layton, Jill C A1 - Li, Man A1 - Hua Zhao, Jing A1 - Meidtner, Karina A1 - Morrison, Alanna C A1 - Nalls, Mike A A1 - Peters, Marjolein J A1 - Sabater-Lleal, Maria A1 - Schurmann, Claudia A1 - Silveira, Angela A1 - Smith, Albert V A1 - Southam, Lorraine A1 - Stoiber, Marcus H A1 - Strawbridge, Rona J A1 - Taylor, Kent D A1 - Varga, Tibor V A1 - Allin, Kristine H A1 - Amin, Najaf A1 - Aponte, Jennifer L A1 - Aung, Tin A1 - Barbieri, Caterina A1 - Bihlmeyer, Nathan A A1 - Boehnke, Michael A1 - Bombieri, Cristina A1 - Bowden, Donald W A1 - Burns, Sean M A1 - Chen, Yuning A1 - Chen, Yii-DerI A1 - Cheng, Ching-Yu A1 - Correa, Adolfo A1 - Czajkowski, Jacek A1 - Dehghan, Abbas A1 - Ehret, Georg B A1 - Eiriksdottir, Gudny A1 - Escher, Stefan A A1 - Farmaki, Aliki-Eleni A1 - Frånberg, Mattias A1 - Gambaro, Giovanni A1 - Giulianini, Franco A1 - Goddard, William A A1 - Goel, Anuj A1 - Gottesman, Omri A1 - Grove, Megan L A1 - Gustafsson, Stefan A1 - Hai, Yang A1 - Hallmans, Göran A1 - Heo, Jiyoung A1 - Hoffmann, Per A1 - Ikram, Mohammad K A1 - Jensen, Richard A A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Karaleftheri, Maria A1 - Khor, Chiea C A1 - Kirkpatrick, Andrea A1 - Kraja, Aldi T A1 - Kuusisto, Johanna A1 - Lange, Ethan M A1 - Lee, I T A1 - Lee, Wen-Jane A1 - Leong, Aaron A1 - Liao, Jiemin A1 - Liu, Chunyu A1 - Liu, Yongmei A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Malerba, Giovanni A1 - Mamakou, Vasiliki A1 - Marouli, Eirini A1 - Maruthur, Nisa M A1 - Matchan, Angela A1 - McKean-Cowdin, Roberta A1 - McLeod, Olga A1 - Metcalf, Ginger A A1 - Mohlke, Karen L A1 - Muzny, Donna M A1 - Ntalla, Ioanna A1 - Palmer, Nicholette D A1 - Pasko, Dorota A1 - Peter, Andreas A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rice, Ken A1 - Sala, Cinzia F A1 - Sennblad, Bengt A1 - Serafetinidis, Ioannis A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Speliotes, Elizabeth K A1 - Stahl, Eli A A1 - Stirrups, Kathleen A1 - Tentolouris, Nikos A1 - Thanopoulou, Anastasia A1 - Torres, Mina A1 - Traglia, Michela A1 - Tsafantakis, Emmanouil A1 - Javad, Sundas A1 - Yanek, Lisa R A1 - Zengini, Eleni A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Brown, James B A1 - Cupples, L Adrienne A1 - Hansen, Torben A1 - Ingelsson, Erik A1 - Karter, Andrew J A1 - Lorenzo, Carlos A1 - Mathias, Rasika A A1 - Norris, Jill M A1 - Peloso, Gina M A1 - Sheu, Wayne H-H A1 - Toniolo, Daniela A1 - Vaidya, Dhananjay A1 - Varma, Rohit A1 - Wagenknecht, Lynne E A1 - Boeing, Heiner A1 - Bottinger, Erwin P A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Ferrannini, Ele A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Gibbs, Richard A A1 - Gudnason, Vilmundur A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Jansson, Jan-Håkan A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Padmanabhan, Sandosh A1 - Pankow, James S A1 - Polasek, Ozren A1 - Province, Michael A A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rudan, Igor A1 - Schulze, Matthias B A1 - Smith, Blair H A1 - Uitterlinden, André G A1 - Walker, Mark A1 - Watkins, Hugh A1 - Wong, Tien Y A1 - Zeggini, Eleftheria A1 - Laakso, Markku A1 - Borecki, Ingrid B A1 - Chasman, Daniel I A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Tai, E Shyong A1 - van Duijn, Cornelia M A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Boerwinkle, Eric A1 - Kao, W H Linda A1 - Florez, Jose C A1 - Loos, Ruth J F A1 - Wilson, James G A1 - Frayling, Timothy M A1 - Siscovick, David S A1 - Dupuis, Josée A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Scott, Robert A A1 - Goodarzi, Mark O KW - African Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Exome KW - Fasting KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glucagon-Like Peptide-1 Receptor KW - Glucose-6-Phosphatase KW - Humans KW - Insulin KW - Mutation Rate KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide AB -

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - LV Mass as a Predictor of CVD Events in Older Adults With and Without Metabolic Syndrome and Diabetes. JF - JACC Cardiovasc Imaging Y1 - 2015 A1 - Hoang, Khiet A1 - Zhao, Yanglu A1 - Gardin, Julius M A1 - Carnethon, Mercedes A1 - Mukamal, Ken A1 - Yanez, David A1 - Wong, Nathan D KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Heart Ventricles KW - Humans KW - Hypertrophy, Left Ventricular KW - Logistic Models KW - Male KW - Metabolic Syndrome X KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVES: The purpose of this study was to examine the prognostic significance of left ventricular (LV) mass for cardiovascular disease (CVD) events in older adults with and without metabolic syndrome (MetS) and diabetes mellitus (DM).

BACKGROUND: MetS and DM are associated with increased CVD risk, but it is unclear in these groups whether subclinical CVD as shown by increased LV mass improves risk prediction compared to standard risk factors in older individuals.

METHODS: We studied 3,724 adults (mean 72.4 ± 5.4 years of age, 61.0% female, 4.4% African-American) from the Cardiovascular Health Study who had MetS but not DM or had DM alone or had neither condition. Cox regression was used to examine the association of LV mass, (alone and indexed by height and body surface area [BSA]) as determined by echocardiography, with CVD events, including coronary heart disease (CHD), stroke, heart failure (HF), and CVD death, as well as total mortality. We also assessed the added prediction, discriminative value, and net reclassification improvement (NRI) for clinical utility of LV mass compared to standard risk factors.

RESULTS: Over a mean follow-up of 14.2 ± 6.3 years, 2,180 subjects experienced CVD events, including 986 CVD deaths. After adjustment for age, sex and standard risk factors, LV mass was positively associated with CVD events in those with MetS (hazard ratio [HR]: 1.4, p < 0.001) and without MetS (HR: 1.4, p < 0.001), but not DM (HR: 1.0, p = 0.62), with similar findings for LV mass indexed for height or BSA. Adding LV mass to standard risk factors moderately improved the prediction accuracy in the overall sample and MetS group from changes in C-statistics (p < 0.05). Categorical-free net reclassification improvement increased significantly by 17% to 19% in those with MetS. Findings were comparable for CHD, CVD mortality, and total mortality.

CONCLUSIONS: LV mass is associated with increased CVD risk and provides modest added prediction and clinical utility compared to standard risk factors in older persons with and without MetS but not with DM.

VL - 8 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26319502?dopt=Abstract ER - TY - JOUR T1 - Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. JF - Stroke Y1 - 2015 A1 - Carty, Cara L A1 - Keene, Keith L A1 - Cheng, Yu-Ching A1 - Meschia, James F A1 - Chen, Wei-Min A1 - Nalls, Mike A1 - Bis, Joshua C A1 - Kittner, Steven J A1 - Rich, Stephen S A1 - Tajuddin, Salman A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Langefeld, Carl D A1 - Gottesman, Rebecca A1 - Mosley, Thomas H A1 - Shahar, Eyal A1 - Woo, Daniel A1 - Yaffe, Kristine A1 - Liu, Yongmei A1 - Sale, Michèle M A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Longstreth, W T A1 - Mitchell, Braxton D A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Reiner, Alexander A1 - Worrall, Bradford B A1 - Fornage, Myriam KW - African Americans KW - Case-Control Studies KW - Cohort Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract ER - TY - JOUR T1 - Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Ikram, M Kamran A1 - Adams, Hieab H A1 - Beecham, Ashley H A1 - Rajan, Kumar B A1 - Lopez, Lorna M A1 - Barral, Sandra A1 - van Buchem, Mark A A1 - van der Grond, Jeroen A1 - Smith, Albert V A1 - Hegenscheid, Katrin A1 - Aggarwal, Neelum T A1 - de Andrade, Mariza A1 - Atkinson, Elizabeth J A1 - Beekman, Marian A1 - Beiser, Alexa S A1 - Blanton, Susan H A1 - Boerwinkle, Eric A1 - Brickman, Adam M A1 - Bryan, R Nick A1 - Chauhan, Ganesh A1 - Chen, Christopher P L H A1 - Chouraki, Vincent A1 - de Craen, Anton J M A1 - Crivello, Fabrice A1 - Deary, Ian J A1 - Deelen, Joris A1 - De Jager, Philip L A1 - Dufouil, Carole A1 - Elkind, Mitchell S V A1 - Evans, Denis A A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Guðnason, Vilmundur A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hilal, Saima A1 - Hofer, Edith A1 - Hofman, Albert A1 - Ibrahim-Verbaas, Carla A A1 - Knopman, David S A1 - Lewis, Cora E A1 - Liao, Jiemin A1 - Liewald, David C M A1 - Luciano, Michelle A1 - van der Lugt, Aad A1 - Martinez, Oliver O A1 - Mayeux, Richard A1 - Mazoyer, Bernard A1 - Nalls, Mike A1 - Nauck, Matthias A1 - Niessen, Wiro J A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - von Sarnowski, Bettina A1 - Schmidt, Helena A1 - Schreiner, Pamela J A1 - Schuur, Maaike A1 - Sidney, Stephen S A1 - Sigurdsson, Sigurdur A1 - Slagboom, P Eline A1 - Stott, David J M A1 - van Swieten, John C A1 - Teumer, Alexander A1 - Töglhofer, Anna Maria A1 - Traylor, Matthew A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Tzourio, Christophe A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Wang, Jing J A1 - Wong, Tien Y A1 - Wardlaw, Joanna M A1 - Windham, B Gwen A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wright, Clinton B A1 - Yang, Qiong A1 - Zhao, Wei A1 - Zijdenbos, Alex A1 - Jukema, J Wouter A1 - Sacco, Ralph L A1 - Kardia, Sharon L R A1 - Amouyel, Philippe A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - DeCarli, Charles C A1 - van Duijn, Cornelia M A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Grabe, Hans J A1 - Seshadri, Sudha S A1 - Ikram, M Arfan A1 - Fornage, Myriam KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human KW - Continental Population Groups KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Models, Genetic KW - Stroke KW - White Matter AB -

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. JF - Mol Psychiatry Y1 - 2015 A1 - Gottlieb, D J A1 - Hek, K A1 - Chen, T-H A1 - Watson, N F A1 - Eiriksdottir, G A1 - Byrne, E M A1 - Cornelis, M A1 - Warby, S C A1 - Bandinelli, S A1 - Cherkas, L A1 - Evans, D S A1 - Grabe, H J A1 - Lahti, J A1 - Li, M A1 - Lehtimäki, T A1 - Lumley, T A1 - Marciante, K D A1 - Pérusse, L A1 - Psaty, B M A1 - Robbins, J A1 - Tranah, G J A1 - Vink, J M A1 - Wilk, J B A1 - Stafford, J M A1 - Bellis, C A1 - Biffar, R A1 - Bouchard, C A1 - Cade, B A1 - Curhan, G C A1 - Eriksson, J G A1 - Ewert, R A1 - Ferrucci, L A1 - Fülöp, T A1 - Gehrman, P R A1 - Goodloe, R A1 - Harris, T B A1 - Heath, A C A1 - Hernandez, D A1 - Hofman, A A1 - Hottenga, J-J A1 - Hunter, D J A1 - Jensen, M K A1 - Johnson, A D A1 - Kähönen, M A1 - Kao, L A1 - Kraft, P A1 - Larkin, E K A1 - Lauderdale, D S A1 - Luik, A I A1 - Medici, M A1 - Montgomery, G W A1 - Palotie, A A1 - Patel, S R A1 - Pistis, G A1 - Porcu, E A1 - Quaye, L A1 - Raitakari, O A1 - Redline, S A1 - Rimm, E B A1 - Rotter, J I A1 - Smith, A V A1 - Spector, T D A1 - Teumer, A A1 - Uitterlinden, A G A1 - Vohl, M-C A1 - Widen, E A1 - Willemsen, G A1 - Young, T A1 - Zhang, X A1 - Liu, Y A1 - Blangero, J A1 - Boomsma, D I A1 - Gudnason, V A1 - Hu, F A1 - Mangino, M A1 - Martin, N G A1 - O'Connor, G T A1 - Stone, K L A1 - Tanaka, T A1 - Viikari, J A1 - Gharib, S A A1 - Punjabi, N M A1 - Räikkönen, K A1 - Völzke, H A1 - Mignot, E A1 - Tiemeier, H KW - Adult KW - African Americans KW - Aged KW - Dyssomnias KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Self Report KW - Sleep AB -

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

VL - 20 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25469926?dopt=Abstract ER - TY - JOUR T1 - Population genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions. JF - PLoS One Y1 - 2015 A1 - Yu, Fuli A1 - Lu, Jian A1 - Liu, Xiaoming A1 - Gazave, Elodie A1 - Chang, Diana A1 - Raj, Srilakshmi A1 - Hunter-Zinck, Haley A1 - Blekhman, Ran A1 - Arbiza, Leonardo A1 - Van Hout, Cris A1 - Morrison, Alanna A1 - Johnson, Andrew D A1 - Bis, Joshua A1 - Cupples, L Adrienne A1 - Psaty, Bruce M A1 - Muzny, Donna A1 - Yu, Jin A1 - Gibbs, Richard A A1 - Keinan, Alon A1 - Clark, Andrew G A1 - Boerwinkle, Eric KW - DNA, Intergenic KW - Genetic Loci KW - Humans KW - Metagenomics KW - Open Reading Frames KW - Polymorphism, Single Nucleotide AB -

Whole genome analysis in large samples from a single population is needed to provide adequate power to assess relative strengths of natural selection across different functional components of the genome. In this study, we analyzed next-generation sequencing data from 962 European Americans, and found that as expected approximately 60% of the top 1% of positive selection signals lie in intergenic regions, 33% in intronic regions, and slightly over 1% in coding regions. Several detailed functional annotation categories in intergenic regions showed statistically significant enrichment in positively selected loci when compared to the null distribution of the genomic span of ENCODE categories. There was a significant enrichment of purifying selection signals detected in enhancers, transcription factor binding sites, microRNAs and target sites, but not on lincRNA or piRNAs, suggesting different evolutionary constraints for these domains. Loci in "repressed or low activity regions" and loci near or overlapping the transcription start site were the most significantly over-represented annotations among the top 1% of signals for positive selection.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25807536?dopt=Abstract ER - TY - JOUR T1 - Predicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults. JF - Gerontol Geriatr Med Y1 - 2015 A1 - Diehr, Paula A1 - Diehr, Michael A1 - Arnold, Alice A1 - Yee, Laura M A1 - Odden, Michelle C A1 - Hirsch, Calvin H A1 - Thielke, Stephen A1 - Psaty, Bruce M A1 - Johnson, W Craig A1 - Kizer Md, Jorge R A1 - Newman, Anne AB -

To create personalized estimates of future health and ability status for older adults.Data came from the Cardiovascular Health Study (CHS), a large longitudinal study. Outcomes included years of life, years of healthy life (based on self-rated health), years of able life (based on activities of daily living), and years of healthy and able life. We developed regression estimates using the demographic and health characteristics that best predicted the four outcomes. Internal and external validity were assessed.A prediction equation based on 11 variables accounted for about 40% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. The resulting CHS Healthy Life Calculator (CHSHLC) is available at http://healthylifecalculator.org.CHSHLC provides a well-documented estimate of future years of healthy and able life for older adults, who may use it in planning for the future.

VL - 1 ER - TY - JOUR T1 - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. JF - Blood Y1 - 2015 A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Morrison, Alanna C A1 - Sabater-Lleal, Maria A1 - Kacprowski, Tim A1 - Auer, Paul L A1 - Brody, Jennifer A A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Guo, Xiuqing A1 - Lin, Li-An A1 - Marioni, Riccardo E A1 - Müller-Nurasyid, Martina A1 - Yanek, Lisa R A1 - Pankratz, Nathan A1 - Grove, Megan L A1 - de Maat, Moniek P M A1 - Cushman, Mary A1 - Wiggins, Kerri L A1 - Qi, Lihong A1 - Sennblad, Bengt A1 - Harris, Sarah E A1 - Polasek, Ozren A1 - Riess, Helene A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Goel, Anuj A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - Yao, Jie A1 - Tang, Weihong A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Becker, Diane M A1 - Folsom, Aaron R A1 - Giulianini, Franco A1 - Greinacher, Andreas A1 - Hofman, Albert A1 - Huang, Chiang-Ching A1 - Kooperberg, Charles A1 - Silveira, Angela A1 - Starr, John M A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Wright, Alan F A1 - McKnight, Barbara A1 - Franco, Oscar H A1 - Zakai, Neil A1 - Mathias, Rasika A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Tofler, Geoffrey H A1 - Völker, Uwe A1 - Watkins, Hugh A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - Deary, Ian J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Dehghan, Abbas A1 - Reiner, Alex P A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels KW - von Willebrand Factor AB -

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

VL - 126 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract ER - TY - JOUR T1 - Sex, Race, and Age Differences in Observed Years of Life, Healthy Life, and Able Life among Older Adults in The Cardiovascular Health Study. JF - J Pers Med Y1 - 2015 A1 - Thielke, Stephen M A1 - Diehr, Paula H A1 - Yee, Laura M A1 - Arnold, Alice M A1 - Quiñones, Ana R A1 - Whitson, Heather E A1 - Jacob, Mini E A1 - Newman, Anne B AB -

OBJECTIVE: Longevity fails to account for health and functional status during aging. We sought to quantify differences in years of total life, years of healthy life, and years of able life among groups defined by age, sex, and race.

DESIGN: Primary analysis of a cohort study.

SETTING: 18 years of annual evaluations in four U.S. communities.

PARTICIPANTS: 5888 men and women aged 65 and older.

MEASUREMENTS: Years of life were calculated as the time from enrollment to death or 18 years. Years of total, healthy, and able life were determined from self-report during annual or semi-annual contacts. Cumulative years were summed across each of the age and sex groups.

RESULTS: White women had the best outcomes for all three measures, followed by white men, non-white women, and non-white men. For example, at the mean age of 73, a white female participant could expect 12.9 years of life, 8.9 of healthy life and 9.5 of able life, while a non-white female could expect 12.6, 7.0, and 8.0 years, respectively. A white male could expect 11.2, 8.1, and 8.9 years of life, healthy life, and able life, and a non-white male 10.3, 6.2, and 7.9 years. Regardless of starting age, individuals of the same race and sex groups spent similar amounts (not proportions) of time in an unhealthy or unable state.

CONCLUSION: Gender had a greater effect on longevity than did race, but race had a greater effect on years spent healthy or able. The mean number of years spent in an unable or sick state was surprisingly independent of the lifespan.

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26610574?dopt=Abstract ER - TY - JOUR T1 - White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. JF - Stroke Y1 - 2015 A1 - Hofer, Edith A1 - Cavalieri, Margherita A1 - Bis, Joshua C A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Sigurdsson, Sigurdur A1 - Srikanth, Velandai A1 - Trompet, Stella A1 - Verhaaren, Benjamin F J A1 - Wolf, Christiane A1 - Yang, Qiong A1 - Adams, Hieab H H A1 - Amouyel, Philippe A1 - Beiser, Alexa A1 - Buckley, Brendan M A1 - Callisaya, Michele A1 - Chauhan, Ganesh A1 - de Craen, Anton J M A1 - Dufouil, Carole A1 - van Duijn, Cornelia M A1 - Ford, Ian A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Gudnason, Vilmundur A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Martinez, Oliver A1 - Mazoyer, Bernard A1 - Moran, Chris A1 - Niessen, Wiro J A1 - Phan, Thanh A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Sattar, Naveed A1 - Schilling, Sabrina A1 - Shibata, Dean K A1 - Slagboom, P Eline A1 - Smith, Albert A1 - Stott, David J A1 - Taylor, Kent D A1 - Thomson, Russell A1 - Töglhofer, Anna M A1 - Tzourio, Christophe A1 - van Buchem, Mark A1 - Wang, Jing A1 - Westendorp, Rudi G J A1 - Windham, B Gwen A1 - Vernooij, Meike W A1 - Zijdenbos, Alex A1 - Beare, Richard A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Launer, Lenore J A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Schmidt, Helena A1 - Schmidt, Reinhold KW - Adult KW - Aged KW - Cohort Studies KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Middle Aged KW - Prospective Studies KW - White Matter AB -

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

VL - 46 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract ER - TY - JOUR T1 - Years of able life in older persons--the role of cardiovascular imaging and biomarkers: the Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2015 A1 - Alshawabkeh, Laith I A1 - Yee, Laura M A1 - Gardin, Julius M A1 - Gottdiener, John S A1 - Odden, Michelle C A1 - Bartz, Traci M A1 - Arnold, Alice M A1 - Mukamal, Kenneth J A1 - Wallace, Robert B KW - Activities of Daily Living KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Echocardiography KW - Female KW - Humans KW - Independent Living KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Procollagen KW - Prospective Studies KW - Stroke Volume KW - Troponin I AB -

BACKGROUND: As the U.S. population grows older, there is greater need to examine physical independence. Previous studies have assessed risk factors in relation to either disability or mortality, but an outcome that combines both is still needed.

METHODS AND RESULTS: The Cardiovascular Health Study is a population-based, prospective study where participants underwent baseline echocardiogram, measurement of carotid intima-media thickness (IMT), and various biomarkers, then followed for up to 18 years. Years of able life (YAL) constituted the number of years the participant was able to perform all activities of daily living. Linear regression was used to model the relationship between selected measures and outcomes, adjusted for confounding variables. Among 4902 participants, mean age was 72.6 ± 5.4 years, median YAL for males was 8.8 (interquartile range [IQR], 4.3 to 13.8) and 10.3 (IQR, 5.8 to 15.8) for females. Reductions in YAL in the fully adjusted model for females and males, respectively, were: -1.34 (95% confidence interval [CI], -2.18, -0.49) and -1.41 (95% CI, -2.03, -0.8) for abnormal left ventricular (LV) ejection fraction, -0.5 (95% CI, -0.78, -0.22) and -0.62 (95% CI, -0.87, -0.36) per SD increase in LV mass, -0.5 (95% CI, -0.7, -0.29) and -0.79 (95% CI, -0.99, -0.58) for IMT, -0.5 (95% CI, -0.64, -0.37) and -0.79 (95% CI, -0.94, -0.65) for N-terminal pro-brain natriuretic peptide, -1.08 (95% CI, -1.34, -0.83) and -0.73 (95% CI, -0.97, -0.5) for high-sensitivity troponin-T, and -0.26 (95% CI, -0.42, -0.09) and -0.23 (95% CI, -0.41, -0.05) for procollagen-III N-terminal propeptide. Most tested variables remained significant even after adjusting for incident cardiovascular (CV) disease.

CONCLUSIONS: In this population-based cohort, variables obtained by CV imaging and biomarkers of inflammation, coagulation, atherosclerosis, myocardial injury and stress, and cardiac collagen turnover were associated with YAL, an important outcome that integrates physical ability and longevity in older persons.

VL - 4 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25907126?dopt=Abstract ER - TY - JOUR T1 - -3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies JF - JAMA Intern Med Y1 - 2016 A1 - Del Gobbo, L. C. A1 - Imamura, F. A1 - Aslibekyan, S. A1 - Marklund, M. A1 - Virtanen, J. K. A1 - Wennberg, M. A1 - Yakoob, M. Y. A1 - Chiuve, S. E. A1 - Dela Cruz, L. A1 - Frazier-Wood, A. C. A1 - Fretts, A. M. A1 - Guallar, E. A1 - Matsumoto, C. A1 - Prem, K. A1 - Tanaka, T. A1 - Wu, J. H. A1 - Zhou, X. A1 - Helmer, C. A1 - Ingelsson, E. A1 - Yuan, J. M. A1 - Barberger-Gateau, P. A1 - Campos, H. A1 - Chaves, P. H. A1 - é, L. A1 - Giles, G. G. A1 - mez-Aracena, J. A1 - Hodge, A. M. A1 - Hu, F. B. A1 - Jansson, J. H. A1 - Johansson, I. A1 - Khaw, K. T. A1 - Koh, W. P. A1 - Lemaitre, R. N. A1 - Lind, L. A1 - Luben, R. N. A1 - Rimm, E. B. A1 - rus, U. A1 - Samieri, C. A1 - Franks, P. W. A1 - Siscovick, D. S. A1 - Stampfer, M. A1 - Steffen, L. M. A1 - Steffen, B. T. A1 - Tsai, M. Y. A1 - van Dam, R. M. A1 - Voutilainen, S. A1 - Willett, W. C. A1 - Woodward, M. A1 - Mozaffarian, D. AB - -3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers.\ -3) for incident CHD.\ A global consortium of 19 studies identified by November 2014.\ -3 biomarkers and ascertained CHD.\ -6 levels, and FADS desaturase genes.\ Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI).\ -3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses.\ -3 fatty acids are associated with a modestly lower incidence of fatal CHD. VL - 176 ER - TY - JOUR T1 - 52 Genetic Loci Influencing Myocardial Mass. JF - J Am Coll Cardiol Y1 - 2016 A1 - van der Harst, Pim A1 - van Setten, Jessica A1 - Verweij, Niek A1 - Vogler, Georg A1 - Franke, Lude A1 - Maurano, Matthew T A1 - Wang, Xinchen A1 - Mateo Leach, Irene A1 - Eijgelsheim, Mark A1 - Sotoodehnia, Nona A1 - Hayward, Caroline A1 - Sorice, Rossella A1 - Meirelles, Osorio A1 - Lyytikäinen, Leo-Pekka A1 - Polasek, Ozren A1 - Tanaka, Toshiko A1 - Arking, Dan E A1 - Ulivi, Sheila A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Smith, Albert V A1 - Dörr, Marcus A1 - Kerr, Kathleen F A1 - Magnani, Jared W A1 - del Greco M, Fabiola A1 - Zhang, Weihua A1 - Nolte, Ilja M A1 - Silva, Claudia T A1 - Padmanabhan, Sandosh A1 - Tragante, Vinicius A1 - Esko, Tõnu A1 - Abecasis, Goncalo R A1 - Adriaens, Michiel E A1 - Andersen, Karl A1 - Barnett, Phil A1 - Bis, Joshua C A1 - Bodmer, Rolf A1 - Buckley, Brendan M A1 - Campbell, Harry A1 - Cannon, Megan V A1 - Chakravarti, Aravinda A1 - Chen, Lin Y A1 - Delitala, Alessandro A1 - Devereux, Richard B A1 - Doevendans, Pieter A A1 - Dominiczak, Anna F A1 - Ferrucci, Luigi A1 - Ford, Ian A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Haugen, Eric A1 - Heinig, Matthias A1 - Hernandez, Dena G A1 - Hillege, Hans L A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hubner, Norbert A1 - Hwang, Shih-Jen A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kellis, Manolis A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Kooner, Jaspal S A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Lage, Kasper A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Lundby, Alicia A1 - Macfarlane, Peter W A1 - May, Dalit A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Nappo, Stefania A1 - Naitza, Silvia A1 - Neph, Shane A1 - Nord, Alex S A1 - Nutile, Teresa A1 - Okin, Peter M A1 - Olsen, Jesper V A1 - Oostra, Ben A A1 - Penninger, Josef M A1 - Pennacchio, Len A A1 - Pers, Tune H A1 - Perz, Siegfried A1 - Peters, Annette A1 - Pinto, Yigal M A1 - Pfeufer, Arne A1 - Pilia, Maria Grazia A1 - Pramstaller, Peter P A1 - Prins, Bram P A1 - Raitakari, Olli T A1 - Raychaudhuri, Soumya A1 - Rice, Ken M A1 - Rossin, Elizabeth J A1 - Rotter, Jerome I A1 - Schafer, Sebastian A1 - Schlessinger, David A1 - Schmidt, Carsten O A1 - Sehmi, Jobanpreet A1 - Silljé, Herman H W A1 - Sinagra, Gianfranco A1 - Sinner, Moritz F A1 - Slowikowski, Kamil A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Spiering, Wilko A1 - Stamatoyannopoulos, John A A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tan, Sian-Tsung A1 - Tarasov, Kirill V A1 - Trinh, Bosco A1 - Uitterlinden, André G A1 - van den Boogaard, Malou A1 - van Duijn, Cornelia M A1 - van Gilst, Wiek H A1 - Viikari, Jorma S A1 - Visscher, Peter M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Weichenberger, Christian X A1 - Westra, Harm-Jan A1 - Wijmenga, Cisca A1 - Wolffenbuttel, Bruce H A1 - Yang, Jian A1 - Bezzina, Connie R A1 - Munroe, Patricia B A1 - Snieder, Harold A1 - Wright, Alan F A1 - Rudan, Igor A1 - Boyer, Laurie A A1 - Asselbergs, Folkert W A1 - van Veldhuisen, Dirk J A1 - Stricker, Bruno H A1 - Psaty, Bruce M A1 - Ciullo, Marina A1 - Sanna, Serena A1 - Lehtimäki, Terho A1 - Wilson, James F A1 - Bandinelli, Stefania A1 - Alonso, Alvaro A1 - Gasparini, Paolo A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Felix, Stephan B A1 - Heckbert, Susan R A1 - de Boer, Rudolf A A1 - Newton-Cheh, Christopher A1 - Hicks, Andrew A A1 - Chambers, John C A1 - Jamshidi, Yalda A1 - Visel, Axel A1 - Christoffels, Vincent M A1 - Isaacs, Aaron A1 - Samani, Nilesh J A1 - de Bakker, Paul I W AB -

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.

CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

VL - 68 IS - 13 ER - TY - JOUR T1 - Can a Healthy Lifestyle Compress the Disabled Period in Older Adults? JF - J Am Geriatr Soc Y1 - 2016 A1 - Jacob, Mini E A1 - Yee, Laura M A1 - Diehr, Paula H A1 - Arnold, Alice M A1 - Thielke, Stephen M A1 - Chaves, Paulo H M A1 - Gobbo, Liana Del A1 - Hirsch, Calvin A1 - Siscovick, David A1 - Newman, Anne B AB -

OBJECTIVES: To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life.

DESIGN: Community-based cohort study of older adults followed from 1989 to 2015.

SETTING: Four U.S. communities.

PARTICIPANTS: Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 ± 5.5, 57% female, 15.2% minority) who were not wheelchair dependent and were able to give informed consent at baseline.

MEASUREMENTS: Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period.

RESULTS: The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95% confidence interval (CI) = 5.4-9.2) lower YAL/YoL% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7% (95% CI = 1.6-5.9) lower YAL/YoL% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95% CI = 0.3-0.8) higher YAL/YoL%.

CONCLUSION: The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.

VL - 64 IS - 10 ER - TY - JOUR T1 - Common variants in DRD2 are associated with sleep duration: the CARe consortium. JF - Hum Mol Genet Y1 - 2016 A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Lauderdale, Diane S A1 - Bennett, David A A1 - Buchman, Aron S A1 - Buxbaum, Sarah G A1 - De Jager, Philip L A1 - Evans, Daniel S A1 - Fulop, Tibor A1 - Gharib, Sina A A1 - Johnson, W Craig A1 - Kim, Hyun A1 - Larkin, Emma K A1 - Lee, Seung Ku A1 - Lim, Andrew S A1 - Punjabi, Naresh M A1 - Shin, Chol A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Weng, Jia A1 - Yaffe, Kristine A1 - Zee, Phyllis C A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Redline, Susan A1 - Saxena, Richa KW - Cohort Studies KW - Ethnic Groups KW - Humans KW - Polymorphism, Single Nucleotide KW - Polysomnography KW - Receptors, Dopamine D2 KW - Sleep KW - Time Factors AB -

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract ER - TY - JOUR T1 - Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. JF - PLoS Genet Y1 - 2016 A1 - Smith, J Gustav A1 - Felix, Janine F A1 - Morrison, Alanna C A1 - Kalogeropoulos, Andreas A1 - Trompet, Stella A1 - Wilk, Jemma B A1 - Gidlöf, Olof A1 - Wang, Xinchen A1 - Morley, Michael A1 - Mendelson, Michael A1 - Joehanes, Roby A1 - Ligthart, Symen A1 - Shan, Xiaoyin A1 - Bis, Joshua C A1 - Wang, Ying A A1 - Sjögren, Marketa A1 - Ngwa, Julius A1 - Brandimarto, Jeffrey A1 - Stott, David J A1 - Aguilar, David A1 - Rice, Kenneth M A1 - Sesso, Howard D A1 - Demissie, Serkalem A1 - Buckley, Brendan M A1 - Taylor, Kent D A1 - Ford, Ian A1 - Yao, Chen A1 - Liu, Chunyu A1 - Sotoodehnia, Nona A1 - van der Harst, Pim A1 - Stricker, Bruno H Ch A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Gaziano, J Michael A1 - Hofman, Albert A1 - Moravec, Christine S A1 - Uitterlinden, André G A1 - Kellis, Manolis A1 - van Meurs, Joyce B A1 - Margulies, Kenneth B A1 - Dehghan, Abbas A1 - Levy, Daniel A1 - Olde, Björn A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Jukema, J Wouter A1 - Djoussé, Luc A1 - Franco, Oscar H A1 - Boerwinkle, Eric A1 - Boyer, Laurie A A1 - Newton-Cheh, Christopher A1 - Butler, Javed A1 - Vasan, Ramachandran S A1 - Cappola, Thomas P A1 - Smith, Nicholas L AB -

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

VL - 12 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27149122?dopt=Abstract ER - TY - JOUR T1 - A DNA methylation biomarker of alcohol consumption. JF - Mol Psychiatry Y1 - 2016 A1 - Liu, C A1 - Marioni, R E A1 - Hedman, Å K A1 - Pfeiffer, L A1 - Tsai, P-C A1 - Reynolds, L M A1 - Just, A C A1 - Duan, Q A1 - Boer, C G A1 - Tanaka, T A1 - Elks, C E A1 - Aslibekyan, S A1 - Brody, J A A1 - Kühnel, B A1 - Herder, C A1 - Almli, L M A1 - Zhi, D A1 - Wang, Y A1 - Huan, T A1 - Yao, C A1 - Mendelson, M M A1 - Joehanes, R A1 - Liang, L A1 - Love, S-A A1 - Guan, W A1 - Shah, S A1 - McRae, A F A1 - Kretschmer, A A1 - Prokisch, H A1 - Strauch, K A1 - Peters, A A1 - Visscher, P M A1 - Wray, N R A1 - Guo, X A1 - Wiggins, K L A1 - Smith, A K A1 - Binder, E B A1 - Ressler, K J A1 - Irvin, M R A1 - Absher, D M A1 - Hernandez, D A1 - Ferrucci, L A1 - Bandinelli, S A1 - Lohman, K A1 - Ding, J A1 - Trevisi, L A1 - Gustafsson, S A1 - Sandling, J H A1 - Stolk, L A1 - Uitterlinden, A G A1 - Yet, I A1 - Castillo-Fernandez, J E A1 - Spector, T D A1 - Schwartz, J D A1 - Vokonas, P A1 - Lind, L A1 - Li, Y A1 - Fornage, M A1 - Arnett, D K A1 - Wareham, N J A1 - Sotoodehnia, N A1 - Ong, K K A1 - van Meurs, J B J A1 - Conneely, K N A1 - Baccarelli, A A A1 - Deary, I J A1 - Bell, J T A1 - North, K E A1 - Liu, Y A1 - Waldenberger, M A1 - London, S J A1 - Ingelsson, E A1 - Levy, D AB -

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Molecular Psychiatry advance online publication, 15 November 2016; doi:10.1038/mp.2016.192.

ER - TY - JOUR T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. JF - Genome Biol Y1 - 2016 A1 - Ligthart, Symen A1 - Marzi, Carola A1 - Aslibekyan, Stella A1 - Mendelson, Michael M A1 - Conneely, Karen N A1 - Tanaka, Toshiko A1 - Colicino, Elena A1 - Waite, Lindsay L A1 - Joehanes, Roby A1 - Guan, Weihua A1 - Brody, Jennifer A A1 - Elks, Cathy A1 - Marioni, Riccardo A1 - Jhun, Min A A1 - Agha, Golareh A1 - Bressler, Jan A1 - Ward-Caviness, Cavin K A1 - Chen, Brian H A1 - Huan, Tianxiao A1 - Bakulski, Kelly A1 - Salfati, Elias L A1 - Fiorito, Giovanni A1 - Wahl, Simone A1 - Schramm, Katharina A1 - Sha, Jin A1 - Hernandez, Dena G A1 - Just, Allan C A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Pilling, Luke C A1 - Pankow, James S A1 - Tsao, Phil S A1 - Liu, Chunyu A1 - Zhao, Wei A1 - Guarrera, Simonetta A1 - Michopoulos, Vasiliki J A1 - Smith, Alicia K A1 - Peters, Marjolein J A1 - Melzer, David A1 - Vokonas, Pantel A1 - Fornage, Myriam A1 - Prokisch, Holger A1 - Bis, Joshua C A1 - Chu, Audrey Y A1 - Herder, Christian A1 - Grallert, Harald A1 - Yao, Chen A1 - Shah, Sonia A1 - McRae, Allan F A1 - Lin, Honghuang A1 - Horvath, Steve A1 - Fallin, Daniele A1 - Hofman, Albert A1 - Wareham, Nicholas J A1 - Wiggins, Kerri L A1 - Feinberg, Andrew P A1 - Starr, John M A1 - Visscher, Peter M A1 - Murabito, Joanne M A1 - Kardia, Sharon L R A1 - Absher, Devin M A1 - Binder, Elisabeth B A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Matullo, Giuseppe A1 - Schwartz, Joel D A1 - Demerath, Ellen W A1 - Uitterlinden, André G A1 - van Meurs, Joyce B J A1 - Franco, Oscar H A1 - Chen, Yii-Der Ida A1 - Levy, Daniel A1 - Turner, Stephen T A1 - Deary, Ian J A1 - Ressler, Kerry J A1 - Dupuis, Josée A1 - Ferrucci, Luigi A1 - Ong, Ken K A1 - Assimes, Themistocles L A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Arnett, Donna K A1 - Baccarelli, Andrea A A1 - Benjamin, Emelia J A1 - Dehghan, Abbas AB -

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

VL - 17 IS - 1 ER - TY - JOUR T1 - Epigenetic Signatures of Cigarette Smoking. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Joehanes, Roby A1 - Just, Allan C A1 - Marioni, Riccardo E A1 - Pilling, Luke C A1 - Reynolds, Lindsay M A1 - Mandaviya, Pooja R A1 - Guan, Weihua A1 - Xu, Tao A1 - Elks, Cathy E A1 - Aslibekyan, Stella A1 - Moreno-Macias, Hortensia A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Dhingra, Radhika A1 - Yousefi, Paul A1 - Pankow, James S A1 - Kunze, Sonja A1 - Shah, Sonia H A1 - McRae, Allan F A1 - Lohman, Kurt A1 - Sha, Jin A1 - Absher, Devin M A1 - Ferrucci, Luigi A1 - Zhao, Wei A1 - Demerath, Ellen W A1 - Bressler, Jan A1 - Grove, Megan L A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Yao, Chen A1 - Kiel, Douglas P A1 - Peters, Annette A1 - Wang-Sattler, Rui A1 - Visscher, Peter M A1 - Wray, Naomi R A1 - Starr, John M A1 - Ding, Jingzhong A1 - Rodriguez, Carlos J A1 - Wareham, Nicholas J A1 - Irvin, Marguerite R A1 - Zhi, Degui A1 - Barrdahl, Myrto A1 - Vineis, Paolo A1 - Ambatipudi, Srikant A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Schwartz, Joel A1 - Colicino, Elena A1 - Hou, Lifang A1 - Vokonas, Pantel S A1 - Hernandez, Dena G A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Turner, Stephen T A1 - Ware, Erin B A1 - Smith, Alicia K A1 - Klengel, Torsten A1 - Binder, Elisabeth B A1 - Psaty, Bruce M A1 - Taylor, Kent D A1 - Gharib, Sina A A1 - Swenson, Brenton R A1 - Liang, Liming A1 - DeMeo, Dawn L A1 - O'Connor, George T A1 - Herceg, Zdenko A1 - Ressler, Kerry J A1 - Conneely, Karen N A1 - Sotoodehnia, Nona A1 - Kardia, Sharon L R A1 - Melzer, David A1 - Baccarelli, Andrea A A1 - van Meurs, Joyce B J A1 - Romieu, Isabelle A1 - Arnett, Donna K A1 - Ong, Ken K A1 - Liu, Yongmei A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Fornage, Myriam A1 - Levy, Daniel A1 - London, Stephanie J AB -

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

VL - 9 IS - 5 ER - TY - JOUR T1 - Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. JF - J Alzheimers Dis Y1 - 2016 A1 - Chouraki, Vincent A1 - Reitz, Christiane A1 - Maury, Fleur A1 - Bis, Joshua C A1 - Bellenguez, Céline A1 - Yu, Lei A1 - Jakobsdottir, Johanna A1 - Mukherjee, Shubhabrata A1 - Adams, Hieab H A1 - Choi, Seung Hoan A1 - Larson, Eric B A1 - Fitzpatrick, Annette A1 - Uitterlinden, André G A1 - De Jager, Philip L A1 - Hofman, Albert A1 - Gudnason, Vilmundur A1 - Vardarajan, Badri A1 - Ibrahim-Verbaas, Carla A1 - van der Lee, Sven J A1 - Lopez, Oscar A1 - Dartigues, Jean-François A1 - Berr, Claudine A1 - Amouyel, Philippe A1 - Bennett, David A A1 - van Duijn, Cornelia A1 - DeStefano, Anita L A1 - Launer, Lenore J A1 - Ikram, M Arfan A1 - Crane, Paul K A1 - Lambert, Jean-Charles A1 - Mayeux, Richard A1 - Seshadri, Sudha AB -

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

VL - 53 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract ER - TY - JOUR T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. JF - Am J Hum Genet Y1 - 2016 A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Slater, Andrew J A1 - Eicher, John D A1 - Evangelou, Evangelos A1 - Tajuddin, Salman M A1 - Love-Gregory, Latisha A1 - Kacprowski, Tim A1 - Schick, Ursula M A1 - Nomura, Akihiro A1 - Giri, Ayush A1 - Lessard, Samuel A1 - Brody, Jennifer A A1 - Schurmann, Claudia A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Manichaikul, Ani A1 - Pazoki, Raha A1 - Mihailov, Evelin A1 - Hill, W David A1 - Raffield, Laura M A1 - Burt, Amber A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - O'Donoghue, Michelle L A1 - Crosslin, David R A1 - de Denus, Simon A1 - Dubé, Marie-Pierre A1 - Elliott, Paul A1 - Engström, Gunnar A1 - Evans, Michele K A1 - Floyd, James S A1 - Fornage, Myriam A1 - Gao, He A1 - Greinacher, Andreas A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hernesniemi, Jussi A1 - Highland, Heather M A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Li, Jin A1 - Liewald, David C M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mathias, Rasika A A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mononen, Nina A1 - Nalls, Mike A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - O'Donnell, Chris J A1 - Orho-Melander, Marju A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Polfus, Linda A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Raitoharju, Emma A1 - Richard, Melissa A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schmidt, Frank A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thuesen, Betina H A1 - Torstenson, Eric S A1 - Tracy, Russell P A1 - Tzoulaki, Ioanna A1 - Zakai, Neil A A1 - Vacchi-Suzzi, Caterina A1 - van Duijn, Cornelia M A1 - van Rooij, Frank J A A1 - Cushman, Mary A1 - Deary, Ian J A1 - Velez Edwards, Digna R A1 - Vergnaud, Anne-Claire A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Zonderman, Alan B A1 - Kathiresan, Sekar A1 - Grarup, Niels A1 - Esko, Tõnu A1 - Loos, Ruth J F A1 - Lange, Leslie A A1 - Faraday, Nauder A1 - Abumrad, Nada A A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Auer, Paul L A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Lettre, Guillaume AB -

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. JF - Hum Mol Genet Y1 - 2016 A1 - Evans, Daniel S A1 - Avery, Christy L A1 - Nalls, Mike A A1 - Li, Guo A1 - Barnard, John A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Butler, Anne M A1 - Buxbaum, Sarah G A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Berenson, Gerald S A1 - Bis, Joshua C A1 - Buyske, Steven A1 - Carty, Cara L A1 - Chen, Wei A1 - Chung, Mina K A1 - Cummings, Steven R A1 - Deo, Rajat A1 - Eaton, Charles B A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Hsueh, Wen-Chi A1 - Isaacs, Aaron A1 - Jamshidi, Yalda A1 - Kerr, Kathleen F A1 - Liu, Felix A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Magnani, Jared W A1 - Maher, Joseph F A1 - Mehra, Reena A1 - Meng, Yan A A1 - Musani, Solomon K A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Shohet, Ralph V A1 - Singleton, Andrew B A1 - Smith, Jonathan D A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Taylor, Herman A A1 - Van Wagoner, David R A1 - Wilson, James G A1 - Young, Taylor A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Tranah, Gregory J A1 - Whitsel, Eric A A1 - Reiner, Alex P A1 - Sotoodehnia, Nona AB -

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

ER - TY - JOUR T1 - General Framework for Meta-Analysis of Haplotype Association Tests. JF - Genet Epidemiol Y1 - 2016 A1 - Wang, Shuai A1 - Zhao, Jing Hua A1 - An, Ping A1 - Guo, Xiuqing A1 - Jensen, Richard A A1 - Marten, Jonathan A1 - Huffman, Jennifer E A1 - Meidtner, Karina A1 - Boeing, Heiner A1 - Campbell, Archie A1 - Rice, Kenneth M A1 - Scott, Robert A A1 - Yao, Jie A1 - Schulze, Matthias B A1 - Wareham, Nicholas J A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Dupuis, Josée AB -

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

VL - 40 IS - 3 ER - TY - JOUR T1 - {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function JF - Nat Commun Y1 - 2016 A1 - Pattaro, C. A1 - Teumer, A. A1 - Gorski, M. A1 - Chu, A. Y. A1 - Li, M. A1 - Mijatovic, V. A1 - Garnaas, M. A1 - Tin, A. A1 - Sorice, R. A1 - Li, Y. A1 - Taliun, D. A1 - Olden, M. A1 - Foster, M. A1 - Yang, Q. A1 - Chen, M. H. A1 - Pers, T. H. A1 - Johnson, A. D. A1 - Ko, Y. A. A1 - Fuchsberger, C. A1 - Tayo, B. A1 - Nalls, M. A1 - Feitosa, M. F. A1 - Isaacs, A. A1 - Dehghan, A. A1 - d'Adamo, P. A1 - Adeyemo, A. A1 - Dieffenbach, A. K. A1 - Zonderman, A. B. A1 - Nolte, I. M. A1 - van der Most, P. J. A1 - Wright, A. F. A1 - Shuldiner, A. R. A1 - Morrison, A. C. A1 - Hofman, A. A1 - Smith, A. V. A1 - Dreisbach, A. W. A1 - Franke, A. A1 - Uitterlinden, A. G. A1 - Metspalu, A. A1 - Tonjes, A. A1 - Lupo, A. A1 - Robino, A. A1 - Johansson, ?. A1 - Demirkan, A. A1 - Kollerits, B. A1 - Freedman, B. I. A1 - Ponte, B. 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We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. VL - 7 ER - TY - JOUR T1 - {The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals JF - Nat Genet Y1 - 2016 A1 - Ehret, G. B. A1 - Ferreira, T. A1 - Chasman, D. I. A1 - Jackson, A. U. A1 - Schmidt, E. M. A1 - Johnson, T. A1 - Thorleifsson, G. A1 - Luan, J. A1 - Donnelly, L. A. A1 - Kanoni, S. A1 - Petersen, A. K. A1 - Pihur, V. A1 - Strawbridge, R. J. A1 - Shungin, D. A1 - Hughes, M. F. A1 - Meirelles, O. A1 - Kaakinen, M. A1 - Bouatia-Naji, N. A1 - Kristiansson, K. A1 - Shah, S. A1 - Kleber, M. E. A1 - Guo, X. A1 - Lyytik?inen, L. P. A1 - Fava, C. A1 - Eriksson, N. A1 - Nolte, I. M. A1 - Magnusson, P. K. A1 - Salfati, E. L. A1 - Rallidis, L. S. A1 - Theusch, E. A1 - Smith, A. J. P. A1 - Folkersen, L. A1 - Witkowska, K. A1 - Pers, T. H. A1 - Joehanes, R. A1 - Kim, S. K. A1 - Lataniotis, L. A1 - Jansen, R. A1 - Johnson, A. D. A1 - Warren, H. A1 - Kim, Y. J. A1 - Zhao, W. A1 - Wu, Y. A1 - Tayo, B. O. A1 - Bochud, M. A1 - Absher, D. A1 - Adair, L. S. A1 - Amin, N. A1 - Arking, D. E. A1 - Axelsson, T. A1 - Baldassarre, D. A1 - Balkau, B. A1 - Bandinelli, S. A1 - Barnes, M. R. A1 - Barroso, I. A1 - Bevan, S. A1 - Bis, J. C. A1 - Bjornsdottir, G. A1 - Boehnke, M. A1 - Boerwinkle, E. A1 - Bonnycastle, L. L. A1 - Boomsma, D. I. A1 - Bornstein, S. R. A1 - Brown, M. J. A1 - Burnier, M. A1 - Cabrera, C. P. A1 - Chambers, J. C. A1 - Chang, I. S. A1 - Cheng, C. Y. A1 - Chines, P. S. A1 - Chung, R. H. A1 - Collins, F. S. A1 - Connell, J. M. A1 - D?ring, A. A1 - Dallongeville, J. A1 - Danesh, J. A1 - de Faire, U. A1 - Delgado, G. A1 - Dominiczak, A. F. A1 - Doney, A. S. F. A1 - Drenos, F. A1 - Edkins, S. A1 - Eicher, J. D. A1 - Elosua, R. A1 - Enroth, S. A1 - Erdmann, J. A1 - Eriksson, P. A1 - Esko, T. A1 - Evangelou, E. A1 - Evans, A. A1 - Fall, T. A1 - Farrall, M. A1 - Felix, J. F. A1 - Ferri?res, J. A1 - Ferrucci, L. A1 - Fornage, M. A1 - Forrester, T. A1 - Franceschini, N. A1 - Duran, O. H. F. A1 - Franco-Cereceda, A. A1 - Fraser, R. M. A1 - Ganesh, S. K. A1 - Gao, H. A1 - Gertow, K. A1 - Gianfagna, F. A1 - Gigante, B. A1 - Giulianini, F. A1 - Goel, A. A1 - Goodall, A. H. A1 - Goodarzi, M. O. A1 - Gorski, M. A1 - Gr??ler, J. A1 - Groves, C. A1 - Gudnason, V. A1 - Gyllensten, U. A1 - Hallmans, G. A1 - Hartikainen, A. L. A1 - Hassinen, M. A1 - Havulinna, A. S. A1 - Hayward, C. A1 - Hercberg, S. A1 - Herzig, K. H. A1 - Hicks, A. A. A1 - Hingorani, A. D. A1 - Hirschhorn, J. N. A1 - Hofman, A. A1 - Holmen, J. A1 - Holmen, O. L. A1 - Hottenga, J. J. A1 - Howard, P. A1 - Hsiung, C. A. A1 - Hunt, S. C. A1 - Ikram, M. A. A1 - Illig, T. A1 - Iribarren, C. A1 - Jensen, R. A. A1 - K?h?nen, M. A1 - Kang, H. A1 - Kathiresan, S. A1 - Keating, B. J. A1 - Khaw, K. T. A1 - Kim, Y. K. A1 - Kim, E. A1 - Kivimaki, M. A1 - Klopp, N. A1 - Kolovou, G. A1 - Komulainen, P. A1 - Kooner, J. S. A1 - Kosova, G. A1 - Krauss, R. M. A1 - Kuh, D. A1 - Kutalik, Z. A1 - Kuusisto, J. A1 - Kval?y, K. A1 - Lakka, T. A. A1 - Lee, N. R. A1 - Lee, I. T. A1 - Lee, W. J. A1 - Levy, D. A1 - Li, X. A1 - Liang, K. W. A1 - Lin, H. A1 - Lin, L. A1 - Lindstr?m, J. A1 - Lobbens, S. A1 - M?nnist?, S. A1 - M?ller, G. A1 - M?ller-Nurasyid, M. A1 - Mach, F. A1 - Markus, H. S. A1 - Marouli, E. A1 - McCarthy, M. I. A1 - McKenzie, C. A. A1 - Meneton, P. A1 - Menni, C. A1 - Metspalu, A. A1 - Mijatovic, V. A1 - Moilanen, L. A1 - Montasser, M. E. A1 - Morris, A. D. A1 - Morrison, A. C. A1 - Mulas, A. A1 - Nagaraja, R. A1 - Narisu, N. A1 - Nikus, K. A1 - O'Donnell, C. J. A1 - O'Reilly, P. F. A1 - Ong, K. K. A1 - Paccaud, F. A1 - Palmer, C. D. A1 - Parsa, A. A1 - Pedersen, N. L. A1 - Penninx, B. W. A1 - Perola, M. A1 - Peters, A. A1 - Poulter, N. A1 - Pramstaller, P. P. A1 - Psaty, B. M. A1 - Quertermous, T. A1 - Rao, D. C. A1 - Rasheed, A. A1 - Rayner, N. W. N. W. R. A1 - Renstr?m, F. A1 - Rettig, R. A1 - Rice, K. M. A1 - Roberts, R. A1 - Rose, L. M. A1 - Rossouw, J. A1 - Samani, N. J. A1 - Sanna, S. A1 - Saramies, J. A1 - Schunkert, H. A1 - Sebert, S. A1 - Sheu, W. H. A1 - Shin, Y. A. A1 - Sim, X. A1 - Smit, J. H. A1 - Smith, A. V. A1 - Sosa, M. X. A1 - Spector, T. D. A1 - Stan??kov?, A. A1 - Stanton, A. A1 - Stirrups, K. E. A1 - Stringham, H. M. A1 - Sundstrom, J. A1 - Swift, A. J. A1 - Syv?nen, A. C. A1 - Tai, E. S. A1 - Tanaka, T. A1 - Tarasov, K. V. A1 - Teumer, A. A1 - Thorsteinsdottir, U. A1 - Tobin, M. D. A1 - Tremoli, E. A1 - Uitterlinden, A. G. A1 - Uusitupa, M. A1 - Vaez, A. A1 - Vaidya, D. A1 - van Duijn, C. M. A1 - van Iperen, E. P. A. A1 - Vasan, R. S. A1 - Verwoert, G. C. A1 - Virtamo, J. A1 - Vitart, V. A1 - Voight, B. F. A1 - Vollenweider, P. A1 - Wagner, A. A1 - Wain, L. V. A1 - Wareham, N. J. A1 - Watkins, H. A1 - Weder, A. B. A1 - Westra, H. J. A1 - Wilks, R. A1 - Wilsgaard, T. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Yang, T. P. A1 - Yao, J. A1 - Yengo, L. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Zhu, X. A1 - Bovet, P. A1 - Cooper, R. S. A1 - Mohlke, K. L. A1 - Saleheen, D. A1 - Lee, J. Y. A1 - Elliott, P. A1 - Gierman, H. J. A1 - Willer, C. J. A1 - Franke, L. A1 - Hovingh, G. K. A1 - Taylor, K. D. A1 - Dedoussis, G. A1 - Sever, P. A1 - Wong, A. A1 - Lind, L. A1 - Assimes, T. L. A1 - Nj?lstad, I. A1 - Schwarz, P. E. A1 - Langenberg, C. A1 - Snieder, H. A1 - Caulfield, M. J. A1 - Melander, O. A1 - Laakso, M. A1 - Saltevo, J. A1 - Rauramaa, R. A1 - Tuomilehto, J. A1 - Ingelsson, E. A1 - Lehtim?ki, T. A1 - Hveem, K. A1 - Palmas, W. A1 - M?rz, W. A1 - Kumari, M. A1 - Salomaa, V. A1 - Chen, Y. I. A1 - Rotter, J. I. A1 - Froguel, P. A1 - Jarvelin, M. R. A1 - Lakatta, E. G. A1 - Kuulasmaa, K. A1 - Franks, P. W. A1 - Hamsten, A. A1 - Wichmann, H. E. A1 - Palmer, C. N. A. A1 - Stefansson, K. A1 - Ridker, P. M. A1 - Loos, R. J. F. A1 - Chakravarti, A. A1 - Deloukas, P. A1 - Morris, A. P. A1 - Newton-Cheh, C. A1 - Munroe, P. B. AB - To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. VL - 48 ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Matteini, Amy M A1 - Tanaka, Toshiko A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - Eicher, John D A1 - Johnson, Andrew D A1 - Arnold, Alice M A1 - Callisaya, Michele L A1 - Davies, Gail A1 - Evans, Daniel S A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Yu, Lei A1 - Arking, Dan E A1 - Buchman, Aron S A1 - Chibinik, Lori B A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Faul, Jessica D A1 - Garcia, Melissa E A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - Liewald, David C A1 - Liu, Yongmei A1 - Lopez, Lorna A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - Starr, John M A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Weir, David R A1 - Yaffe, Kristine A1 - Zhao, Wei A1 - Zhuang, Wei Vivian A1 - Zmuda, Joseph M A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Kocher, Thomas A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Spector, Timothy D A1 - Srikanth, Velandai K A1 - Windham, B Gwen A1 - Zillikens, M Carola A1 - Newman, Anne B A1 - Walston, Jeremy D A1 - Kiel, Douglas P A1 - Murabito, Joanne M AB -

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - GWAS for executive function and processing speed suggests involvement of the CADM2 gene. JF - Mol Psychiatry Y1 - 2016 A1 - Ibrahim-Verbaas, C A A1 - Bressler, J A1 - Debette, S A1 - Schuur, M A1 - Smith, A V A1 - Bis, J C A1 - Davies, G A1 - Trompet, S A1 - Smith, J A A1 - Wolf, C A1 - Chibnik, L B A1 - Liu, Y A1 - Vitart, V A1 - Kirin, M A1 - Petrovic, K A1 - Polasek, O A1 - Zgaga, L A1 - Fawns-Ritchie, C A1 - Hoffmann, P A1 - Karjalainen, J A1 - Lahti, J A1 - Llewellyn, D J A1 - Schmidt, C O A1 - Mather, K A A1 - Chouraki, V A1 - Sun, Q A1 - Resnick, S M A1 - Rose, L M A1 - Oldmeadow, C A1 - Stewart, M A1 - Smith, B H A1 - Gudnason, V A1 - Yang, Q A1 - Mirza, S S A1 - Jukema, J W A1 - deJager, P L A1 - Harris, T B A1 - Liewald, D C A1 - Amin, N A1 - Coker, L H A1 - Stegle, O A1 - Lopez, O L A1 - Schmidt, R A1 - Teumer, A A1 - Ford, I A1 - Karbalai, N A1 - Becker, J T A1 - Jonsdottir, M K A1 - Au, R A1 - Fehrmann, R S N A1 - Herms, S A1 - Nalls, M A1 - Zhao, W A1 - Turner, S T A1 - Yaffe, K A1 - Lohman, K A1 - van Swieten, J C A1 - Kardia, S L R A1 - Knopman, D S A1 - Meeks, W M A1 - Heiss, G A1 - Holliday, E G A1 - Schofield, P W A1 - Tanaka, T A1 - Stott, D J A1 - Wang, J A1 - Ridker, P A1 - Gow, A J A1 - Pattie, A A1 - Starr, J M A1 - Hocking, L J A1 - Armstrong, N J A1 - McLachlan, S A1 - Shulman, J M A1 - Pilling, L C A1 - Eiriksdottir, G A1 - Scott, R J A1 - Kochan, N A A1 - Palotie, A A1 - Hsieh, Y-C A1 - Eriksson, J G A1 - Penman, A A1 - Gottesman, R F A1 - Oostra, B A A1 - Yu, L A1 - DeStefano, A L A1 - Beiser, A A1 - Garcia, M A1 - Rotter, J I A1 - Nöthen, M M A1 - Hofman, A A1 - Slagboom, P E A1 - Westendorp, R G J A1 - Buckley, B M A1 - Wolf, P A A1 - Uitterlinden, A G A1 - Psaty, B M A1 - Grabe, H J A1 - Bandinelli, S A1 - Chasman, D I A1 - Grodstein, F A1 - Räikkönen, K A1 - Lambert, J-C A1 - Porteous, D J A1 - Price, J F A1 - Sachdev, P S A1 - Ferrucci, L A1 - Attia, J R A1 - Rudan, I A1 - Hayward, C A1 - Wright, A F A1 - Wilson, J F A1 - Cichon, S A1 - Franke, L A1 - Schmidt, H A1 - Ding, J A1 - de Craen, A J M A1 - Fornage, M A1 - Bennett, D A A1 - Deary, I J A1 - Ikram, M A A1 - Launer, L J A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - van Duijn, C M A1 - Mosley, T H AB -

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

VL - 21 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25869804?dopt=Abstract ER - TY - JOUR T1 - A hybrid computational strategy to address WGS variant analysis in >5000 samples. JF - BMC Bioinformatics Y1 - 2016 A1 - Huang, Zhuoyi A1 - Rustagi, Navin A1 - Veeraraghavan, Narayanan A1 - Carroll, Andrew A1 - Gibbs, Richard A1 - Boerwinkle, Eric A1 - Venkata, Manjunath Gorentla A1 - Yu, Fuli KW - Databases, Genetic KW - Genome, Human KW - Genomics KW - High-Throughput Nucleotide Sequencing KW - Humans AB -

BACKGROUND: The decreasing costs of sequencing are driving the need for cost effective and real time variant calling of whole genome sequencing data. The scale of these projects are far beyond the capacity of typical computing resources available with most research labs. Other infrastructures like the cloud AWS environment and supercomputers also have limitations due to which large scale joint variant calling becomes infeasible, and infrastructure specific variant calling strategies either fail to scale up to large datasets or abandon joint calling strategies.

RESULTS: We present a high throughput framework including multiple variant callers for single nucleotide variant (SNV) calling, which leverages hybrid computing infrastructure consisting of cloud AWS, supercomputers and local high performance computing infrastructures. We present a novel binning approach for large scale joint variant calling and imputation which can scale up to over 10,000 samples while producing SNV callsets with high sensitivity and specificity. As a proof of principle, we present results of analysis on Cohorts for Heart And Aging Research in Genomic Epidemiology (CHARGE) WGS freeze 3 dataset in which joint calling, imputation and phasing of over 5300 whole genome samples was produced in under 6 weeks using four state-of-the-art callers. The callers used were SNPTools, GATK-HaplotypeCaller, GATK-UnifiedGenotyper and GotCloud. We used Amazon AWS, a 4000-core in-house cluster at Baylor College of Medicine, IBM power PC Blue BioU at Rice and Rhea at Oak Ridge National Laboratory (ORNL) for the computation. AWS was used for joint calling of 180 TB of BAM files, and ORNL and Rice supercomputers were used for the imputation and phasing step. All other steps were carried out on the local compute cluster. The entire operation used 5.2 million core hours and only transferred a total of 6 TB of data across the platforms.

CONCLUSIONS: Even with increasing sizes of whole genome datasets, ensemble joint calling of SNVs for low coverage data can be accomplished in a scalable, cost effective and fast manner by using heterogeneous computing platforms without compromising on the quality of variants.

VL - 17 IS - 1 ER - TY - JOUR T1 - Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. JF - Eur J Prev Cardiol Y1 - 2016 A1 - Willeit, Peter A1 - Thompson, Simon G A1 - Agewall, Stefan A1 - Bergström, Göran A1 - Bickel, Horst A1 - Catapano, Alberico L A1 - Chien, Kuo-Liong A1 - de Groot, Eric A1 - Empana, Jean-Philippe A1 - Etgen, Thorleif A1 - Franco, Oscar H A1 - Iglseder, Bernhard A1 - Johnsen, Stein H A1 - Kavousi, Maryam A1 - Lind, Lars A1 - Liu, Jing A1 - Mathiesen, Ellisiv B A1 - Norata, Giuseppe D A1 - Olsen, Michael H A1 - Papagianni, Aikaterini A1 - Poppert, Holger A1 - Price, Jackie F A1 - Sacco, Ralph L A1 - Yanez, David N A1 - Zhao, Dong A1 - Schminke, Ulf A1 - Bülbül, Alpaslan A1 - Polak, Joseph F A1 - Sitzer, Matthias A1 - Hofman, Albert A1 - Grigore, Liliana A1 - Dörr, Marcus A1 - Su, Ta-Chen A1 - Ducimetiere, Pierre A1 - Xie, Wuxiang A1 - Ronkainen, Kimmo A1 - Kiechl, Stefan A1 - Rundek, Tatjana A1 - Robertson, Christine A1 - Fagerberg, Björn A1 - Bokemark, Lena A1 - Steinmetz, Helmuth A1 - Ikram, M Arfan A1 - Völzke, Henry A1 - Lin, Hung-Ju A1 - Plichart, Matthieu A1 - Tuomainen, Tomi-Pekka A1 - Desvarieux, Moïse A1 - McLachlan, Stela A1 - Schmidt, Caroline A1 - Kauhanen, Jussi A1 - Willeit, Johann A1 - Lorenz, Matthias W A1 - Sander, Dirk AB -

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).

CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25416041?dopt=Abstract ER - TY - JOUR T1 - KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. JF - Proc Natl Acad Sci U S A Y1 - 2016 A1 - Schumann, Gunter A1 - Liu, Chunyu A1 - O'Reilly, Paul A1 - Gao, He A1 - Song, Parkyong A1 - Xu, Bing A1 - Ruggeri, Barbara A1 - Amin, Najaf A1 - Jia, Tianye A1 - Preis, Sarah A1 - Segura Lepe, Marcelo A1 - Akira, Shizuo A1 - Barbieri, Caterina A1 - Baumeister, Sebastian A1 - Cauchi, Stephane A1 - Clarke, Toni-Kim A1 - Enroth, Stefan A1 - Fischer, Krista A1 - Hällfors, Jenni A1 - Harris, Sarah E A1 - Hieber, Saskia A1 - Hofer, Edith A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Joshi, Peter K A1 - Kaartinen, Niina A1 - Laitinen, Jaana A1 - Lemaitre, Rozenn A1 - Loukola, Anu A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Mangino, Massimo A1 - Manichaikul, Ani A1 - Mbarek, Hamdi A1 - Milaneschi, Yuri A1 - Moayyeri, Alireza A1 - Mukamal, Kenneth A1 - Nelson, Christopher A1 - Nettleton, Jennifer A1 - Partinen, Eemil A1 - Rawal, Rajesh A1 - Robino, Antonietta A1 - Rose, Lynda A1 - Sala, Cinzia A1 - Satoh, Takashi A1 - Schmidt, Reinhold A1 - Schraut, Katharina A1 - Scott, Robert A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Uitterlinden, André G A1 - Venturini, Cristina A1 - Vergnaud, Anne-Claire A1 - Verweij, Niek A1 - Vitart, Veronique A1 - Vuckovic, Dragana A1 - Wedenoja, Juho A1 - Yengo, Loic A1 - Yu, Bing A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Boomsma, Dorret I A1 - Chambers, John A1 - Chasman, Daniel I A1 - Daniela, Toniolo A1 - de Geus, Eco A1 - Deary, Ian A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Eulenburg, Volker A1 - Franco, Oscar H A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Heath, Andrew C A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Huth, Cornelia A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Kaprio, Jaakko A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Madden, Pamela A F A1 - Martin, Nicholas A1 - Morrison, Alanna A1 - Penninx, Brenda A1 - Pirastu, Nicola A1 - Psaty, Bruce A1 - Raitakari, Olli A1 - Ridker, Paul A1 - Rose, Richard A1 - Rotter, Jerome I A1 - Samani, Nilesh J A1 - Schmidt, Helena A1 - Spector, Tim D A1 - Stott, David A1 - Strachan, David A1 - Tzoulaki, Ioanna A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Marques-Vidal, Pedro A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wilson, James A1 - Wolffenbuttel, Bruce A1 - Bakalkin, Georgy A1 - Evangelou, Evangelos A1 - Liu, Yun A1 - Rice, Kenneth M A1 - Desrivières, Sylvane A1 - Kliewer, Steven A A1 - Mangelsdorf, David J A1 - Müller, Christian P A1 - Levy, Daniel A1 - Elliott, Paul AB -

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

VL - 113 IS - 50 ER - TY - JOUR T1 - Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. JF - Am J Hum Genet Y1 - 2016 A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Eicher, John D A1 - Chami, Nathalie A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Hill, W David A1 - Kacprowski, Tim A1 - Li, Jin A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Mihailov, Evelin A1 - O'Donoghue, Michelle L A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Polfus, Linda M A1 - Smith, Albert Vernon A1 - Schurmann, Claudia A1 - Vacchi-Suzzi, Caterina A1 - Waterworth, Dawn M A1 - Evangelou, Evangelos A1 - Yanek, Lisa R A1 - Burt, Amber A1 - Chen, Ming-Huei A1 - van Rooij, Frank J A A1 - Floyd, James S A1 - Greinacher, Andreas A1 - Harris, Tamara B A1 - Highland, Heather M A1 - Lange, Leslie A A1 - Liu, Yongmei A1 - Mägi, Reedik A1 - Nalls, Mike A A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - Starr, John M A1 - Tardif, Jean-Claude A1 - Tzoulaki, Ioanna A1 - Velez Edwards, Digna R A1 - Wallentin, Lars A1 - Bartz, Traci M A1 - Becker, Lewis C A1 - Denny, Joshua C A1 - Raffield, Laura M A1 - Rioux, John D A1 - Friedrich, Nele A1 - Fornage, Myriam A1 - Gao, He A1 - Hirschhorn, Joel N A1 - Liewald, David C M A1 - Rich, Stephen S A1 - Uitterlinden, Andre A1 - Bastarache, Lisa A1 - Becker, Diane M A1 - Boerwinkle, Eric A1 - de Denus, Simon A1 - Bottinger, Erwin P A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Lu, Yingchang A1 - Metspalu, Andres A1 - O'Donnell, Chris J A1 - Quarells, Rakale C A1 - Richard, Melissa A1 - Torstenson, Eric S A1 - Taylor, Kent D A1 - Vergnaud, Anne-Claire A1 - Zonderman, Alan B A1 - Crosslin, David R A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Slater, Andrew J A1 - Dehghan, Abbas A1 - White, Harvey D A1 - Ganesh, Santhi K A1 - Loos, Ruth J F A1 - Esko, Tõnu A1 - Faraday, Nauder A1 - Wilson, James G A1 - Cushman, Mary A1 - Johnson, Andrew D A1 - Edwards, Todd L A1 - Zakai, Neil A A1 - Lettre, Guillaume A1 - Reiner, Alex P A1 - Auer, Paul L AB -

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract ER - TY - JOUR T1 - Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study. JF - Am J Epidemiol Y1 - 2016 A1 - Karas, Maria G A1 - Yee, Laura M A1 - Biggs, Mary L A1 - Djoussé, Luc A1 - Mukamal, Kenneth J A1 - Ix, Joachim H A1 - Zieman, Susan J A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Rosenberg, Michael A A1 - Kronmal, Richard A A1 - Heckbert, Susan R A1 - Kizer, Jorge R AB -

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

VL - 183 IS - 11 ER - TY - JOUR T1 - Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. JF - Nat Genet Y1 - 2016 A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Martin, Lisa W A1 - Chen, Yii-Der Ida A1 - Surendran, Praveen A1 - Drenos, Fotios A1 - Cook, James P A1 - Auer, Paul L A1 - Chu, Audrey Y A1 - Giri, Ayush A1 - Zhao, Wei A1 - Jakobsdottir, Johanna A1 - Lin, Li-An A1 - Stafford, Jeanette M A1 - Amin, Najaf A1 - Mei, Hao A1 - Yao, Jie A1 - Voorman, Arend A1 - Larson, Martin G A1 - Grove, Megan L A1 - Smith, Albert V A1 - Hwang, Shih-Jen A1 - Chen, Han A1 - Huan, Tianxiao A1 - Kosova, Gulum A1 - Stitziel, Nathan O A1 - Kathiresan, Sekar A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Deloukas, Panos A1 - Li, Man A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Gorski, Mathias A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Rossouw, Jacques E A1 - Faul, Jessica D A1 - Kardia, Sharon L R A1 - Bouchard, Claude A1 - Raffel, Leslie J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Vasan, Ramachandran S A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Liu, Kiang A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Daw, E Warwick A1 - Giulianini, Franco A1 - Ganesh, Santhi A1 - Salfati, Elias A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Rettig, Rainer A1 - Völzke, Henry A1 - Kim, Eric A1 - Lee, Wen-Jane A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Tsosie, Krystal S A1 - Edwards, Digna R Velez A1 - Liu, Yongmei A1 - Correa, Adolfo A1 - Weir, David R A1 - Völker, Uwe A1 - Ridker, Paul M A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Reiner, Alexander P A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Edwards, Todd L A1 - Chakravarti, Aravinda A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Ehret, Georg B A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Chasman, Daniel I AB -

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

VL - 48 IS - 10 ER - TY - JOUR T1 - A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. JF - Hum Mol Genet Y1 - 2016 A1 - de Vries, Paul S A1 - Chasman, Daniel I A1 - Sabater-Lleal, Maria A1 - Chen, Ming-Huei A1 - Huffman, Jennifer E A1 - Steri, Maristella A1 - Tang, Weihong A1 - Teumer, Alexander A1 - Marioni, Riccardo E A1 - Grossmann, Vera A1 - Hottenga, Jouke J A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Zhao, Jing Hua A1 - Brody, Jennifer A A1 - Kleber, Marcus E A1 - Guo, Xiuqing A1 - Wang, Jie Jin A1 - Auer, Paul L A1 - Attia, John R A1 - Yanek, Lisa R A1 - Ahluwalia, Tarunveer S A1 - Lahti, Jari A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Bielak, Lawrence F A1 - Joshi, Peter K A1 - Rocanin-Arjo, Ares A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Riess, Helene A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Goel, Anuj A1 - Yang, Qiong A1 - Ghanbari, Mohsen A1 - Willemsen, Gonneke A1 - Rumley, Ann A1 - Fiorillo, Edoardo A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Scott, Robert A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Yao, Jie A1 - Kifley, Annette A1 - Kooperberg, Charles A1 - Qayyum, Rehan A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Räikkönen, Katri A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Peyser, Patricia A A1 - Wild, Sarah A1 - Trégouët, David-Alexandre A1 - Wright, Alan F A1 - Marten, Jonathan A1 - Zemunik, Tatijana A1 - Morrison, Alanna C A1 - Sennblad, Bengt A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - de Geus, Eco J C A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Binder, Harald A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Khaw, Kay-Tee A1 - McKnight, Barbara A1 - Huang, Jie A1 - Jenny, Nancy S A1 - Holliday, Elizabeth G A1 - Qi, Lihong A1 - Mcevoy, Mark G A1 - Becker, Diane M A1 - Starr, John M A1 - Sarin, Antti-Pekka A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Jhun, Min A A1 - Campbell, Harry A1 - Hamsten, Anders A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Koenig, Wolfgang A1 - Psaty, Bruce M A1 - Haritunians, Talin A1 - Liu, Jingmin A1 - Palotie, Aarno A1 - Uitterlinden, André G A1 - Stott, David J A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Morange, Pierre-Emmanuel A1 - Wilson, James F A1 - Kardia, Sharon L R A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Eriksson, Johan G A1 - Hansen, Torben A1 - Deary, Ian J A1 - Becker, Lewis C A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - März, Winfried A1 - Wareham, Nick J A1 - Peters, Annette A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Jukema, J Wouter A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Cucca, Francesco A1 - Tracy, Russell A1 - Watkins, Hugh A1 - Reiner, Alex P A1 - Folsom, Aaron R A1 - Ridker, Paul M A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

VL - 25 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract ER - TY - JOUR T1 - Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Natarajan, Pradeep A1 - Bis, Joshua C A1 - Bielak, Lawrence F A1 - Cox, Amanda J A1 - Dörr, Marcus A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Isaacs, Aaron A1 - Jhun, Min A A1 - Kavousi, Maryam A1 - Li-Gao, Ruifang A1 - Lyytikäinen, Leo-Pekka A1 - Marioni, Riccardo E A1 - Schminke, Ulf A1 - Stitziel, Nathan O A1 - Tada, Hayato A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Baber, Usman A1 - Borecki, Ingrid B A1 - Carr, J Jeffrey A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - de Jong, Pim A A1 - de Koning, Harry A1 - de Vos, Bob D A1 - Demirkan, Ayse A1 - Fuster, Valentin A1 - Franco, Oscar H A1 - Goodarzi, Mark O A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hoffmann, Udo A1 - Hofman, Albert A1 - Išgum, Ivana A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Massaro, Joseph A1 - Mehran, Roxana A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - de Mutsert, Renée A1 - Newman, Anne B A1 - Nguyen, Khanh-Dung A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Oudkerk, Matthijs A1 - Pankow, James S A1 - Peloso, Gina M A1 - Post, Wendy A1 - Province, Michael A A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rivadeneira, Fernando A1 - Rosendaal, Frits A1 - Sartori, Samantha A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Lugt, Aad A1 - Völker, Uwe A1 - Wardlaw, Joanna M A1 - Wassel, Christina L A1 - Weiss, Stefan A1 - Wojczynski, Mary K A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dehghan, Abbas A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Lehtimäki, Terho A1 - Mathias, Rasika A1 - Mook-Kanamori, Dennis O A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Kathiresan, Sekar A1 - Peyser, Patricia A A1 - O'Donnell, Christopher J AB -

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

ER - TY - JOUR T1 - Neighborhood Characteristics are Associated with Racial and Gender Variation in Walking among Older Adults: the Cardiovascular Health Study. JF - Ethn Dis Y1 - 2016 A1 - Yan, Tingjian A1 - Liang, Li-Jung A1 - Vassar, Stefanie A1 - Katz, Monica Cheung A1 - Escarce, José J A1 - Longstreth, W T Jr A1 - Merkin, Sharon Stein A1 - Brown, Arleen F AB -

OBJECTIVE: To examine variation by race and gender in the association between neighborhood socioeconomic status and walking among community-dwelling older adults.

DESIGN: Cross-sectional.

SETTING: Cardiovascular Health Study, a longitudinal population-based cohort.

PARTICIPANTS: 4,849 adults, aged > 65 years.

MEASUREMENTS: Participants reported the number of city blocks walked in the prior week. Neighborhood socioeconomic status (NSES) was measured at the level of the census tract. Negative binominal regression models were constructed to test the association between NSES and blocks walked. In the fully adjusted models, we included two-way and three-way interaction terms among race, gender, and NSES.

RESULTS: In adjusted analyses, among White residents in the lowest NSES quartile (most disadvantaged), men walked 64% more than women (P<.001), while in the highest NSES (most advantaged), men walked 43% more than women (P<.001). Among African American residents in the lowest NSES quartile, men walked 196% more blocks than women (P<.001).

CONCLUSIONS: Female gender is more strongly associated with walking for African Americans than for Whites in low SES neighborhoods but had a similar association with walking for both African Americans and Whites in high SES neighborhoods.

VL - 26 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26843792?dopt=Abstract ER - TY - JOUR T1 - A novel Alzheimer disease locus located near the gene encoding tau protein. JF - Mol Psychiatry Y1 - 2016 A1 - Jun, G A1 - Ibrahim-Verbaas, C A A1 - Vronskaya, M A1 - Lambert, J-C A1 - Chung, J A1 - Naj, A C A1 - Kunkle, B W A1 - Wang, L-S A1 - Bis, J C A1 - Bellenguez, C A1 - Harold, D A1 - Lunetta, K L A1 - DeStefano, A L A1 - Grenier-Boley, B A1 - Sims, R A1 - Beecham, G W A1 - Smith, A V A1 - Chouraki, V A1 - Hamilton-Nelson, K L A1 - Ikram, M A A1 - Fiévet, N A1 - Denning, N A1 - Martin, E R A1 - Schmidt, H A1 - Kamatani, Y A1 - Dunstan, M L A1 - Valladares, O A1 - Laza, A R A1 - Zelenika, D A1 - Ramirez, A A1 - Foroud, T M A1 - Choi, S-H A1 - Boland, A A1 - Becker, T A1 - Kukull, W A A1 - van der Lee, S J A1 - Pasquier, F A1 - Cruchaga, C A1 - Beekly, D A1 - Fitzpatrick, A L A1 - Hanon, O A1 - Gill, M A1 - Barber, R A1 - Gudnason, V A1 - Campion, D A1 - Love, S A1 - Bennett, D A A1 - Amin, N A1 - Berr, C A1 - Tsolaki, Magda A1 - Buxbaum, J D A1 - Lopez, O L A1 - Deramecourt, V A1 - Fox, N C A1 - Cantwell, L B A1 - Tárraga, L A1 - Dufouil, C A1 - Hardy, J A1 - Crane, P K A1 - Eiriksdottir, G A1 - Hannequin, D A1 - Clarke, R A1 - Evans, D A1 - Mosley, T H A1 - Letenneur, L A1 - Brayne, C A1 - Maier, W A1 - De Jager, P A1 - Emilsson, V A1 - Dartigues, J-F A1 - Hampel, H A1 - Kamboh, M I A1 - de Bruijn, R F A G A1 - Tzourio, C A1 - Pastor, P A1 - Larson, E B A1 - Rotter, J I A1 - O'Donovan, M C A1 - Montine, T J A1 - Nalls, M A A1 - Mead, S A1 - Reiman, E M A1 - Jonsson, P V A1 - Holmes, C A1 - St George-Hyslop, P H A1 - Boada, M A1 - Passmore, P A1 - Wendland, J R A1 - Schmidt, R A1 - Morgan, K A1 - Winslow, A R A1 - Powell, J F A1 - Carasquillo, M A1 - Younkin, S G A1 - Jakobsdóttir, J A1 - Kauwe, J S K A1 - Wilhelmsen, K C A1 - Rujescu, D A1 - Nöthen, M M A1 - Hofman, A A1 - Jones, L A1 - Haines, J L A1 - Psaty, B M A1 - Van Broeckhoven, C A1 - Holmans, P A1 - Launer, L J A1 - Mayeux, R A1 - Lathrop, M A1 - Goate, A M A1 - Escott-Price, V A1 - Seshadri, S A1 - Pericak-Vance, M A A1 - Amouyel, P A1 - Williams, J A1 - van Duijn, C M A1 - Schellenberg, G D A1 - Farrer, L A KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Chromosomes, Human, Pair 17 KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - tau Proteins AB -

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

VL - 21 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25778476?dopt=Abstract ER - TY - JOUR T1 - {Novel genetic loci underlying human intracranial volume identified through genome-wide association JF - Nat Neurosci Y1 - 2016 A1 - Adams, H. H. A1 - Hibar, D. P. A1 - Chouraki, V. A1 - Stein, J. L. A1 - Nyquist, P. A. A1 - Renter?a, M. E. A1 - Trompet, S. A1 - Arias-Vasquez, A. A1 - Seshadri, S. A1 - Desrivi?res, S. A1 - Beecham, A. H. A1 - Jahanshad, N. A1 - Wittfeld, K. A1 - van der Lee, S. J. A1 - Abramovic, L. A1 - Alhusaini, S. A1 - Amin, N. A1 - Andersson, M. A1 - Arfanakis, K. A1 - Aribisala, B. S. A1 - Armstrong, N. J. A1 - Athanasiu, L. A1 - Axelsson, T. A1 - Beiser, A. A1 - Bernard, M. A1 - Bis, J. C. A1 - Blanken, L. M. A1 - Blanton, S. H. A1 - Bohlken, M. M. A1 - Boks, M. P. A1 - Bralten, J. A1 - Brickman, A. M. A1 - Carmichael, O. A1 - Chakravarty, M. M. A1 - Chauhan, G. A1 - Chen, Q. A1 - Ching, C. R. A1 - Cuellar-Partida, G. A1 - Braber, A. D. A1 - Doan, N. T. A1 - Ehrlich, S. A1 - Filippi, I. A1 - Ge, T. A1 - Giddaluru, S. A1 - Goldman, A. L. A1 - Gottesman, R. F. A1 - Greven, C. U. A1 - Grimm, O. A1 - Griswold, M. E. A1 - Guadalupe, T. A1 - Hass, J. A1 - Haukvik, U. K. A1 - Hilal, S. A1 - Hofer, E. A1 - Hoehn, D. A1 - Holmes, A. J. A1 - Hoogman, M. A1 - Janowitz, D. A1 - Jia, T. A1 - Kasperaviciute, D. A1 - Kim, S. A1 - Klein, M. A1 - Kraemer, B. A1 - Lee, P. H. A1 - Liao, J. A1 - Liewald, D. C. A1 - Lopez, L. M. A1 - Luciano, M. A1 - Macare, C. A1 - Marquand, A. A1 - Matarin, M. A1 - Mather, K. A. A1 - Mattheisen, M. A1 - Mazoyer, B. A1 - McKay, D. R. A1 - McWhirter, R. A1 - Milaneschi, Y. A1 - Mirza-Schreiber, N. A1 - Muetzel, R. L. A1 - Maniega, S. M. A1 - Nho, K. A1 - Nugent, A. C. A1 - Loohuis, L. M. A1 - Oosterlaan, J. A1 - Papmeyer, M. A1 - Pappa, I. A1 - Pirpamer, L. A1 - Pudas, S. A1 - P?tz, B. A1 - Rajan, K. B. A1 - Ramasamy, A. A1 - Richards, J. S. A1 - Risacher, S. L. A1 - Roiz-Santia?ez, R. A1 - Rommelse, N. A1 - Rose, E. J. A1 - Royle, N. A. A1 - Rundek, T. A1 - S?mann, P. G. A1 - Satizabal, C. L. A1 - Schmaal, L. A1 - Schork, A. J. A1 - Shen, L. A1 - Shin, J. A1 - Shumskaya, E. A1 - Smith, A. V. A1 - Sprooten, E. A1 - Strike, L. T. A1 - Teumer, A. A1 - Thomson, R. A1 - Tordesillas-Gutierrez, D. A1 - Toro, R. A1 - Trabzuni, D. A1 - Vaidya, D. A1 - van der Grond, J. A1 - van der Meer, D. A1 - Van Donkelaar, M. M. A1 - Van Eijk, K. R. A1 - Van Erp, T. G. A1 - van Rooij, D. A1 - Walton, E. A1 - Westlye, L. T. A1 - Whelan, C. D. A1 - Windham, B. G. A1 - Winkler, A. M. A1 - Woldehawariat, G. A1 - Wolf, C. A1 - Wolfers, T. A1 - Xu, B. A1 - Yanek, L. R. A1 - Yang, J. A1 - Zijdenbos, A. A1 - Zwiers, M. P. A1 - Agartz, I. A1 - Aggarwal, N. T. A1 - Almasy, L. A1 - Ames, D. A1 - Amouyel, P. A1 - Andreassen, O. A. A1 - Arepalli, S. A1 - Assareh, A. A. A1 - Barral, S. A1 - Bastin, M. E. A1 - Becker, D. M. A1 - Becker, J. T. A1 - Bennett, D. A. A1 - Blangero, J. A1 - van Bokhoven, H. A1 - Boomsma, D. I. A1 - Brodaty, H. A1 - Brouwer, R. M. A1 - Brunner, H. G. A1 - Buckner, R. L. A1 - Buitelaar, J. K. A1 - Bulayeva, K. B. A1 - Cahn, W. A1 - Calhoun, V. D. A1 - Cannon, D. M. A1 - Cavalleri, G. L. A1 - Chen, C. A1 - Cheng, C. Y. A1 - Cichon, S. A1 - Cookson, M. R. A1 - Corvin, A. A1 - Crespo-Facorro, B. A1 - Curran, J. E. A1 - Czisch, M. A1 - Dale, A. M. A1 - Davies, G. E. A1 - De Geus, E. J. A1 - De Jager, P. L. A1 - de Zubicaray, G. I. A1 - Delanty, N. A1 - Depondt, C. A1 - DeStefano, A. L. A1 - Dillman, A. A1 - Djurovic, S. A1 - Donohoe, G. A1 - Drevets, W. C. A1 - Duggirala, R. A1 - Dyer, T. D. A1 - Erk, S. A1 - Espeseth, T. A1 - Evans, D. A. A1 - Fedko, I. O. A1 - Fern?ndez, G. A1 - Ferrucci, L. A1 - Fisher, S. E. A1 - Fleischman, D. A. A1 - Ford, I. A1 - Foroud, T. M. A1 - Fox, P. T. A1 - Francks, C. A1 - Fukunaga, M. A1 - Gibbs, J. R. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - G?ring, H. H. A1 - Grabe, H. J. A1 - Green, R. C. A1 - Gruber, O. A1 - Gudnason, V. A1 - Guelfi, S. A1 - Hansell, N. K. A1 - Hardy, J. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Hegenscheid, K. A1 - Heinz, A. A1 - Le Hellard, S. A1 - Hernandez, D. G. A1 - Heslenfeld, D. J. A1 - Ho, B. C. A1 - Hoekstra, P. J. A1 - Hoffmann, W. A1 - Hofman, A. A1 - Holsboer, F. A1 - Homuth, G. A1 - Hosten, N. A1 - Hottenga, J. J. A1 - Hulshoff Pol, H. E. A1 - Ikeda, M. A1 - Ikram, M. K. A1 - Jack, C. R. A1 - Jenkinson, M. A1 - Johnson, R. A1 - J?nsson, E. G. A1 - Jukema, J. W. A1 - Kahn, R. S. A1 - Kanai, R. A1 - Kloszewska, I. A1 - Knopman, D. S. A1 - Kochunov, P. A1 - Kwok, J. B. A1 - Lawrie, S. M. A1 - Lema?tre, H. A1 - Liu, X. A1 - Longo, D. L. A1 - Longstreth, W. T. A1 - Lopez, O. L. A1 - Lovestone, S. A1 - Martinez, O. A1 - Martinot, J. L. A1 - Mattay, V. S. A1 - McDonald, C. A1 - McIntosh, A. M. A1 - McMahon, K. L. A1 - McMahon, F. J. A1 - Mecocci, P. A1 - Melle, I. A1 - Meyer-Lindenberg, A. A1 - Mohnke, S. A1 - Montgomery, G. W. A1 - Morris, D. W. A1 - Mosley, T. H. A1 - M?hleisen, T. W. A1 - M?ller-Myhsok, B. A1 - Nalls, M. A. A1 - Nauck, M. A1 - Nichols, T. E. A1 - Niessen, W. J. A1 - N?then, M. M. A1 - Nyberg, L. A1 - Ohi, K. A1 - Olvera, R. L. A1 - Ophoff, R. A. A1 - Pandolfo, M. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. A1 - Pike, G. B. A1 - Potkin, S. G. A1 - Psaty, B. M. A1 - Reppermund, S. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Romanczuk-Seiferth, N. A1 - Rotter, J. I. A1 - Ryten, M. A1 - Sacco, R. L. A1 - Sachdev, P. S. A1 - Saykin, A. J. A1 - Schmidt, R. A1 - Schofield, P. R. A1 - Sigurdsson, S. A1 - Simmons, A. A1 - Singleton, A. A1 - Sisodiya, S. M. A1 - Smith, C. A1 - Smoller, J. W. A1 - Soininen, H. A1 - Srikanth, V. A1 - Steen, V. M. A1 - Stott, D. J. A1 - Sussmann, J. E. A1 - Thalamuthu, A. A1 - Tiemeier, H. A1 - Toga, A. W. A1 - Traynor, B. J. A1 - Troncoso, J. A1 - Turner, J. A. A1 - Tzourio, C. A1 - Uitterlinden, A. G. A1 - Hern?ndez, M. C. A1 - Van der Brug, M. A1 - van der Lugt, A. A1 - Van der Wee, N. J. A1 - van Duijn, C. M. A1 - Van Haren, N. E. A1 - Van T Ent, D. A1 - van Tol, M. J. A1 - Vardarajan, B. N. A1 - Veltman, D. J. A1 - Vernooij, M. W. A1 - V?lzke, H. A1 - Walter, H. A1 - Wardlaw, J. M. A1 - Wassink, T. H. A1 - Weale, M. E. A1 - Weinberger, D. R. A1 - Weiner, M. W. A1 - Wen, W. A1 - Westman, E. A1 - White, T. A1 - Wong, T. Y. A1 - Wright, C. B. A1 - Zielke, H. R. A1 - Zonderman, A. B. A1 - Deary, I. J. A1 - DeCarli, C. A1 - Schmidt, H. A1 - Martin, N. G. A1 - De Craen, A. J. A1 - Wright, M. J. A1 - Launer, L. J. A1 - Schumann, G. A1 - Fornage, M. A1 - Franke, B. A1 - Debette, S. A1 - Medland, S. E. A1 - Ikram, M. A. A1 - Thompson, P. M. AB - Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits. VL - 19 ER - TY - JOUR T1 - Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. JF - Am J Hum Genet Y1 - 2016 A1 - Eicher, John D A1 - Chami, Nathalie A1 - Kacprowski, Tim A1 - Nomura, Akihiro A1 - Chen, Ming-Huei A1 - Yanek, Lisa R A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Slater, Andrew J A1 - Pankratz, Nathan A1 - Polfus, Linda A1 - Schurmann, Claudia A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Hill, W David A1 - Pazoki, Raha A1 - Elliot, Paul A1 - Evangelou, Evangelos A1 - Tzoulaki, Ioanna A1 - Gao, He A1 - Vergnaud, Anne-Claire A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Burt, Amber A1 - Crosslin, David R A1 - Lyytikäinen, Leo-Pekka A1 - Nikus, Kjell A1 - Hernesniemi, Jussi A1 - Kähönen, Mika A1 - Raitoharju, Emma A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Lehtimäki, Terho A1 - Cushman, Mary A1 - Zakai, Neil A A1 - Nickerson, Deborah A A1 - Raffield, Laura M A1 - Quarells, Rakale A1 - Willer, Cristen J A1 - Peloso, Gina M A1 - Abecasis, Goncalo R A1 - Liu, Dajiang J A1 - Deloukas, Panos A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Fornage, Myriam A1 - Richard, Melissa A1 - Tardif, Jean-Claude A1 - Rioux, John D A1 - Dubé, Marie-Pierre A1 - de Denus, Simon A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Smith, Albert Vernon A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Gudnason, Vilmundur A1 - Velez Edwards, Digna R A1 - Torstenson, Eric S A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Highland, Heather M A1 - Boerwinkle, Eric A1 - Li, Jin A1 - Lange, Ethan A1 - Wilson, James G A1 - Mihailov, Evelin A1 - Mägi, Reedik A1 - Hirschhorn, Joel A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Vacchi-Suzzi, Caterina A1 - Nalls, Mike A A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Engström, Gunnar A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - O'Donoghue, Michelle L A1 - Waterworth, Dawn M A1 - Wallentin, Lars A1 - White, Harvey D A1 - Floyd, James S A1 - Bartz, Traci M A1 - Rice, Kenneth M A1 - Psaty, Bruce M A1 - Starr, J M A1 - Liewald, David C M A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Greinacher, Andreas A1 - Völker, Uwe A1 - Thiele, Thomas A1 - Völzke, Henry A1 - van Rooij, Frank J A A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Dehghan, Abbas A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Kathiresan, Sekar A1 - Faraday, Nauder A1 - Auer, Paul L A1 - Reiner, Alex P A1 - Lettre, Guillaume A1 - Johnson, Andrew D AB -

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract ER - TY - JOUR T1 - Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases. JF - Front Genet Y1 - 2016 A1 - He, Liang A1 - Kernogitski, Yelena A1 - Kulminskaya, Irina A1 - Loika, Yury A1 - Arbeev, Konstantin G A1 - Loiko, Elena A1 - Bagley, Olivia A1 - Duan, Matt A1 - Yashkin, Arseniy A1 - Ukraintseva, Svetlana V A1 - Kovtun, Mikhail A1 - Yashin, Anatoliy I A1 - Kulminski, Alexander M AB -

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in , rs460976 on 21q22.3 (1 kb from ) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in associated with stroke and heart failure, rs7081476 on 10p12.1 in associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.

VL - 7 ER - TY - JOUR T1 - A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. JF - Nat Commun Y1 - 2016 A1 - Ried, Janina S A1 - Jeff M, Janina A1 - Chu, Audrey Y A1 - Bragg-Gresham, Jennifer L A1 - van Dongen, Jenny A1 - Huffman, Jennifer E A1 - Ahluwalia, Tarunveer S A1 - Cadby, Gemma A1 - Eklund, Niina A1 - Eriksson, Joel A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Goel, Anuj A1 - Gorski, Mathias A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Jackson, Anne U A1 - Jokinen, Eero A1 - Kanoni, Stavroula A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Mangino, Massimo A1 - Medina-Gómez, Carolina A1 - Monda, Keri L A1 - Nolte, Ilja M A1 - Perusse, Louis A1 - Prokopenko, Inga A1 - Qi, Lu A1 - Rose, Lynda M A1 - Salvi, Erika A1 - Smith, Megan T A1 - Snieder, Harold A1 - Stančáková, Alena A1 - Ju Sung, Yun A1 - Tachmazidou, Ioanna A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - van der Harst, Pim A1 - Walker, Ryan W A1 - Wang, Sophie R A1 - Wild, Sarah H A1 - Willems, Sara M A1 - Wong, Andrew A1 - Zhang, Weihua A1 - Albrecht, Eva A1 - Couto Alves, Alexessander A1 - Bakker, Stephan J L A1 - Barlassina, Cristina A1 - Bartz, Traci M A1 - Beilby, John A1 - Bellis, Claire A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Blangero, John A1 - Blüher, Matthias A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chen, Yii-Der Ida A1 - Chiang, Charleston W K A1 - Chines, Peter S A1 - Collins, Francis S A1 - Cucca, Fracensco A1 - Cupples, L Adrienne A1 - D'Avila, Francesca A1 - de Geus, Eco J C A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Döring, Angela A1 - Eriksson, Johan G A1 - Farmaki, Aliki-Eleni A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Forouhi, Nita G A1 - Friedrich, Nele A1 - Gjesing, Anette Prior A1 - Glorioso, Nicola A1 - Graff, Mariaelisa A1 - Grallert, Harald A1 - Grarup, Niels A1 - Gräßler, Jürgen A1 - Grewal, Jagvir A1 - Hamsten, Anders A1 - Harder, Marie Neergaard A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hastie, Nicholas A1 - Hattersley, Andrew Tym A1 - Havulinna, Aki S A1 - Heliövaara, Markku A1 - Hillege, Hans A1 - Hofman, Albert A1 - Holmen, Oddgeir A1 - Homuth, Georg A1 - Hottenga, Jouke-Jan A1 - Hui, Jennie A1 - Husemoen, Lise Lotte A1 - Hysi, Pirro G A1 - Isaacs, Aaron A1 - Ittermann, Till A1 - Jalilzadeh, Shapour A1 - James, Alan L A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Marie Justesen, Johanne A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Karaleftheri, Maria A1 - Tee Khaw, Kay A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kinnunen, Leena A1 - Knekt, Paul B A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyriakou, Theodosios A1 - Laitinen, Tomi A1 - Langenberg, Claudia A1 - Lewin, Alexandra M A1 - Lichtner, Peter A1 - Lindgren, Cecilia M A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Lorbeer, Roberto A1 - Lorentzon, Mattias A1 - Luben, Robert A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Manunta, Paolo A1 - Leach, Irene Mateo A1 - McArdle, Wendy L A1 - McKnight, Barbara A1 - Mohlke, Karen L A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Mills, Rebecca A1 - Montasser, May E A1 - Morris, Andrew P A1 - Müller, Gabriele A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Osmond, Clive A1 - Palotie, Aarno A1 - Pankow, James S A1 - Paternoster, Lavinia A1 - Penninx, Brenda W A1 - Pichler, Irene A1 - Pilia, Maria G A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rayner, Nigel W A1 - Ribel-Madsen, Rasmus A1 - Rice, Treva K A1 - Richards, Marcus A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ryan, Kathy A A1 - Sanna, Serena A1 - Sarzynski, Mark A A1 - Scholtens, Salome A1 - Scott, Robert A A1 - Sebert, Sylvain A1 - Southam, Lorraine A1 - Sparsø, Thomas Hempel A1 - Steinthorsdottir, Valgerdur A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Tönjes, Anke A1 - Tsafantakis, Emmanouil A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Vartiainen, Erkki A1 - Venturini, Cristina A1 - Verweij, Niek A1 - Viikari, Jorma S A1 - Vitart, Veronique A1 - Vohl, Marie-Claude A1 - Vonk, Judith M A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Winkler, Thomas W A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Zillikens, M Carola A1 - Boomsma, Dorret I A1 - Bouchard, Claude A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Cusi, Daniele A1 - Gansevoort, Ron T A1 - Gieger, Christian A1 - Hansen, Torben A1 - Hicks, Andrew A A1 - Hu, Frank A1 - Hveem, Kristian A1 - Jarvelin, Marjo-Riitta A1 - Kajantie, Eero A1 - Kooner, Jaspal S A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Metspalu, Andres A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Puolijoki, Hannu A1 - Rauramaa, Rainer A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Shudiner, Alan R A1 - Smit, Jan H A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Tremblay, Angelo A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Zeggini, Eleftheria A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - van Duijn, Cornelia M A1 - Fox, Caroline A1 - Groop, Leif C A1 - Heid, Iris M A1 - Hunter, David J A1 - Kaplan, Robert C A1 - McCarthy, Mark I A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Thorsteinsdottir, Unnur A1 - Strachan, David P A1 - Frayling, Timothy A1 - Hirschhorn, Joel N A1 - Müller-Nurasyid, Martina A1 - Loos, Ruth J F KW - Anthropometry KW - Body Size KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Models, Genetic KW - Principal Component Analysis AB -

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

VL - 7 ER - TY - JOUR T1 - Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Yu, Bing A1 - Pulit, Sara L A1 - Hwang, Shih-Jen A1 - Brody, Jennifer A A1 - Amin, Najaf A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Burke, Gregory L A1 - Chakravarti, Aravinda A1 - Correa, Adolfo A1 - Dreisbach, Albert W A1 - Franco, Oscar H A1 - Ehret, Georg B A1 - Franceschini, Nora A1 - Hofman, Albert A1 - Lin, Dan-Yu A1 - Metcalf, Ginger A A1 - Musani, Solomon K A1 - Muzny, Donna A1 - Palmas, Walter A1 - Raffel, Leslie A1 - Reiner, Alex A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Veeraraghavan, Narayanan A1 - Fox, Ervin A1 - Guo, Xiuqing A1 - North, Kari E A1 - Gibbs, Richard A A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Morrison, Alanna C AB -

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract ER - TY - JOUR T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. JF - PLoS Genet Y1 - 2016 A1 - Jakobsdottir, Johanna A1 - van der Lee, Sven J A1 - Bis, Joshua C A1 - Chouraki, Vincent A1 - Li-Kroeger, David A1 - Yamamoto, Shinya A1 - Grove, Megan L A1 - Naj, Adam A1 - Vronskaya, Maria A1 - Salazar, Jose L A1 - DeStefano, Anita L A1 - Brody, Jennifer A A1 - Smith, Albert V A1 - Amin, Najaf A1 - Sims, Rebecca A1 - Ibrahim-Verbaas, Carla A A1 - Choi, Seung-Hoan A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Beiser, Alexa A1 - Ikram, M Arfan A1 - Garcia, Melissa E A1 - Hayward, Caroline A1 - Varga, Tibor V A1 - Ripatti, Samuli A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Rolandsson, Olov A1 - Jansson, Jan-Håkon A1 - Porteous, David J A1 - Salomaa, Veikko A1 - Eiriksdottir, Gudny A1 - Rice, Kenneth M A1 - Bellen, Hugo J A1 - Levy, Daniel A1 - Uitterlinden, André G A1 - Emilsson, Valur A1 - Rotter, Jerome I A1 - Aspelund, Thor A1 - O'Donnell, Christopher J A1 - Fitzpatrick, Annette L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Wang, Li-San A1 - Williams, Julie A1 - Schellenberg, Gerard D A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Shulman, Joshua M A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M AB -

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

VL - 12 IS - 10 ER - TY - JOUR T1 - Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. JF - Mol Psychiatry Y1 - 2016 A1 - Olfson, E A1 - Saccone, N L A1 - Johnson, E O A1 - Chen, L-S A1 - Culverhouse, R A1 - Doheny, K A1 - Foltz, S M A1 - Fox, L A1 - Gogarten, S M A1 - Hartz, S A1 - Hetrick, K A1 - Laurie, C C A1 - Marosy, B A1 - Amin, N A1 - Arnett, D A1 - Barr, R G A1 - Bartz, T M A1 - Bertelsen, S A1 - Borecki, I B A1 - Brown, M R A1 - Chasman, D I A1 - van Duijn, C M A1 - Feitosa, M F A1 - Fox, E R A1 - Franceschini, N A1 - Franco, O H A1 - Grove, M L A1 - Guo, X A1 - Hofman, A A1 - Kardia, S L R A1 - Morrison, A C A1 - Musani, S K A1 - Psaty, B M A1 - Rao, D C A1 - Reiner, A P A1 - Rice, K A1 - Ridker, P M A1 - Rose, L M A1 - Schick, U M A1 - Schwander, K A1 - Uitterlinden, A G A1 - Vojinovic, D A1 - Wang, J-C A1 - Ware, E B A1 - Wilson, G A1 - Yao, J A1 - Zhao, W A1 - Breslau, N A1 - Hatsukami, D A1 - Stitzel, J A A1 - Rice, J A1 - Goate, A A1 - Bierut, L J AB -

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

VL - 21 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239294?dopt=Abstract ER - TY - JOUR T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2016 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y AB -

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

ER - TY - JOUR T1 - Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. JF - Am J Hum Genet Y1 - 2016 A1 - Liu, Ching-Ti A1 - Raghavan, Sridharan A1 - Maruthur, Nisa A1 - Kabagambe, Edmond Kato A1 - Hong, Jaeyoung A1 - Ng, Maggie C Y A1 - Hivert, Marie-France A1 - Lu, Yingchang A1 - An, Ping A1 - Bentley, Amy R A1 - Drolet, Anne M A1 - Gaulton, Kyle J A1 - Guo, Xiuqing A1 - Armstrong, Loren L A1 - Irvin, Marguerite R A1 - Li, Man A1 - Lipovich, Leonard A1 - Rybin, Denis V A1 - Taylor, Kent D A1 - Agyemang, Charles A1 - Palmer, Nicholette D A1 - Cade, Brian E A1 - Chen, Wei-Min A1 - Dauriz, Marco A1 - Delaney, Joseph A C A1 - Edwards, Todd L A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Lange, Leslie A A1 - Leong, Aaron A1 - Liu, Jingmin A1 - Liu, Yongmei A1 - Nayak, Uma A1 - Patel, Sanjay R A1 - Porneala, Bianca C A1 - Rasmussen-Torvik, Laura J A1 - Snijder, Marieke B A1 - Stallings, Sarah C A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Biggs, Mary L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Chen, Guanjie A1 - Correa, Adolfo A1 - Couper, David J A1 - Crawford, Dana C A1 - Cushman, Mary A1 - Eicher, John D A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fu, Yi-Ping A1 - Goodarzi, Mark O A1 - Gottesman, Omri A1 - Hara, Kazuo A1 - Harris, Tamara B A1 - Jensen, Richard A A1 - Johnson, Andrew D A1 - Jhun, Min A A1 - Karter, Andrew J A1 - Keller, Margaux F A1 - Kho, Abel N A1 - Kizer, Jorge R A1 - Krauss, Ronald M A1 - Langefeld, Carl D A1 - Li, Xiaohui A1 - Liang, Jingling A1 - Liu, Simin A1 - Lowe, William L A1 - Mosley, Thomas H A1 - North, Kari E A1 - Pacheco, Jennifer A A1 - Peyser, Patricia A A1 - Patrick, Alan L A1 - Rice, Kenneth M A1 - Selvin, Elizabeth A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Tajuddin, Salman M A1 - Vaidya, Dhananjay A1 - Wren, Mary P A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Julie T A1 - Zmuda, Joseph M A1 - Zonderman, Alan B A1 - Zwinderman, Aeilko H A1 - Adeyemo, Adebowale A1 - Boerwinkle, Eric A1 - Ferrucci, Luigi A1 - Hayes, M Geoffrey A1 - Kardia, Sharon L R A1 - Miljkovic, Iva A1 - Pankow, James S A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Wagenknecht, Lynne E A1 - Arnett, Donna K A1 - Chen, Yii-Der Ida A1 - Nalls, Michael A A1 - Province, Michael A A1 - Kao, W H Linda A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Loos, Ruth J F A1 - Dupuis, Josée A1 - Rich, Stephen S A1 - Florez, Jose C A1 - Rotter, Jerome I A1 - Morris, Andrew P A1 - Meigs, James B AB -

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract ER - TY - JOUR T1 - Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. JF - Am J Hum Genet Y1 - 2016 A1 - Polfus, Linda M A1 - Khajuria, Rajiv K A1 - Schick, Ursula M A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Auer, Paul L A1 - Floyd, James S A1 - Huang, Jie A1 - Lange, Leslie A1 - van Rooij, Frank J A A1 - Gibbs, Richard A A1 - Metcalf, Ginger A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - Walter, Klaudia A1 - Chen, Lu A1 - Yanek, Lisa A1 - Becker, Lewis C A1 - Peloso, Gina M A1 - Wakabayashi, Aoi A1 - Kals, Mart A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Fox, Keolu A1 - Wallace, Robert A1 - Franceschini, Nora A1 - Matijevic, Nena A1 - Rice, Kenneth M A1 - Bartz, Traci M A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Li-Gao, Ruifang A1 - Mook-Kanamori, Dennis O A1 - Lettre, Guillaume A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Soranzo, Nicole A1 - Dehghan, Abbas A1 - Boerwinkle, Eric A1 - Zhang, Xiaoling A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Johnsen, Jill M A1 - Reiner, Alexander P A1 - Ganesh, Santhi K A1 - Sankaran, Vijay G VL - 99 IS - 3 ER - TY - JOUR T1 - 740 adults from 20 prospective cohort studies JF - Lancet Diabetes Endocrinol Y1 - 2017 A1 - Wu, J. H. Y. A1 - Marklund, M. A1 - Imamura, F. A1 - Tintle, N. A1 - Ardisson Korat, A. V. A1 - de Goede, J. A1 - Zhou, X. A1 - Yang, W. S. A1 - de Oliveira Otto, M. C. A1 - ger, J. A1 - Qureshi, W. A1 - Virtanen, J. K. A1 - Bassett, J. K. A1 - Frazier-Wood, A. C. A1 - Lankinen, M. A1 - Murphy, R. A. A1 - Rajaobelina, K. A1 - Del Gobbo, L. C. A1 - Forouhi, N. G. A1 - Luben, R. A1 - Khaw, K. T. A1 - Wareham, N. A1 - Kalsbeek, A. A1 - Veenstra, J. A1 - Luo, J. A1 - Hu, F. B. A1 - Lin, H. J. A1 - Siscovick, D. S. A1 - Boeing, H. A1 - Chen, T. A. A1 - Steffen, B. A1 - Steffen, L. M. A1 - Hodge, A. A1 - Eriksdottir, G. A1 - Smith, A. V. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Brouwer, I. A. A1 - Berr, C. A1 - Helmer, C. A1 - Samieri, C. A1 - Laakso, M. A1 - Tsai, M. Y. A1 - Giles, G. G. A1 - Nurmi, T. A1 - Wagenknecht, L. A1 - Schulze, M. B. A1 - Lemaitre, R. N. A1 - Chien, K. L. A1 - Soedamah-Muthu, S. S. A1 - Geleijnse, J. M. A1 - Sun, Q. A1 - Harris, W. S. A1 - Lind, L. A1 - v, J. A1 - Riserus, U. A1 - Micha, R. A1 - Mozaffarian, D. AB - The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.\ We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.\ 13).\ Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.\ Funders are shown in the appendix. VL - 5 ER - TY - JOUR T1 - Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. JF - JAMA Cardiol Y1 - 2017 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Robinson-Cohen, Cassianne A1 - Odden, Michelle C A1 - Dalrymple, Lorien A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Siscovick, David S A1 - Zelnick, Leila A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Correa, Adolfo A1 - Afkarian, Maryam A1 - Young, Bessie A1 - de Boer, Ian H AB -

Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.

Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.

Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.

Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.

Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.

Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.

Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.

VL - 2 IS - 3 ER - TY - JOUR T1 - Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. JF - JAMA Oncol Y1 - 2017 A1 - Haycock, Philip C A1 - Burgess, Stephen A1 - Nounu, Aayah A1 - Zheng, Jie A1 - Okoli, George N A1 - Bowden, Jack A1 - Wade, Kaitlin Hazel A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Willeit, Peter A1 - Aviv, Abraham A1 - Gaunt, Tom R A1 - Hemani, Gibran A1 - Mangino, Massimo A1 - Ellis, Hayley Patricia A1 - Kurian, Kathreena M A1 - Pooley, Karen A A1 - Eeles, Rosalind A A1 - Lee, Jeffrey E A1 - Fang, Shenying A1 - Chen, Wei V A1 - Law, Matthew H A1 - Bowdler, Lisa M A1 - Iles, Mark M A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Markus, Hugh Stephen A1 - Hung, Rayjean J A1 - Amos, Chris I A1 - Spurdle, Amanda B A1 - Thompson, Deborah J A1 - O'Mara, Tracy A A1 - Wolpin, Brian A1 - Amundadottir, Laufey A1 - Stolzenberg-Solomon, Rachael A1 - Trichopoulou, Antonia A1 - Onland-Moret, N Charlotte A1 - Lund, Eiliv A1 - Duell, Eric J A1 - Canzian, Federico A1 - Severi, Gianluca A1 - Overvad, Kim A1 - Gunter, Marc J A1 - Tumino, Rosario A1 - Svenson, Ulrika A1 - van Rij, Andre A1 - Baas, Annette F A1 - Bown, Matthew J A1 - Samani, Nilesh J A1 - van t'Hof, Femke N G A1 - Tromp, Gerard A1 - Jones, Gregory T A1 - Kuivaniemi, Helena A1 - Elmore, James R A1 - Johansson, Mattias A1 - Mckay, James A1 - Scelo, Ghislaine A1 - Carreras-Torres, Robert A1 - Gaborieau, Valerie A1 - Brennan, Paul A1 - Bracci, Paige M A1 - Neale, Rachel E A1 - Olson, Sara H A1 - Gallinger, Steven A1 - Li, Donghui A1 - Petersen, Gloria M A1 - Risch, Harvey A A1 - Klein, Alison P A1 - Han, Jiali A1 - Abnet, Christian C A1 - Freedman, Neal D A1 - Taylor, Philip R A1 - Maris, John M A1 - Aben, Katja K A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Wiencke, John K A1 - Walsh, Kyle M A1 - Wrensch, Margaret A1 - Rice, Terri A1 - Turnbull, Clare A1 - Litchfield, Kevin A1 - Paternoster, Lavinia A1 - Standl, Marie A1 - Abecasis, Goncalo R A1 - SanGiovanni, John Paul A1 - Li, Yong A1 - Mijatovic, Vladan A1 - Sapkota, Yadav A1 - Low, Siew-Kee A1 - Zondervan, Krina T A1 - Montgomery, Grant W A1 - Nyholt, Dale R A1 - van Heel, David A A1 - Hunt, Karen A1 - Arking, Dan E A1 - Ashar, Foram N A1 - Sotoodehnia, Nona A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Comeau, Mary E A1 - Brown, W Mark A1 - Silverman, Edwin K A1 - Hokanson, John E A1 - Cho, Michael H A1 - Hui, Jennie A1 - Ferreira, Manuel A A1 - Thompson, Philip J A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Smith, Nicholas L A1 - Christiano, Angela M A1 - Petukhova, Lynn A1 - Betz, Regina C A1 - Fan, Xing A1 - Zhang, Xuejun A1 - Zhu, Caihong A1 - Langefeld, Carl D A1 - Thompson, Susan D A1 - Wang, Feijie A1 - Lin, Xu A1 - Schwartz, David A A1 - Fingerlin, Tasha A1 - Rotter, Jerome I A1 - Cotch, Mary Frances A1 - Jensen, Richard A A1 - Munz, Matthias A1 - Dommisch, Henrik A1 - Schaefer, Arne S A1 - Han, Fang A1 - Ollila, Hanna M A1 - Hillary, Ryan P A1 - Albagha, Omar A1 - Ralston, Stuart H A1 - Zeng, Chenjie A1 - Zheng, Wei A1 - Shu, Xiao-Ou A1 - Reis, Andre A1 - Uebe, Steffen A1 - Hüffmeier, Ulrike A1 - Kawamura, Yoshiya A1 - Otowa, Takeshi A1 - Sasaki, Tsukasa A1 - Hibberd, Martin Lloyd A1 - Davila, Sonia A1 - Xie, Gang A1 - Siminovitch, Katherine A1 - Bei, Jin-Xin A1 - Zeng, Yi-Xin A1 - Försti, Asta A1 - Chen, Bowang A1 - Landi, Stefano A1 - Franke, Andre A1 - Fischer, Annegret A1 - Ellinghaus, David A1 - Flores, Carlos A1 - Noth, Imre A1 - Ma, Shwu-Fan A1 - Foo, Jia Nee A1 - Liu, Jianjun A1 - Kim, Jong-Won A1 - Cox, David G A1 - Delattre, Olivier A1 - Mirabeau, Olivier A1 - Skibola, Christine F A1 - Tang, Clara S A1 - Garcia-Barcelo, Merce A1 - Chang, Kai-Ping A1 - Su, Wen-Hui A1 - Chang, Yu-Sun A1 - Martin, Nicholas G A1 - Gordon, Scott A1 - Wade, Tracey D A1 - Lee, Chaeyoung A1 - Kubo, Michiaki A1 - Cha, Pei-Chieng A1 - Nakamura, Yusuke A1 - Levy, Daniel A1 - Kimura, Masayuki A1 - Hwang, Shih-Jen A1 - Hunt, Steven A1 - Spector, Tim A1 - Soranzo, Nicole A1 - Manichaikul, Ani W A1 - Barr, R Graham A1 - Kahali, Bratati A1 - Speliotes, Elizabeth A1 - Yerges-Armstrong, Laura M A1 - Cheng, Ching-Yu A1 - Jonas, Jost B A1 - Wong, Tien Yin A1 - Fogh, Isabella A1 - Lin, Kuang A1 - Powell, John F A1 - Rice, Kenneth A1 - Relton, Caroline L A1 - Martin, Richard M A1 - Davey Smith, George KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Germ-Line Mutation KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Telomere KW - Telomere Homeostasis AB -

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

VL - 3 IS - 5 ER - TY - JOUR T1 - Association of Coronary Artery Calcium Score vs Age With Cardiovascular Risk in Older Adults: An Analysis of Pooled Population-Based Studies. JF - JAMA Cardiol Y1 - 2017 A1 - Yano, Yuichiro A1 - O'Donnell, Christopher J A1 - Kuller, Lewis A1 - Kavousi, Maryam A1 - Erbel, Raimund A1 - Ning, Hongyan A1 - D'Agostino, Ralph A1 - Newman, Anne B A1 - Nasir, Khurram A1 - Hofman, Albert A1 - Lehmann, Nils A1 - Dhana, Klodian A1 - Blankstein, Ron A1 - Hoffmann, Udo A1 - Möhlenkamp, Stefan A1 - Massaro, Joseph M A1 - Mahabadi, Amir-Abbas A1 - Lima, João A C A1 - Ikram, M Arfan A1 - Jöckel, Karl-Heinz A1 - Franco, Oscar H A1 - Liu, Kiang A1 - Lloyd-Jones, Donald A1 - Greenland, Philip AB -

Importance: Besides age, other discriminators of atherosclerotic cardiovascular disease (ASCVD) risk are needed in older adults.

Objectives: To examine the predictive ability of coronary artery calcium (CAC) score vs age for incident ASCVD and how risk prediction changes by adding CAC score and removing only age from prediction models.

Design, Setting, and Participants: We conducted an analysis of pooled US population-based studies, including the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Results were compared with 2 European cohorts, the Rotterdam Study and the Heinz Nixdorf Recall Study. Participants underwent CAC scoring between 1998 and 2006 using cardiac computed tomography. The participants included adults older than 60 years without known ASCVD at baseline.

Exposures: Coronary artery calcium scores.

Main Outcomes and Measures: Incident ASCVD events including coronary heart disease (CHD) and stroke.

Results: The study included 4778 participants from 3 US cohorts, with a mean age of 70.1 years; 2582 (54.0%) were women, and 2431 (50.9%) were nonwhite. Over 11 years of follow-up (44 152 person-years), 405 CHD and 228 stroke events occurred. Coronary artery calcium score (vs age) had a greater association with incident CHD (C statistic, 0.733 vs 0.690; C statistics difference, 0.043; 95% CI of difference, 0.009-0.075) and modestly improved prediction of incident stroke (C statistic, 0.695 vs 0.670; C statistics difference, 0.025; 95% CI of difference, -0.015 to 0.064). Adding CAC score to models including traditional cardiovascular risk factors, with only age being removed, provided improved discrimination for incident CHD (C statistic, 0.735 vs 0.703; C statistics difference, 0.032; 95% CI of difference, 0.002-0.062) but not for stroke. Coronary artery calcium score was more likely than age to provide higher category-free net reclassification improvement among participants who experienced an ASCVD event (0.390; 95% CI, 0.312-0.467 vs 0.08; 95% CI -0.001 to 0.181) and to result in more accurate reclassification of risk for ASCVD events among these individuals. The findings were similar in the 2 European cohorts (n = 4990).

Conclusions and Relevance: Coronary artery calcium may be an alternative marker besides age to better discriminate between lower and higher CHD risk in older adults. Whether CAC score can assist in guiding the decision to initiate statin treatment for primary prevention in older adults requires further investigation.

ER - TY - JOUR T1 - Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study. JF - Exp Gerontol Y1 - 2017 A1 - He, Liang A1 - Culminskaya, Irina A1 - Loika, Yury A1 - Arbeev, Konstantin G A1 - Bagley, Olivia A1 - Duan, Matt A1 - Yashin, Anatoliy I A1 - Kulminski, Alexander M AB -

BACKGROUNDS: Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures.

METHODS: We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context.

RESULTS: Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326.

CONCLUSIONS: Our results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.

ER - TY - JOUR T1 - Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. JF - PLoS One Y1 - 2017 A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Ahluwalia, Tarunveer S A1 - Teumer, Alexander A1 - Kleber, Marcus E A1 - Chen, Ming-Huei A1 - Wang, Jie Jin A1 - Attia, John R A1 - Marioni, Riccardo E A1 - Steri, Maristella A1 - Weng, Lu-Chen A1 - Pool, Rene A1 - Grossmann, Vera A1 - Brody, Jennifer A A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Frånberg, Mattias A1 - Yang, Qiong A1 - Ligthart, Symen A1 - Hottenga, Jouke J A1 - Rumley, Ann A1 - Mulas, Antonella A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Kifley, Annette A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - Draisma, Harmen H M A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Lackner, Karl J A1 - Völker, Uwe A1 - McKnight, Barbara A1 - Huang, Jie A1 - Holliday, Elizabeth G A1 - McEvoy, Mark A A1 - Starr, John M A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Guan, Weihua A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - de Geus, Eco J C A1 - Stott, David J A1 - Binder, Harald A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Rotter, Jerome I A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Deary, Ian J A1 - März, Winfried A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Cucca, Francesco A1 - Boomsma, Dorret I A1 - Watkins, Hugh A1 - Tang, Weihong A1 - Ridker, Paul M A1 - Jukema, Jan W A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - Hansen, Torben A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

VL - 12 IS - 1 ER - TY - JOUR T1 - The complex genetics of gait speed: genome-wide meta-analysis approach. JF - Aging (Albany NY) Y1 - 2017 A1 - Ben-Avraham, Dan A1 - Karasik, David A1 - Verghese, Joe A1 - Lunetta, Kathryn L A1 - Smith, Jennifer A A1 - Eicher, John D A1 - Vered, Rotem A1 - Deelen, Joris A1 - Arnold, Alice M A1 - Buchman, Aron S A1 - Tanaka, Toshiko A1 - Faul, Jessica D A1 - Nethander, Maria A1 - Fornage, Myriam A1 - Adams, Hieab H A1 - Matteini, Amy M A1 - Callisaya, Michele L A1 - Smith, Albert V A1 - Yu, Lei A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Pattie, Alison A1 - Corley, Janie A1 - Launer, Lenore J A1 - Knopman, Davis S A1 - Parimi, Neeta A1 - Turner, Stephen T A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Gutman, Danielle A1 - Sharvit, Lital A1 - Mooijaart, Simon P A1 - Liewald, David C A1 - Houwing-Duistermaat, Jeanine J A1 - Ohlsson, Claes A1 - Moed, Matthijs A1 - Verlinden, Vincent J A1 - Mellström, Dan A1 - van der Geest, Jos N A1 - Karlsson, Magnus A1 - Hernandez, Dena A1 - McWhirter, Rebekah A1 - Liu, Yongmei A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Weir, David R A1 - Zhao, Wei A1 - Starr, John M A1 - Johnson, Andrew D A1 - Ikram, M Arfan A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Mosley, Thomas H A1 - Srikanth, Velandai K A1 - Windham, Beverly G A1 - Newman, Ann B A1 - Walston, Jeremy D A1 - Davies, Gail A1 - Evans, Daniel S A1 - Slagboom, Eline P A1 - Ferrucci, Luigi A1 - Kiel, Douglas P A1 - Murabito, Joanne M A1 - Atzmon, Gil AB -

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

VL - 9 IS - 1 ER - TY - JOUR T1 - Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium. JF - Hum Mol Genet Y1 - 2017 A1 - Jensen, Majken K A1 - Jensen, Richard A A1 - Mukamal, Kenneth J A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Sun, Qi A1 - Cornelis, Marilyn A1 - Liu, Yongmei A1 - Chen, Ming-Huei A1 - Kizer, Jorge R A1 - Djoussé, Luc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Zmuda, Joseph M A1 - Rotter, Jerome I A1 - Garcia, Melissa A1 - Harris, Tamara A1 - Chen, Ida A1 - Goodarzi, Mark O A1 - Nalls, Michael A A1 - Keller, Margaux A1 - Arnold, Alice M A1 - Newman, Anne A1 - Hoogeeven, Ron C A1 - Rexrode, Kathryn M A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Vasan, Ramachandran S A1 - Katz, Ronit A1 - Pankow, James S A1 - Ix, Joachim H AB -

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

ER - TY - JOUR T1 - Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium. JF - PLoS Genet Y1 - 2017 A1 - Ng, Maggie C Y A1 - Graff, Mariaelisa A1 - Lu, Yingchang A1 - Justice, Anne E A1 - Mudgal, Poorva A1 - Liu, Ching-Ti A1 - Young, Kristin A1 - Yanek, Lisa R A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Rand, Kristin A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Dimitrov, Latchezar A1 - Duan, Qing A1 - Guo, Xiuqing A1 - Lange, Leslie A A1 - Nalls, Michael A A1 - Okut, Hayrettin A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vedantam, Sailaja A1 - Bradfield, Jonathan P A1 - Chen, Guanjie A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Irvin, Marguerite R A1 - Padhukasahasram, Badri A1 - Smith, Jennifer A A1 - Zheng, Wei A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bartz, Traci M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Carpten, John A1 - Chanock, Stephen J A1 - Chen, Yii-Der Ida A1 - Conti, David V A1 - Cooper, Richard S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Goodman, Phyllis J A1 - Hsu, Yu-Han H A1 - Hu, Jennifer A1 - Huff, Chad D A1 - Ingles, Sue A A1 - John, Esther M A1 - Kittles, Rick A1 - Klein, Eric A1 - Li, Jin A1 - McKnight, Barbara A1 - Nayak, Uma A1 - Nemesure, Barbara A1 - Ogunniyi, Adesola A1 - Olshan, Andrew A1 - Press, Michael F A1 - Rohde, Rebecca A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sanderson, Maureen A1 - Shao, Yaming A1 - Siscovick, David S A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Vaidya, Dhananjay A1 - Witte, John S A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A1 - Ambs, Stefan A1 - Cushman, Mary A1 - Faul, Jessica D A1 - Hakonarson, Hakon A1 - Levin, Albert M A1 - Nathanson, Katherine L A1 - Ware, Erin B A1 - Weir, David R A1 - Zhao, Wei A1 - Zhi, Degui A1 - Arnett, Donna K A1 - Grant, Struan F A A1 - Kardia, Sharon L R A1 - Oloapde, Olufunmilayo I A1 - Rao, D C A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Williams, L Keoki A1 - Zemel, Babette S A1 - Becker, Diane M A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Hirschhorn, Joel N A1 - Li, Yun A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - North, Kari E AB -

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

VL - 13 IS - 4 ER - TY - JOUR T1 - Discovery of novel heart rate-associated loci using the Exome Chip. JF - Hum Mol Genet Y1 - 2017 A1 - van den Berg, Marten E A1 - Warren, Helen R A1 - Cabrera, Claudia P A1 - Verweij, Niek A1 - Mifsud, Borbala A1 - Haessler, Jeffrey A1 - Bihlmeyer, Nathan A A1 - Fu, Yi-Ping A1 - Weiss, Stefan A1 - Lin, Henry J A1 - Grarup, Niels A1 - Li-Gao, Ruifang A1 - Pistis, Giorgio A1 - Shah, Nabi A1 - Brody, Jennifer A A1 - Müller-Nurasyid, Martina A1 - Lin, Honghuang A1 - Mei, Hao A1 - Smith, Albert V A1 - Lyytikäinen, Leo-Pekka A1 - Hall, Leanne M A1 - van Setten, Jessica A1 - Trompet, Stella A1 - Prins, Bram P A1 - Isaacs, Aaron A1 - Radmanesh, Farid A1 - Marten, Jonathan A1 - Entwistle, Aiman A1 - Kors, Jan A A1 - Silva, Claudia T A1 - Alonso, Alvaro A1 - Bis, Joshua C A1 - de Boer, Rudolf A1 - de Haan, Hugoline G A1 - de Mutsert, Renée A1 - Dedoussis, George A1 - Dominiczak, Anna F A1 - Doney, Alex S F A1 - Ellinor, Patrick T A1 - Eppinga, Ruben N A1 - Felix, Stephan B A1 - Guo, Xiuqing A1 - Hagemeijer, Yanick A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Hwang, Shih-Jen A1 - Kähönen, Mika A1 - Kanters, Jørgen K A1 - Kolcic, Ivana A1 - Launer, Lenore J A1 - Li, Man A1 - Yao, Jie A1 - Linneberg, Allan A1 - Liu, Simin A1 - Macfarlane, Peter W A1 - Mangino, Massimo A1 - Morris, Andrew D A1 - Mulas, Antonella A1 - Murray, Alison D A1 - Nelson, Christopher P A1 - Orrù, Marco A1 - Padmanabhan, Sandosh A1 - Peters, Annette A1 - Porteous, David J A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Qi, Lihong A1 - Raitakari, Olli T A1 - Rivadeneira, Fernando A1 - Roselli, Carolina A1 - Rudan, Igor A1 - Sattar, Naveed A1 - Sever, Peter A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stanton, Alice V A1 - Stirrups, Kathleen E A1 - Taylor, Kent D A1 - Tobin, Martin D A1 - Uitterlinden, Andre A1 - Vaartjes, Ilonca A1 - Hoes, Arno W A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Xie, Zhijun A1 - Zoledziewska, Magdalena A1 - Tinker, Andrew A1 - Polasek, Ozren A1 - Rosand, Jonathan A1 - Jamshidi, Yalda A1 - van Duijn, Cornelia M A1 - Zeggini, Eleftheria A1 - Wouter Jukema, J A1 - Asselbergs, Folkert W A1 - Samani, Nilesh J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Wilson, James A1 - Lubitz, Steven A A1 - Kääb, Stefan A1 - Sotoodehnia, Nona A1 - Caulfield, Mark J A1 - Palmer, Colin N A A1 - Sanna, Serena A1 - Mook-Kanamori, Dennis O A1 - Deloukas, Panos A1 - Pedersen, Oluf A1 - Rotter, Jerome I A1 - Dörr, Marcus A1 - O'Donnell, Chris J A1 - Hayward, Caroline A1 - Arking, Dan E A1 - Kooperberg, Charles A1 - van der Harst, Pim A1 - Eijgelsheim, Mark A1 - Stricker, Bruno H A1 - Munroe, Patricia B AB -

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

ER - TY - JOUR T1 - eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. JF - Clin J Am Soc Nephrol Y1 - 2017 A1 - Bansal, Nisha A1 - Zelnick, Leila R A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - de Boer, Ian H A1 - Deo, Rajat A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Mathew, Jehu A1 - Robinson-Cohen, Cassianne A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Sotoodehnia, Nona A1 - Young, Bessie A1 - Heckbert, Susan R AB -

BACKGROUND AND OBJECTIVES: The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.

RESULTS: In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m(2)), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.

CONCLUSIONS: In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.

VL - 12 IS - 9 ER - TY - JOUR T1 - Exome-wide association study of plasma lipids in >300,000 individuals. JF - Nat Genet Y1 - 2017 A1 - Liu, Dajiang J A1 - Peloso, Gina M A1 - Yu, Haojie A1 - Butterworth, Adam S A1 - Wang, Xiao A1 - Mahajan, Anubha A1 - Saleheen, Danish A1 - Emdin, Connor A1 - Alam, Dewan A1 - Alves, Alexessander Couto A1 - Amouyel, Philippe A1 - Di Angelantonio, Emanuele A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Baber, Usman A1 - Ballantyne, Christie M A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bis, Joshua C A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brandslund, Ivan A1 - Brown, Morris A1 - Busonero, Fabio A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Y Eugene A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Connell, John M A1 - Cucca, Francesco A1 - Cupples, L Adrienne A1 - Damrauer, Scott M A1 - Davies, Gail A1 - Deary, Ian J A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Dominiczak, Anna A1 - Dubé, Marie-Pierre A1 - Ebeling, Tapani A1 - Eiriksdottir, Gudny A1 - Esko, Tõnu A1 - Farmaki, Aliki-Eleni A1 - Feitosa, Mary F A1 - Ferrario, Marco A1 - Ferrieres, Jean A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frayling, Timothy M A1 - Frikke-Schmidt, Ruth A1 - Fritsche, Lars G A1 - Frossard, Philippe A1 - Fuster, Valentin A1 - Ganesh, Santhi K A1 - Gao, Wei A1 - Garcia, Melissa E A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Grarup, Niels A1 - Groop, Leif A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hirschhorn, Joel N A1 - Holmen, Oddgeir L A1 - Huffman, Jennifer A1 - Huo, Yong A1 - Hveem, Kristian A1 - Jabeen, Sehrish A1 - Jackson, Anne U A1 - Jakobsdottir, Johanna A1 - Jarvelin, Marjo-Riitta A1 - Jensen, Gorm B A1 - Jørgensen, Marit E A1 - Jukema, J Wouter A1 - Justesen, Johanne M A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Khera, Amit V A1 - Klarin, Derek A1 - Koistinen, Heikki A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A1 - Langenberg, Claudia A1 - Langsted, Anne A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Liewald, David C M A1 - Lin, Li An A1 - Linneberg, Allan A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lu, Xiangfeng A1 - Mägi, Reedik A1 - Mälarstig, Anders A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mäntyselkä, Pekka A1 - Marouli, Eirini A1 - Masca, Nicholas G D A1 - Maschio, Andrea A1 - Meigs, James B A1 - Melander, Olle A1 - Metspalu, Andres A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Mulas, Antonella A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Neville, Matt J A1 - Nielsen, Jonas B A1 - Nielsen, Sune F A1 - Nordestgaard, Børge G A1 - Ordovas, Jose M A1 - Mehran, Roxana A1 - O'Donnell, Christoper J A1 - Orho-Melander, Marju A1 - Molony, Cliona M A1 - Muntendam, Pieter A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasko, Dorota A1 - Patel, Aniruddh P A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Pisinger, Charlotta A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil R A1 - Roden, Dan M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sanna, Serena A1 - Sattar, Naveed A1 - Schmidt, Ellen M A1 - Scott, Robert A A1 - Sever, Peter A1 - Sevilla, Raquel S A1 - Shaffer, Christian M A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert V A1 - Smith, Blair H A1 - Somayajula, Sangeetha A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Stirrups, Kathleen E A1 - Stitziel, Nathan A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Surendran, Praveen A1 - Tada, Hayato A1 - Tall, Alan R A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Trompet, Stella A1 - Tsao, Philip S A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - van Zuydam, Natalie R A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Virtamo, Jarmo A1 - Waldenberger, Melanie A1 - Wang, Nan A1 - Wareham, Nick J A1 - Warren, Helen R A1 - Weeke, Peter E A1 - Weinstock, Joshua A1 - Wessel, Jennifer A1 - Wilson, James G A1 - Wilson, Peter W F A1 - Xu, Ming A1 - Yaghootkar, Hanieh A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhang, He A1 - Zheng, Neil S A1 - Zhang, Weihua A1 - Zhang, Yan A1 - Zhou, Wei A1 - Zhou, Yanhua A1 - Zoledziewska, Magdalena A1 - Howson, Joanna M M A1 - Danesh, John A1 - McCarthy, Mark I A1 - Cowan, Chad A A1 - Abecasis, Goncalo A1 - Deloukas, Panos A1 - Musunuru, Kiran A1 - Willer, Cristen J A1 - Kathiresan, Sekar KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Lipids KW - Macular Degeneration KW - Phenotype KW - Risk Factors AB -

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

VL - 49 IS - 12 ER - TY - JOUR T1 - Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Magnani, Jared W A1 - Yin, Xiaoyan A1 - Barnard, John A1 - Weng, Lu-Chen A1 - Arking, Dan E A1 - Niemeijer, Maartje N A1 - Lubitz, Steven A A1 - Avery, Christy L A1 - Duan, Qing A1 - Felix, Stephan B A1 - Bis, Joshua C A1 - Kerr, Kathleen F A1 - Isaacs, Aaron A1 - Müller-Nurasyid, Martina A1 - Müller, Christian A1 - North, Kari E A1 - Reiner, Alex P A1 - Tinker, Lesley F A1 - Kors, Jan A A1 - Teumer, Alexander A1 - Petersmann, Astrid A1 - Sinner, Moritz F A1 - Bůzková, Petra A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Meitinger, Thomas A1 - Limacher, Marian C A1 - Wilhelmsen, Kirk C A1 - Psaty, Bruce M A1 - Hofman, Albert A1 - Uitterlinden, Andre A1 - Krijthe, Bouwe P A1 - Zhang, Zhu-Ming A1 - Schnabel, Renate B A1 - Kääb, Stefan A1 - van Duijn, Cornelia A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Dörr, Marcus A1 - Li, Yun A1 - Chung, Mina K A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Whitsel, Eric A A1 - Stricker, Bruno H A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Ellinor, Patrick T KW - Arrhythmias, Cardiac KW - Caveolin 1 KW - Caveolin 2 KW - Electrocardiography KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Heart Atria KW - Humans KW - NAV1.5 Voltage-Gated Sodium Channel KW - NAV1.8 Voltage-Gated Sodium Channel KW - T-Box Domain Proteins AB -

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

VL - 10 IS - 4 ER - TY - JOUR T1 - Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. JF - Int J Obes (Lond) Y1 - 2017 A1 - Yoneyama, S A1 - Yao, J A1 - Guo, X A1 - Fernandez-Rhodes, L A1 - Lim, U A1 - Boston, J A1 - Bůžková, P A1 - Carlson, C S A1 - Cheng, I A1 - Cochran, B A1 - Cooper, R A1 - Ehret, G A1 - Fornage, M A1 - Gong, J A1 - Gross, M A1 - Gu, C C A1 - Haessler, J A1 - Haiman, C A A1 - Henderson, B A1 - Hindorff, L A A1 - Houston, D A1 - Irvin, M R A1 - Jackson, R A1 - Kuller, L A1 - Leppert, M A1 - Lewis, C E A1 - Li, R A1 - Le Marchand, L A1 - Matise, T C A1 - Nguyen, K-Dh A1 - Chakravarti, A A1 - Pankow, J S A1 - Pankratz, N A1 - Pooler, L A1 - Ritchie, M D A1 - Bien, S A A1 - Wassel, C L A1 - Chen, Y-DI A1 - Taylor, K D A1 - Allison, M A1 - Rotter, J I A1 - Schreiner, P J A1 - Schumacher, F A1 - Wilkens, L A1 - Boerwinkle, E A1 - Kooperberg, C A1 - Peters, U A1 - Buyske, S A1 - Graff, M A1 - North, K E AB -

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.

SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.

RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.

CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

VL - 41 IS - 2 ER - TY - JOUR T1 - Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. JF - Sci Rep Y1 - 2017 A1 - Weng, Lu-Chen A1 - Lunetta, Kathryn L A1 - Müller-Nurasyid, Martina A1 - Smith, Albert Vernon A1 - Thériault, Sébastien A1 - Weeke, Peter E A1 - Barnard, John A1 - Bis, Joshua C A1 - Lyytikäinen, Leo-Pekka A1 - Kleber, Marcus E A1 - Martinsson, Andreas A1 - Lin, Henry J A1 - Rienstra, Michiel A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Dörr, Marcus A1 - Klarin, Derek A1 - Chasman, Daniel I A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Paré, Guillaume A1 - Teixeira, Pedro L A1 - Denny, Joshua C A1 - Shoemaker, M Benjamin A1 - Van Wagoner, David R A1 - Smith, Jonathan D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Kähönen, Mika A1 - Nikus, Kjell A1 - Delgado, Graciela E A1 - Melander, Olle A1 - Engström, Gunnar A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Christophersen, Ingrid E A1 - Ellinor, Patrick T A1 - Geelhoed, Bastiaan A1 - Verweij, Niek A1 - Macfarlane, Peter A1 - Ford, Ian A1 - Heeringa, Jan A1 - Franco, Oscar H A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Teumer, Alexander A1 - Rose, Lynda M A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Arking, Dan E A1 - Conen, David A1 - Roden, Dan M A1 - Chung, Mina K A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Lehtimäki, Terho A1 - März, Winfried A1 - Smith, J Gustav A1 - Rotter, Jerome I A1 - van der Harst, Pim A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Felix, Stephan B A1 - Albert, Christine M A1 - Lubitz, Steven A AB -

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

VL - 7 IS - 1 ER - TY - JOUR T1 - Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. JF - Nat Genet Y1 - 2017 A1 - Hobbs, Brian D A1 - de Jong, Kim A1 - Lamontagne, Maxime A1 - Bossé, Yohan A1 - Shrine, Nick A1 - Artigas, Maria Soler A1 - Wain, Louise V A1 - Hall, Ian P A1 - Jackson, Victoria E A1 - Wyss, Annah B A1 - London, Stephanie J A1 - North, Kari E A1 - Franceschini, Nora A1 - Strachan, David P A1 - Beaty, Terri H A1 - Hokanson, John E A1 - Crapo, James D A1 - Castaldi, Peter J A1 - Chase, Robert P A1 - Bartz, Traci M A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Gharib, Sina A A1 - Zanen, Pieter A1 - Lammers, Jan W A1 - Oudkerk, Matthijs A1 - Groen, H J A1 - Locantore, Nicholas A1 - Tal-Singer, Ruth A1 - Rennard, Stephen I A1 - Vestbo, Jørgen A1 - Timens, Wim A1 - Paré, Peter D A1 - Latourelle, Jeanne C A1 - Dupuis, Josée A1 - O'Connor, George T A1 - Wilk, Jemma B A1 - Kim, Woo Jin A1 - Lee, Mi Kyeong A1 - Oh, Yeon-Mok A1 - Vonk, Judith M A1 - de Koning, Harry J A1 - Leng, Shuguang A1 - Belinsky, Steven A A1 - Tesfaigzi, Yohannes A1 - Manichaikul, Ani A1 - Wang, Xin-Qun A1 - Rich, Stephen S A1 - Barr, R Graham A1 - Sparrow, David A1 - Litonjua, Augusto A A1 - Bakke, Per A1 - Gulsvik, Amund A1 - Lahousse, Lies A1 - Brusselle, Guy G A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Ampleford, Elizabeth J A1 - Bleecker, Eugene R A1 - Woodruff, Prescott G A1 - Meyers, Deborah A A1 - Qiao, Dandi A1 - Lomas, David A A1 - Yim, Jae-Joon A1 - Kim, Deog Kyeom A1 - Hawrylkiewicz, Iwona A1 - Sliwinski, Pawel A1 - Hardin, Megan A1 - Fingerlin, Tasha E A1 - Schwartz, David A A1 - Postma, Dirkje S A1 - MacNee, William A1 - Tobin, Martin D A1 - Silverman, Edwin K A1 - Boezen, H Marike A1 - Cho, Michael H AB -

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

VL - 49 IS - 3 ER - TY - JOUR T1 - {Genetic Risk Prediction of Atrial Fibrillation JF - Circulation Y1 - 2017 A1 - Lubitz, S. A. A1 - Yin, X. A1 - Lin, H. J. A1 - Kolek, M. A1 - Smith, J. G. A1 - Trompet, S. A1 - Rienstra, M. A1 - Rost, N. S. A1 - Teixeira, P. L. A1 - Almgren, P. A1 - Anderson, C. D. A1 - Chen, L. Y. A1 - Engstr?m, G. A1 - Ford, I. A1 - Furie, K. L. A1 - Guo, X. A1 - Larson, M. G. A1 - Lunetta, K. L. A1 - Macfarlane, P. W. A1 - Psaty, B. M. A1 - Soliman, E. Z. A1 - Sotoodehnia, N. A1 - Stott, D. J. A1 - Taylor, K. D. A1 - Weng, L. C. A1 - Yao, J. A1 - Geelhoed, B. A1 - Verweij, N. A1 - Siland, J. E. A1 - Kathiresan, S. A1 - Roselli, C. A1 - Roden, D. M. A1 - van der Harst, P. A1 - Darbar, D. A1 - Jukema, J. W. A1 - Melander, O. A1 - Rosand, J. A1 - Rotter, J. I. A1 - Heckbert, S. R. A1 - Ellinor, P. T. A1 - Alonso, A. A1 - Benjamin, E. J. AB - Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.\ To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study.\ Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01).\ Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms. VL - 135 ER - TY - JOUR T1 - {Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk JF - Nat Genet Y1 - 2017 A1 - Warren, H. R. A1 - Evangelou, E. A1 - Cabrera, C. P. A1 - Gao, H. A1 - Ren, M. A1 - Mifsud, B. A1 - Ntalla, I. A1 - Surendran, P. A1 - Liu, C. A1 - Cook, J. P. A1 - Kraja, A. T. A1 - Drenos, F. A1 - Loh, M. A1 - Verweij, N. A1 - Marten, J. A1 - Karaman, I. A1 - Lepe, M. P. A1 - O'Reilly, P. F. A1 - Knight, J. A1 - Snieder, H. A1 - Kato, N. A1 - He, J. A1 - Tai, E. S. A1 - Said, M. A. A1 - Porteous, D. A1 - Alver, M. A1 - Poulter, N. A1 - Farrall, M. A1 - Gansevoort, R. T. A1 - Padmanabhan, S. A1 - M?gi, R. A1 - Stanton, A. A1 - Connell, J. A1 - Bakker, S. J. A1 - Metspalu, A. A1 - Shields, D. C. A1 - Thom, S. A1 - Brown, M. A1 - Sever, P. A1 - Esko, T. A1 - Hayward, C. A1 - van der Harst, P. A1 - Saleheen, D. A1 - Chowdhury, R. A1 - Chambers, J. C. A1 - Chasman, D. I. A1 - Chakravarti, A. A1 - Newton-Cheh, C. A1 - Lindgren, C. M. A1 - Levy, D. A1 - Kooner, J. S. A1 - Keavney, B. A1 - Tomaszewski, M. A1 - Samani, N. J. A1 - Howson, J. M. A1 - Tobin, M. D. A1 - Munroe, P. B. A1 - Ehret, G. B. A1 - Wain, L. V. A1 - V?lker, U. A1 - Vollenweider, P. A1 - Wild, S. A1 - Willemsen, G. A1 - Wright, A. F. A1 - Yao, J. A1 - Th?riault, S. A1 - Conen, D. A1 - John, A. A1 - Sever, P. A1 - Debette, S. A1 - Mook-Kanamori, D. O. A1 - Zeggini, E. A1 - Spector, T. D. A1 - van der Harst, P. A1 - Palmer, C. N. A1 - Vergnaud, A. C. A1 - Loos, R. J. A1 - Polasek, O. A1 - Starr, J. M. A1 - Girotto, G. A1 - Hayward, C. A1 - Kooner, J. S. A1 - Lindgren, C. M. A1 - Vitart, V. A1 - Samani, N. J. A1 - Tuomilehto, J. A1 - Gyllensten, U. A1 - Knekt, P. A1 - Deary, I. J. A1 - Ciullo, M. A1 - Elosua, R. A1 - Keavney, B. D. A1 - Hicks, A. A. A1 - Scott, R. A. A1 - Gasparini, P. A1 - Laan, M. A1 - Liu, Y. A1 - Watkins, H. A1 - Hartman, C. A. A1 - Salomaa, V. A1 - Toniolo, D. A1 - Perola, M. A1 - Wilson, J. F. A1 - Schmidt, H. A1 - Zhao, J. H. A1 - Lehtim?ki, T. A1 - van Duijn, C. M. A1 - Gudnason, V. A1 - Psaty, B. M. A1 - Peters, A. A1 - Rettig, R. A1 - James, A. A1 - Jukema, J. W. A1 - Strachan, D. P. A1 - Palmas, W. A1 - Metspalu, A. A1 - Ingelsson, E. A1 - Boomsma, D. I. A1 - Franco, O. H. A1 - Bochud, M. A1 - Newton-Cheh, C. A1 - Munroe, P. B. A1 - Elliott, P. A1 - Chasman, D. I. A1 - Chakravarti, A. A1 - Knight, J. A1 - Morris, A. P. A1 - Levy, D. A1 - Tobin, M. D. A1 - Snieder, H. A1 - Caulfield, M. J. A1 - Ehret, G. B. A1 - Barnes, M. R. A1 - Tzoulaki, I. A1 - Caulfield, M. J. A1 - Elliott, P. AB - Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk. VL - 49 ER - TY - JOUR T1 - Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Li, Changwei A1 - Kim, Yun Kyoung A1 - Dorajoo, Rajkumar A1 - Li, Huaixing A1 - Lee, I-Te A1 - Cheng, Ching-Yu A1 - He, Meian A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Ganesh, Santhi K A1 - He, Jiang A1 - Lee, Juyoung A1 - Liu, Jianjun A1 - Hu, Yao A1 - Rao, Dabeeru C A1 - Tsai, Fuu-Jen A1 - Koh, Jia Yu A1 - Hu, Hua A1 - Liang, Kae-Woei A1 - Palmas, Walter A1 - Hixson, James E A1 - Han, Sohee A1 - Teo, Yik-Ying A1 - Wang, Yiqin A1 - Chen, Jing A1 - Lu, Chieh Hsiang A1 - Zheng, Yingfeng A1 - Gui, Lixuan A1 - Lee, Wen-Jane A1 - Yao, Jie A1 - Gu, Dongfeng A1 - Han, Bok-Ghee A1 - Sim, Xueling A1 - Sun, Liang A1 - Zhao, Jinying A1 - Chen, Chien-Hsiun A1 - Kumari, Neelam A1 - He, Yunfeng A1 - Taylor, Kent D A1 - Raffel, Leslie J A1 - Moon, Sanghoon A1 - Rotter, Jerome I A1 - Ida Chen, Yii-Der A1 - Wu, Tangchun A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Lin, Xu A1 - Tai, E-Shyong A1 - Kim, Bong-Jo A1 - Kelly, Tanika N KW - Asian Continental Ancestry Group KW - Blood Pressure KW - Far East KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

VL - 10 IS - 2 ER - TY - JOUR T1 - Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent. JF - Mol Nutr Food Res Y1 - 2017 A1 - Smith, Caren E A1 - Follis, Jack L A1 - Dashti, Hassan S A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Fretts, Amanda M A1 - Kilpeläinen, Tuomas O A1 - Wojczynski, Mary K A1 - Richardson, Kris A1 - Nalls, Mike A A1 - Schulz, Christina-Alexandra A1 - Liu, Yongmei A1 - Frazier-Wood, Alexis C A1 - van Eekelen, Esther A1 - Wang, Carol A1 - de Vries, Paul S A1 - Mikkilä, Vera A1 - Rohde, Rebecca A1 - Psaty, Bruce M A1 - Hansen, Torben A1 - Feitosa, Mary F A1 - Lai, Chao-Qiang A1 - Houston, Denise K A1 - Ferruci, Luigi A1 - Ericson, Ulrika A1 - Wang, Zhe A1 - de Mutsert, Renée A1 - Oddy, Wendy H A1 - de Jonge, Ester A L A1 - Seppälä, Ilkka A1 - Justice, Anne E A1 - Lemaitre, Rozenn N A1 - Sørensen, Thorkild I A A1 - Province, Michael A A1 - Parnell, Laurence D A1 - Garcia, Melissa E A1 - Bandinelli, Stefania A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Pennell, Craig E A1 - Kiefte-de Jong, Jessica C A1 - Kähönen, Mika A1 - Young, Kristin L A1 - Pedersen, Oluf A1 - Aslibekyan, Stella A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Zillikens, M Carola A1 - Raitakari, Olli T A1 - North, Kari E A1 - Overvad, Kim A1 - Arnett, Donna K A1 - Hofman, Albert A1 - Lehtimäki, Terho A1 - Tjønneland, Anne A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Franco, Oscar H A1 - German, J Bruce A1 - Siscovick, David S A1 - Cupples, L Adrienne A1 - Ordovas, Jose M AB -

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

ER - TY - JOUR T1 - Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. JF - Nat Commun Y1 - 2017 A1 - Joshi, Peter K A1 - Pirastu, Nicola A1 - Kentistou, Katherine A A1 - Fischer, Krista A1 - Hofer, Edith A1 - Schraut, Katharina E A1 - Clark, David W A1 - Nutile, Teresa A1 - Barnes, Catriona L K A1 - Timmers, Paul R H J A1 - Shen, Xia A1 - Gandin, Ilaria A1 - McDaid, Aaron F A1 - Hansen, Thomas Folkmann A1 - Gordon, Scott D A1 - Giulianini, Franco A1 - Boutin, Thibaud S A1 - Abdellaoui, Abdel A1 - Zhao, Wei A1 - Medina-Gómez, Carolina A1 - Bartz, Traci M A1 - Trompet, Stella A1 - Lange, Leslie A A1 - Raffield, Laura A1 - van der Spek, Ashley A1 - Galesloot, Tessel E A1 - Proitsi, Petroula A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Payton, Antony A1 - Murgia, Federico A1 - Concas, Maria Pina A1 - Biino, Ginevra A1 - Tajuddin, Salman M A1 - Seppälä, Ilkka A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Børglum, Anders D A1 - Campbell, Archie A1 - Demerath, Ellen W A1 - Demuth, Ilja A1 - Faul, Jessica D A1 - Ford, Ian A1 - Gialluisi, Alessandro A1 - Gögele, Martin A1 - Graff, Mariaelisa A1 - Hingorani, Aroon A1 - Hottenga, Jouke-Jan A1 - Hougaard, David M A1 - Hurme, Mikko A A1 - Ikram, M Arfan A1 - Jylhä, Marja A1 - Kuh, Diana A1 - Ligthart, Lannie A1 - Lill, Christina M A1 - Lindenberger, Ulman A1 - Lumley, Thomas A1 - Mägi, Reedik A1 - Marques-Vidal, Pedro A1 - Medland, Sarah E A1 - Milani, Lili A1 - Nagy, Reka A1 - Ollier, William E R A1 - Peyser, Patricia A A1 - Pramstaller, Peter P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Steinhagen-Thiessen, Elisabeth A1 - van Rooij, Frank J A A1 - Verbeek, André L A1 - Vermeulen, Sita H A1 - Vollenweider, Peter A1 - Wang, Yunpeng A1 - Werge, Thomas A1 - Whitfield, John B A1 - Zonderman, Alan B A1 - Lehtimäki, Terho A1 - Evans, Michele K A1 - Pirastu, Mario A1 - Fuchsberger, Christian A1 - Bertram, Lars A1 - Pendleton, Neil A1 - Kardia, Sharon L R A1 - Ciullo, Marina A1 - Becker, Diane M A1 - Wong, Andrew A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A1 - Uitterlinden, André G A1 - Franceschini, Nora A1 - North, Kari E A1 - Weir, David R A1 - Metspalu, Andres A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Chasman, Daniel A1 - Martin, Nicholas G A1 - Sattar, Naveed A1 - Campbell, Harry A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F AB -

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

VL - 8 IS - 1 ER - TY - JOUR T1 - {Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits JF - Nat Commun Y1 - 2017 A1 - Justice, A. E. A1 - Winkler, T. W. A1 - Feitosa, M. F. A1 - Graff, M. A1 - Fisher, V. A. A1 - Young, K. A1 - Barata, L. A1 - Deng, X. A1 - Czajkowski, J. A1 - Hadley, D. A1 - Ngwa, J. S. A1 - Ahluwalia, T. S. A1 - Chu, A. Y. A1 - Heard-Costa, N. L. A1 - Lim, E. A1 - Perez, J. A1 - Eicher, J. D. A1 - Kutalik, Z. A1 - Xue, L. A1 - Mahajan, A. A1 - Renstr?m, F. A1 - Wu, J. A1 - Qi, Q. A1 - Ahmad, S. A1 - Alfred, T. A1 - Amin, N. A1 - Bielak, L. F. A1 - Bonnefond, A. A1 - Bragg, J. A1 - Cadby, G. A1 - Chittani, M. A1 - Coggeshall, S. A1 - Corre, T. A1 - Direk, N. A1 - Eriksson, J. A1 - Fischer, K. A1 - Gorski, M. A1 - Neergaard Harder, M. A1 - Horikoshi, M. A1 - Huang, T. A1 - Huffman, J. E. A1 - Jackson, A. U. A1 - Justesen, J. M. A1 - Kanoni, S. A1 - Kinnunen, L. A1 - Kleber, M. E. A1 - Komulainen, P. A1 - Kumari, M. A1 - Lim, U. A1 - Luan, J. A1 - Lyytik?inen, L. P. A1 - Mangino, M. A1 - Manichaikul, A. A1 - Marten, J. A1 - Middelberg, R. P. S. A1 - M?ller-Nurasyid, M. A1 - Navarro, P. A1 - P?russe, L. A1 - Pervjakova, N. A1 - Sarti, C. A1 - Smith, A. V. A1 - Smith, J. A. A1 - Stan??kov?, A. A1 - Strawbridge, R. J. A1 - Stringham, H. M. A1 - Sung, Y. J. A1 - Tanaka, T. A1 - Teumer, A. A1 - Trompet, S. A1 - van der Laan, S. W. A1 - van der Most, P. J. A1 - Van Vliet-Ostaptchouk, J. V. A1 - Vedantam, S. L. A1 - Verweij, N. A1 - Vink, J. M. A1 - Vitart, V. A1 - Wu, Y. A1 - Yengo, L. A1 - Zhang, W. A1 - Hua Zhao, J. A1 - Zimmermann, M. E. A1 - Zubair, N. A1 - Abecasis, G. R. A1 - Adair, L. S. A1 - Afaq, S. A1 - Afzal, U. A1 - Bakker, S. J. L. A1 - Bartz, T. M. A1 - Beilby, J. A1 - Bergman, R. N. A1 - Bergmann, S. A1 - Biffar, R. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bonnycastle, L. L. A1 - Bottinger, E. A1 - Braga, D. A1 - Buckley, B. M. A1 - Buyske, S. A1 - Campbell, H. A1 - Chambers, J. C. A1 - Collins, F. S. A1 - Curran, J. E. A1 - de Borst, G. J. A1 - de Craen, A. J. M. A1 - de Geus, E. J. C. A1 - Dedoussis, G. A1 - Delgado, G. E. A1 - den Ruijter, H. M. A1 - Eiriksdottir, G. A1 - Eriksson, A. L. A1 - Esko, T. A1 - Faul, J. D. A1 - Ford, I. A1 - Forrester, T. A1 - Gertow, K. A1 - Gigante, B. A1 - Glorioso, N. A1 - Gong, J. A1 - Grallert, H. A1 - Grammer, T. B. A1 - Grarup, N. A1 - Haitjema, S. A1 - Hallmans, G. A1 - Hamsten, A. A1 - Hansen, T. A1 - Harris, T. B. A1 - Hartman, C. A. A1 - Hassinen, M. A1 - Hastie, N. D. A1 - Heath, A. C. A1 - Hernandez, D. A1 - Hindorff, L. A1 - Hocking, L. J. A1 - Hollensted, M. A1 - Holmen, O. L. A1 - Homuth, G. A1 - Jan Hottenga, J. A1 - Huang, J. A1 - Hung, J. A1 - Hutri-K?h?nen, N. A1 - Ingelsson, E. A1 - James, A. L. A1 - Jansson, J. O. A1 - Jarvelin, M. R. A1 - Jhun, M. A. A1 - J?rgensen, M. E. A1 - Juonala, M. A1 - K?h?nen, M. A1 - Karlsson, M. A1 - Koistinen, H. A. A1 - Kolcic, I. A1 - Kolovou, G. A1 - Kooperberg, C. A1 - Kr?mer, B. K. A1 - Kuusisto, J. A1 - Kval?y, K. A1 - Lakka, T. A. A1 - Langenberg, C. A1 - Launer, L. J. A1 - Leander, K. A1 - Lee, N. R. A1 - Lind, L. A1 - Lindgren, C. M. A1 - Linneberg, A. A1 - Lobbens, S. A1 - Loh, M. A1 - Lorentzon, M. A1 - Luben, R. A1 - Lubke, G. A1 - Ludolph-Donislawski, A. A1 - Lupoli, S. A1 - Madden, P. A. F. A1 - M?nnikk?, R. A1 - Marques-Vidal, P. A1 - Martin, N. G. A1 - McKenzie, C. A. A1 - McKnight, B. A1 - Mellstr?m, D. A1 - Menni, C. A1 - Montgomery, G. W. A1 - Musk, A. B. A1 - Narisu, N. A1 - Nauck, M. A1 - Nolte, I. M. A1 - Oldehinkel, A. J. A1 - Olden, M. A1 - Ong, K. K. A1 - Padmanabhan, S. A1 - Peyser, P. A. A1 - Pisinger, C. A1 - Porteous, D. J. A1 - Raitakari, O. T. A1 - Rankinen, T. A1 - Rao, D. C. A1 - Rasmussen-Torvik, L. J. A1 - Rawal, R. A1 - Rice, T. A1 - Ridker, P. M. A1 - Rose, L. M. A1 - Bien, S. A. A1 - Rudan, I. A1 - Sanna, S. A1 - Sarzynski, M. A. A1 - Sattar, N. A1 - Savonen, K. A1 - Schlessinger, D. A1 - Scholtens, S. A1 - Schurmann, C. A1 - Scott, R. A. A1 - Sennblad, B. A1 - Siemelink, M. A. A1 - Silbernagel, G. A1 - Slagboom, P. E. A1 - Snieder, H. A1 - Staessen, J. A. A1 - Stott, D. J. A1 - Swertz, M. A. A1 - Swift, A. J. A1 - Taylor, K. D. A1 - Tayo, B. O. A1 - Thorand, B. A1 - Thuillier, D. A1 - Tuomilehto, J. A1 - Uitterlinden, A. G. A1 - Vandenput, L. A1 - Vohl, M. C. A1 - V?lzke, H. A1 - Vonk, J. M. A1 - Waeber, G. A1 - Waldenberger, M. A1 - Westendorp, R. G. J. A1 - Wild, S. A1 - Willemsen, G. A1 - Wolffenbuttel, B. H. R. A1 - Wong, A. A1 - Wright, A. F. A1 - Zhao, W. A1 - Zillikens, M. C. A1 - Baldassarre, D. A1 - Balkau, B. A1 - Bandinelli, S. A1 - B?ger, C. A. A1 - Boomsma, D. I. A1 - Bouchard, C. A1 - Bruinenberg, M. A1 - Chasman, D. I. A1 - Chen, Y. D. A1 - Chines, P. S. A1 - Cooper, R. S. A1 - Cucca, F. A1 - Cusi, D. A1 - Faire, U. A1 - Ferrucci, L. A1 - Franks, P. W. A1 - Froguel, P. A1 - Gordon-Larsen, P. A1 - Grabe, H. J. A1 - Gudnason, V. A1 - Haiman, C. A. A1 - Hayward, C. A1 - Hveem, K. A1 - Johnson, A. D. A1 - Wouter Jukema, J. A1 - Kardia, S. L. R. A1 - Kivimaki, M. A1 - Kooner, J. S. A1 - Kuh, D. A1 - Laakso, M. A1 - Lehtim?ki, T. A1 - Marchand, L. L. A1 - M?rz, W. A1 - McCarthy, M. I. A1 - Metspalu, A. A1 - Morris, A. P. A1 - Ohlsson, C. A1 - Palmer, L. J. A1 - Pasterkamp, G. A1 - Pedersen, O. A1 - Peters, A. A1 - Peters, U. A1 - Polasek, O. A1 - Psaty, B. M. A1 - Qi, L. A1 - Rauramaa, R. A1 - Smith, B. H. A1 - S?rensen, T. I. A. A1 - Strauch, K. A1 - Tiemeier, H. A1 - Tremoli, E. A1 - van der Harst, P. A1 - Vestergaard, H. A1 - Vollenweider, P. A1 - Wareham, N. J. A1 - Weir, D. R. A1 - Whitfield, J. B. A1 - Wilson, J. F. A1 - Tyrrell, J. A1 - Frayling, T. M. A1 - Barroso, I. A1 - Boehnke, M. A1 - Deloukas, P. A1 - Fox, C. S. A1 - Hirschhorn, J. N. A1 - Hunter, D. J. A1 - Spector, T. D. A1 - Strachan, D. P. A1 - van Duijn, C. M. A1 - Heid, I. M. A1 - Mohlke, K. L. A1 - Marchini, J. A1 - Loos, R. J. F. A1 - Kilpel?inen, T. O. A1 - Liu, C. T. A1 - Borecki, I. B. A1 - North, K. E. A1 - Cupples, L. A. AB - Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution. VL - 8 ER - TY - JOUR T1 - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. JF - Am J Hum Genet Y1 - 2017 A1 - van Rooij, Frank J A A1 - Qayyum, Rehan A1 - Smith, Albert V A1 - Zhou, Yi A1 - Trompet, Stella A1 - Tanaka, Toshiko A1 - Keller, Margaux F A1 - Chang, Li-Ching A1 - Schmidt, Helena A1 - Yang, Min-Lee A1 - Chen, Ming-Huei A1 - Hayes, James A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Mueller, Christian A1 - Lange, Leslie A1 - Floyd, James S A1 - Ghanbari, Mohsen A1 - Zonderman, Alan B A1 - Jukema, J Wouter A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Desch, Karl C A1 - Saba, Yasaman A1 - Ozel, Ayse B A1 - Snively, Beverly M A1 - Wu, Jer-Yuarn A1 - Schmidt, Reinhold A1 - Fornage, Myriam A1 - Klein, Robert J A1 - Fox, Caroline S A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Wild, Philipp S A1 - Stott, David J A1 - Ford, Ian A1 - Slagboom, P Eline A1 - Yang, Jaden A1 - Chu, Audrey Y A1 - Lambert, Amy J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofer, Edith A1 - Ginsburg, David A1 - Hu, Bella A1 - Keating, Brendan A1 - Schick, Ursula M A1 - Brody, Jennifer A A1 - Li, Jun Z A1 - Chen, Zhao A1 - Zeller, Tanja A1 - Guralnik, Jack M A1 - Chasman, Daniel I A1 - Peters, Luanne L A1 - Kubo, Michiaki A1 - Becker, Diane M A1 - Li, Jin A1 - Eiriksdottir, Gudny A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Grossmann, Vera A1 - Patel, Kushang V A1 - Chen, Chien-Hsiun A1 - Ridker, Paul M A1 - Tang, Hua A1 - Launer, Lenore J A1 - Rice, Kenneth M A1 - Li-Gao, Ruifang A1 - Ferrucci, Luigi A1 - Evans, Michelle K A1 - Choudhuri, Avik A1 - Trompouki, Eirini A1 - Abraham, Brian J A1 - Yang, Song A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Kooperberg, Charles A1 - Harris, Tamara B A1 - Jee, Sun Ha A1 - Coresh, Josef A1 - Tsai, Fuu-Jen A1 - Longo, Dan L A1 - Chen, Yuan-Tsong A1 - Felix, Janine F A1 - Yang, Qiong A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Mook-Kanamori, Dennis O A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J A1 - Dehghan, Abbas A1 - Cupples, L Adrienne A1 - Nalls, Michael A A1 - Morris, Andrew P A1 - Okada, Yukinori A1 - Reiner, Alexander P A1 - Zon, Leonard I A1 - Ganesh, Santhi K AB -

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

VL - 100 IS - 1 ER - TY - JOUR T1 - Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses. JF - Exp Gerontol Y1 - 2017 A1 - Yashin, Anatoliy I A1 - Fang, Fang A1 - Kovtun, Mikhail A1 - Wu, Deqing A1 - Duan, Matt A1 - Arbeev, Konstantin A1 - Akushevich, Igor A1 - Kulminski, Alexander A1 - Culminskaya, Irina A1 - Zhbannikov, Ilya A1 - Yashkin, Arseniy A1 - Stallard, Eric A1 - Ukraintseva, Svetlana AB -

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

VL - 14 IS - 9 ER - TY - JOUR T1 - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JF - Nat Commun Y1 - 2017 A1 - Zillikens, M Carola A1 - Demissie, Serkalem A1 - Hsu, Yi-Hsiang A1 - Yerges-Armstrong, Laura M A1 - Chou, Wen-Chi A1 - Stolk, Lisette A1 - Livshits, Gregory A1 - Broer, Linda A1 - Johnson, Toby A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Malkin, Ida A1 - Ried, Janina S A1 - Smith, Albert V A1 - Thorleifsson, Gudmar A1 - Vandenput, Liesbeth A1 - Hua Zhao, Jing A1 - Zhang, Weihua A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Baier, Leslie J A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Biffar, Rainer A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos Obanda, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Cederberg, Henna A1 - Chen, Zhao A1 - Cho, Nam H A1 - Jin Choi, Hyung A1 - Claussnitzer, Melina A1 - Collins, Francis A1 - Cummings, Steven R A1 - De Jager, Philip L A1 - Demuth, Ilja A1 - Dhonukshe-Rutten, Rosalie A M A1 - Diatchenko, Luda A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Erdos, Mike A1 - Eriksson, Johan G A1 - Eriksson, Joel A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Girke, Thomas A1 - Glazer, Nicole L A1 - Grallert, Harald A1 - Grewal, Jagvir A1 - Han, Bok-Ghee A1 - Hanson, Robert L A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Hoffman, Eric P A1 - Homuth, Georg A1 - Hsueh, Wen-Chi A1 - Hubal, Monica J A1 - Hubbard, Alan A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koistinen, Heikki A A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Launer, Lenore J A1 - Lee, Jong-Young A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Liu, Tian A1 - Liu, Youfang A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Maixner, William A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Melov, Simon A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Newman, Anne A1 - Nielson, Carrie M A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Parker, Stephen C J A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Prince, Richard L A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schadt, Eric E A1 - Schipf, Sabine A1 - Scott, Laura A1 - Sehmi, Joban A1 - Shen, Jian A1 - Soo Shin, Chan A1 - Sigurdsson, Gunnar A1 - Smith, Shad A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Steinhagen-Thiessen, Elisabeth A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Tan, Sian-Tsung A1 - Tarnopolsky, Mark A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Tuomilehto, Jaakko A1 - van Schoor, Natasja M A1 - Verma, Arjun A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - Weedon, Michael N A1 - Welch, Ryan A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Xie, Weijia A1 - Yu, Lei A1 - Zhou, Yanhua A1 - Chambers, John C A1 - Döring, Angela A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Gudnason, Vilmundur A1 - Kooner, Jaspal S A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Ossowski, Vicky A1 - Waterworth, Dawn A1 - Loos, Ruth J F A1 - Karasik, David A1 - Harris, Tamara B A1 - Ohlsson, Claes A1 - Kiel, Douglas P AB -

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

VL - 8 IS - 1 ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

VL - 49 IS - 6 ER - TY - JOUR T1 - Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. JF - Cell Rep Y1 - 2017 A1 - Lam, Max A1 - Trampush, Joey W A1 - Yu, Jin A1 - Knowles, Emma A1 - Davies, Gail A1 - Liewald, David C A1 - Starr, John M A1 - Djurovic, Srdjan A1 - Melle, Ingrid A1 - Sundet, Kjetil A1 - Christoforou, Andrea A1 - Reinvang, Ivar A1 - DeRosse, Pamela A1 - Lundervold, Astri J A1 - Steen, Vidar M A1 - Espeseth, Thomas A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Eriksson, Johan G A1 - Giegling, Ina A1 - Konte, Bettina A1 - Roussos, Panos A1 - Giakoumaki, Stella A1 - Burdick, Katherine E A1 - Payton, Antony A1 - Ollier, William A1 - Chiba-Falek, Ornit A1 - Attix, Deborah K A1 - Need, Anna C A1 - Cirulli, Elizabeth T A1 - Voineskos, Aristotle N A1 - Stefanis, Nikos C A1 - Avramopoulos, Dimitrios A1 - Hatzimanolis, Alex A1 - Arking, Dan E A1 - Smyrnis, Nikolaos A1 - Bilder, Robert M A1 - Freimer, Nelson A A1 - Cannon, Tyrone D A1 - London, Edythe A1 - Poldrack, Russell A A1 - Sabb, Fred W A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Scult, Matthew A A1 - Dickinson, Dwight A1 - Straub, Richard E A1 - Donohoe, Gary A1 - Morris, Derek A1 - Corvin, Aiden A1 - Gill, Michael A1 - Hariri, Ahmad R A1 - Weinberger, Daniel R A1 - Pendleton, Neil A1 - Bitsios, Panos A1 - Rujescu, Dan A1 - Lahti, Jari A1 - Le Hellard, Stephanie A1 - Keller, Matthew C A1 - Andreassen, Ole A A1 - Deary, Ian J A1 - Glahn, David C A1 - Malhotra, Anil K A1 - Lencz, Todd AB -

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

VL - 21 IS - 9 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

VL - 10 IS - 5 ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Jarvelin, Marjo-Riitta A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stephanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

ER - TY - JOUR T1 - {Novel genetic loci associated with hippocampal volume JF - Nat Commun Y1 - 2017 A1 - Hibar, D. P. A1 - Adams, H. H. H. A1 - Jahanshad, N. A1 - Chauhan, G. A1 - Stein, J. L. A1 - Hofer, E. A1 - Renteria, M. E. A1 - Bis, J. C. A1 - Arias-Vasquez, A. A1 - Ikram, M. K. A1 - Desrivi?res, S. A1 - Vernooij, M. W. A1 - Abramovic, L. A1 - Alhusaini, S. A1 - Amin, N. A1 - Andersson, M. A1 - Arfanakis, K. A1 - Aribisala, B. S. A1 - Armstrong, N. J. A1 - Athanasiu, L. A1 - Axelsson, T. A1 - Beecham, A. H. A1 - Beiser, A. A1 - Bernard, M. A1 - Blanton, S. H. A1 - Bohlken, M. M. A1 - Boks, M. P. A1 - Bralten, J. A1 - Brickman, A. M. A1 - Carmichael, O. A1 - Chakravarty, M. M. A1 - Chen, Q. A1 - Ching, C. R. K. A1 - Chouraki, V. A1 - Cuellar-Partida, G. A1 - Crivello, F. A1 - den Braber, A. A1 - Doan, N. T. A1 - Ehrlich, S. A1 - Giddaluru, S. A1 - Goldman, A. L. A1 - Gottesman, R. F. A1 - Grimm, O. A1 - Griswold, M. E. A1 - Guadalupe, T. A1 - Gutman, B. A. A1 - Hass, J. A1 - Haukvik, U. K. A1 - Hoehn, D. A1 - Holmes, A. J. A1 - Hoogman, M. A1 - Janowitz, D. A1 - Jia, T. A1 - J?rgensen, K. N. A1 - Karbalai, N. A1 - Kasperaviciute, D. A1 - Kim, S. A1 - Klein, M. A1 - Kraemer, B. A1 - Lee, P. H. A1 - Liewald, D. C. M. A1 - Lopez, L. M. A1 - Luciano, M. A1 - Macare, C. A1 - Marquand, A. F. A1 - Matarin, M. A1 - Mather, K. A. A1 - Mattheisen, M. A1 - McKay, D. R. A1 - Milaneschi, Y. A1 - Mu?oz Maniega, S. A1 - Nho, K. A1 - Nugent, A. C. A1 - Nyquist, P. A1 - Loohuis, L. M. O. A1 - Oosterlaan, J. A1 - Papmeyer, M. A1 - Pirpamer, L. A1 - P?tz, B. A1 - Ramasamy, A. A1 - Richards, J. S. A1 - Risacher, S. L. A1 - Roiz-Santia?ez, R. A1 - Rommelse, N. A1 - Ropele, S. A1 - Rose, E. J. A1 - Royle, N. A. A1 - Rundek, T. A1 - S?mann, P. G. A1 - Saremi, A. A1 - Satizabal, C. L. A1 - Schmaal, L. A1 - Schork, A. J. A1 - Shen, L. A1 - Shin, J. A1 - Shumskaya, E. A1 - Smith, A. V. A1 - Sprooten, E. A1 - Strike, L. T. A1 - Teumer, A. A1 - Tordesillas-Gutierrez, D. A1 - Toro, R. A1 - Trabzuni, D. A1 - Trompet, S. A1 - Vaidya, D. A1 - van der Grond, J. A1 - van der Lee, S. J. A1 - van der Meer, D. A1 - van Donkelaar, M. M. J. A1 - Van Eijk, K. R. A1 - van Erp, T. G. M. A1 - van Rooij, D. A1 - Walton, E. A1 - Westlye, L. T. A1 - Whelan, C. D. A1 - Windham, B. G. A1 - Winkler, A. M. A1 - Wittfeld, K. A1 - Woldehawariat, G. A1 - Wolf, C. A1 - Wolfers, T. A1 - Yanek, L. R. A1 - Yang, J. A1 - Zijdenbos, A. A1 - Zwiers, M. P. A1 - Agartz, I. A1 - Almasy, L. A1 - Ames, D. A1 - Amouyel, P. A1 - Andreassen, O. A. A1 - Arepalli, S. A1 - Assareh, A. A. A1 - Barral, S. A1 - Bastin, M. E. A1 - Becker, D. M. A1 - Becker, J. T. A1 - Bennett, D. A. A1 - Blangero, J. A1 - van Bokhoven, H. A1 - Boomsma, D. I. A1 - Brodaty, H. A1 - Brouwer, R. M. A1 - Brunner, H. G. A1 - Buckner, R. L. A1 - Buitelaar, J. K. A1 - Bulayeva, K. B. A1 - Cahn, W. A1 - Calhoun, V. D. A1 - Cannon, D. M. A1 - Cavalleri, G. L. A1 - Cheng, C. Y. A1 - Cichon, S. A1 - Cookson, M. R. A1 - Corvin, A. A1 - Crespo-Facorro, B. A1 - Curran, J. E. A1 - Czisch, M. A1 - Dale, A. M. A1 - Davies, G. E. A1 - de Craen, A. J. M. A1 - de Geus, E. J. C. A1 - De Jager, P. L. A1 - de Zubicaray, G. I. A1 - Deary, I. J. A1 - Debette, S. A1 - DeCarli, C. A1 - Delanty, N. A1 - Depondt, C. A1 - DeStefano, A. A1 - Dillman, A. A1 - Djurovic, S. A1 - Donohoe, G. A1 - Drevets, W. C. A1 - Duggirala, R. A1 - Dyer, T. D. A1 - Enzinger, C. A1 - Erk, S. A1 - Espeseth, T. A1 - Fedko, I. O. A1 - Fern?ndez, G. A1 - Ferrucci, L. A1 - Fisher, S. E. A1 - Fleischman, D. A. A1 - Ford, I. A1 - Fornage, M. A1 - Foroud, T. M. A1 - Fox, P. T. A1 - Francks, C. A1 - Fukunaga, M. A1 - Gibbs, J. R. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - G?ring, H. H. H. A1 - Green, R. C. A1 - Gruber, O. A1 - Gudnason, V. A1 - Guelfi, S. A1 - H?berg, A. K. A1 - Hansell, N. K. A1 - Hardy, J. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Hegenscheid, K. A1 - Heinz, A. A1 - Le Hellard, S. A1 - Hernandez, D. G. A1 - Heslenfeld, D. J. A1 - Ho, B. C. A1 - Hoekstra, P. J. A1 - Hoffmann, W. A1 - Hofman, A. A1 - Holsboer, F. A1 - Homuth, G. A1 - Hosten, N. A1 - Hottenga, J. J. A1 - Huentelman, M. A1 - Hulshoff Pol, H. E. A1 - Ikeda, M. A1 - Jack, C. R. A1 - Jenkinson, M. A1 - Johnson, R. A1 - J?nsson, E. G. A1 - Jukema, J. W. A1 - Kahn, R. S. A1 - Kanai, R. A1 - Kloszewska, I. A1 - Knopman, D. S. A1 - Kochunov, P. A1 - Kwok, J. B. A1 - Lawrie, S. M. A1 - Lema?tre, H. A1 - Liu, X. A1 - Longo, D. L. A1 - Lopez, O. L. A1 - Lovestone, S. A1 - Martinez, O. A1 - Martinot, J. L. A1 - Mattay, V. S. A1 - McDonald, C. A1 - McIntosh, A. M. A1 - McMahon, F. J. A1 - McMahon, K. L. A1 - Mecocci, P. A1 - Melle, I. A1 - Meyer-Lindenberg, A. A1 - Mohnke, S. A1 - Montgomery, G. W. A1 - Morris, D. W. A1 - Mosley, T. H. A1 - M?hleisen, T. W. A1 - M?ller-Myhsok, B. A1 - Nalls, M. A. A1 - Nauck, M. A1 - Nichols, T. E. A1 - Niessen, W. J. A1 - N?then, M. M. A1 - Nyberg, L. A1 - Ohi, K. A1 - Olvera, R. L. A1 - Ophoff, R. A. A1 - Pandolfo, M. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. J. H. A1 - Pike, G. B. A1 - Potkin, S. G. A1 - Psaty, B. M. A1 - Reppermund, S. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Romanczuk-Seiferth, N. A1 - Rotter, J. I. A1 - Ryten, M. A1 - Sacco, R. L. A1 - Sachdev, P. S. A1 - Saykin, A. J. A1 - Schmidt, R. A1 - Schmidt, H. A1 - Schofield, P. R. A1 - Sigursson, S. A1 - Simmons, A. A1 - Singleton, A. A1 - Sisodiya, S. M. A1 - Smith, C. A1 - Smoller, J. W. A1 - Soininen, H. A1 - Steen, V. M. A1 - Stott, D. J. A1 - Sussmann, J. E. A1 - Thalamuthu, A. A1 - Toga, A. W. A1 - Traynor, B. J. A1 - Troncoso, J. A1 - Tsolaki, M. A1 - Tzourio, C. A1 - Uitterlinden, A. G. A1 - Hern?ndez, M. C. V. A1 - Van der Brug, M. A1 - van der Lugt, A. A1 - Van der Wee, N. J. A. A1 - van Haren, N. E. M. A1 - van 't Ent, D. A1 - van Tol, M. J. A1 - Vardarajan, B. N. A1 - Vellas, B. A1 - Veltman, D. J. A1 - V?lzke, H. A1 - Walter, H. A1 - Wardlaw, J. M. A1 - Wassink, T. H. A1 - Weale, M. E. A1 - Weinberger, D. R. A1 - Weiner, M. W. A1 - Wen, W. A1 - Westman, E. A1 - White, T. A1 - Wong, T. Y. A1 - Wright, C. B. A1 - Zielke, R. H. A1 - Zonderman, A. B. A1 - Martin, N. G. A1 - van Duijn, C. M. A1 - Wright, M. J. A1 - Longstreth, W. T. A1 - Schumann, G. A1 - Grabe, H. J. A1 - Franke, B. A1 - Launer, L. J. A1 - Medland, S. E. A1 - Seshadri, S. A1 - Thompson, P. M. A1 - Ikram, M. A. AB - The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. VL - 8 ER - TY - JOUR T1 - Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. JF - Stroke Y1 - 2017 A1 - Saber, Hamidreza A1 - Yakoob, Mohammad Yawar A1 - Shi, Peilin A1 - Longstreth, W T A1 - Lemaitre, Rozenn N A1 - Siscovick, David A1 - Rexrode, Kathryn M A1 - Willett, Walter C A1 - Mozaffarian, Dariush KW - Adult KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Brain Ischemia KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Fatty Acids, Omega-3 KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Intracranial Arteriosclerosis KW - Intracranial Embolism KW - Intracranial Thrombosis KW - Male KW - Middle Aged KW - Prospective Studies KW - Random Allocation KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.

METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis.

RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results.

CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

VL - 48 IS - 10 ER - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - 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De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

VL - 49 IS - 9 ER - TY - JOUR T1 - Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. JF - PLoS Genet Y1 - 2017 A1 - Liang, Jingjing A1 - Le, Thu H A1 - Edwards, Digna R Velez A1 - Tayo, Bamidele O A1 - Gaulton, Kyle J A1 - Smith, Jennifer A A1 - Lu, Yingchang A1 - Jensen, Richard A A1 - Chen, Guanjie A1 - Yanek, Lisa R A1 - Schwander, Karen A1 - Tajuddin, Salman M A1 - Sofer, Tamar A1 - Kim, Wonji A1 - Kayima, James A1 - McKenzie, Colin A A1 - Fox, Ervin A1 - Nalls, Michael A A1 - Young, J Hunter A1 - Sun, Yan V A1 - Lane, Jacqueline M A1 - Cechova, Sylvia A1 - Zhou, Jie A1 - Tang, Hua A1 - Fornage, Myriam A1 - Musani, Solomon K A1 - Wang, Heming A1 - Lee, Juyoung A1 - Adeyemo, Adebowale A1 - Dreisbach, Albert W A1 - Forrester, Terrence A1 - Chu, Pei-Lun A1 - Cappola, Anne A1 - Evans, Michele K A1 - Morrison, Alanna C A1 - Martin, Lisa W A1 - Wiggins, Kerri L A1 - Hui, Qin A1 - Zhao, Wei A1 - Jackson, Rebecca D A1 - Ware, Erin B A1 - Faul, Jessica D A1 - Reiner, Alex P A1 - Bray, Michael A1 - Denny, Joshua C A1 - Mosley, Thomas H A1 - Palmas, Walter A1 - Guo, Xiuqing A1 - Papanicolaou, George J A1 - Penman, Alan D A1 - Polak, Joseph F A1 - Rice, Kenneth A1 - Taylor, Ken D A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Liu, Kiang A1 - Risch, Neil A1 - Hunt, Steven C A1 - Kooperberg, Charles A1 - Zonderman, Alan B A1 - Laurie, Cathy C A1 - Becker, Diane M A1 - Cai, Jianwen A1 - Loos, Ruth J F A1 - Psaty, Bruce M A1 - Weir, David R A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Won, Sungho A1 - Edwards, Todd L A1 - Redline, Susan A1 - Cooper, Richard S A1 - Rao, D C A1 - Rotter, Jerome I A1 - Rotimi, Charles A1 - Levy, Daniel A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Franceschini, Nora KW - African Americans KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Blood Pressure KW - Cadherins KW - Case-Control Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Membrane Proteins KW - Mice KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

VL - 13 IS - 5 ER - TY - JOUR T1 - Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study. JF - J Bone Miner Res Y1 - 2017 A1 - Stojanović, Danijela A1 - Bůzková, Petra A1 - Mukamal, Kenneth J A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Fink, Howard A A1 - Cauley, Jane A A1 - Wallace, Erin A1 - Curtis, Lesley H A1 - Hirsch, Calvin A1 - Budoff, Matthew A1 - Li, Dong A1 - Young, Rebekah A1 - Jalal, Diana A1 - Delaney, Joseph Ac AB -

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research.

ER - TY - JOUR T1 - Telomeres and the natural lifespan limit in humans. JF - Aging (Albany NY) Y1 - 2017 A1 - Steenstrup, Troels A1 - Kark, Jeremy D A1 - Verhulst, Simon A1 - Thinggaard, Mikael A1 - Hjelmborg, Jacob V B A1 - Dalgård, Christine A1 - Kyvik, Kirsten Ohm A1 - Christiansen, Lene A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Petersen, Inge A1 - Kimura, Masayuki A1 - Benetos, Athanase A1 - Labat, Carlos A1 - Sinnreich, Ronit A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Hunt, Steven C A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Barbieri, Michelangela A1 - Paolisso, Giuseppe A1 - Gadalla, Shahinaz M A1 - Savage, Sharon A A1 - Christensen, Kaare A1 - Yashin, Anatoliy I A1 - Arbeev, Konstantin G A1 - Aviv, Abraham AB -

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

VL - 9 IS - 4 ER - TY - JOUR T1 - Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. JF - Hum Genet Y1 - 2017 A1 - Fernandez-Rhodes, Lindsay A1 - Gong, Jian A1 - Haessler, Jeffrey A1 - Franceschini, Nora A1 - Graff, Mariaelisa A1 - Nishimura, Katherine K A1 - Wang, Yujie A1 - Highland, Heather M A1 - Yoneyama, Sachiko A1 - Bush, William S A1 - Goodloe, Robert A1 - Ritchie, Marylyn D A1 - Crawford, Dana A1 - Gross, Myron A1 - Fornage, Myriam A1 - Bůzková, Petra A1 - Tao, Ran A1 - Isasi, Carmen A1 - Avilés-Santa, Larissa A1 - Daviglus, Martha A1 - Mackey, Rachel H A1 - Houston, Denise A1 - Gu, C Charles A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Lim, Unhee A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Schumacher, Fredrick A1 - Wilkens, Lynne A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J L A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Lee, Wen-Jane A1 - Hai, Yang A1 - Hung, Yi-Jen A1 - Absher, Devin A1 - Wu, I-Chien A1 - Taylor, Kent D A1 - Lee, I-Te A1 - Liu, Yeheng A1 - Wang, Tzung-Dau A1 - Quertermous, Thomas A1 - Juang, Jyh-Ming J A1 - Rotter, Jerome I A1 - Assimes, Themistocles A1 - Hsiung, Chao A A1 - Chen, Yii-Der Ida A1 - Prentice, Ross A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Smokowski, Paul A1 - Robinson, Whitney R A1 - Gordon-Larsen, Penny A1 - Li, Rongling A1 - Hindorff, Lucia A1 - Buyske, Steven A1 - Matise, Tara C A1 - Peters, Ulrike A1 - North, Kari E KW - Body Mass Index KW - Ethnic Groups KW - Genetics, Population KW - Humans KW - Obesity AB -

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

VL - 136 IS - 6 ER - TY - JOUR T1 - Atrial fibrillation in an African-American cohort: The Jackson Heart Study. JF - Clin Cardiol Y1 - 2018 A1 - Austin, Thomas R A1 - Wiggins, Kerri L A1 - Blackshear, Chad A1 - Yang, Yi A1 - Benjamin, Emelia J A1 - Curtis, Lesley H A1 - Sotoodehnia, Nona A1 - Correa, Adolfo A1 - Heckbert, Susan R AB -

BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000.

HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS.

METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF.

RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments.

CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs.

ER - TY - JOUR T1 - Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. JF - Circ Genom Precis Med Y1 - 2018 A1 - Lin, Honghuang A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Bihlmeyer, Nathan A A1 - Warren, Helen R A1 - Brody, Jennifer A A1 - Radmanesh, Farid A1 - Hall, Leanne A1 - Grarup, Niels A1 - Müller-Nurasyid, Martina A1 - Boutin, Thibaud A1 - Verweij, Niek A1 - Lin, Henry J A1 - Li-Gao, Ruifang A1 - van den Berg, Marten E A1 - Marten, Jonathan A1 - Weiss, Stefan A1 - Prins, Bram P A1 - Haessler, Jeffrey A1 - Lyytikäinen, Leo-Pekka A1 - Mei, Hao A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Li, Man A1 - Alonso, Alvaro A1 - Soliman, Elsayed Z A1 - Connell, John M A1 - Huang, Paul L A1 - Weng, Lu-Chen A1 - Jameson, Heather S A1 - Hucker, William A1 - Hanley, Alan A1 - Tucker, Nathan R A1 - Chen, Yii-Der Ida A1 - Bis, Joshua C A1 - Rice, Kenneth M A1 - Sitlani, Colleen M A1 - Kors, Jan A A1 - Xie, Zhijun A1 - Wen, Chengping A1 - Magnani, Jared W A1 - Nelson, Christopher P A1 - Kanters, Jørgen K A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Bork-Jensen, Jette A1 - Pedersen, Oluf A1 - Linneberg, Allan A1 - Rudan, Igor A1 - de Boer, Rudolf A A1 - van der Meer, Peter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Sotoodehnia, Nona A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Eijgelsheim, Mark A1 - Padmanabhan, Sandosh A1 - Smith, Blair H A1 - Völzke, Henry A1 - Felix, Stephan B A1 - Homuth, Georg A1 - Völker, Uwe A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Bots, Michiel L A1 - Perez, Marco A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - Arking, Dan E A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Benjamin, Emelia J A1 - Rosand, Jonathan A1 - Samani, Nilesh J A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Polasek, Ozren A1 - van der Harst, Pim A1 - Heckbert, Susan R A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Hayward, Caroline A1 - Dörr, Marcus A1 - Jamshidi, Yalda A1 - Asselbergs, Folkert W A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Wilson, James G A1 - Ellinor, Patrick T A1 - Lubitz, Steven A A1 - Isaacs, Aaron AB -

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

VL - 11 IS - 5 ER - TY - JOUR T1 - Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. JF - Circ Genom Precis Med Y1 - 2018 A1 - Macri, Vincenzo A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Hucker, William J A1 - Yin, Xiaoyan A1 - Lin, Honghuang A1 - Mills, Robert W A1 - Sinner, Moritz F A1 - Lubitz, Steven A A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Alonso, Alvaro A1 - Li, Ning A1 - Fedorov, Vadim V A1 - Janssen, Paul M A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Dolmatova, Elena V A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Chung, Mina K A1 - Vlahakes, Gus J A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Margulies, Kenneth B A1 - Morley, Michael P A1 - Cappola, Thomas P A1 - Benjamin, Emelia J A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Jackson, Rebecca D A1 - Magnani, Jared W A1 - Herndon, Caroline N A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Milan, David J A1 - Boerwinkle, Eric A1 - Mohler, Peter J A1 - Sotoodehnia, Nona A1 - Ellinor, Patrick T AB -

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

VL - 11 IS - 5 ER - TY - JOUR T1 - Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. JF - Stroke Y1 - 2018 A1 - Jian, Xueqiu A1 - Satizabal, Claudia L A1 - Smith, Albert V A1 - Wittfeld, Katharina A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Hsu, Fang-Chi A1 - Nho, Kwangsik A1 - Hofer, Edith A1 - Hagenaars, Saskia P A1 - Nyquist, Paul A A1 - Mishra, Aniket A1 - Adams, Hieab H H A1 - Li, Shuo A1 - Teumer, Alexander A1 - Zhao, Wei A1 - Freedman, Barry I A1 - Saba, Yasaman A1 - Yanek, Lisa R A1 - Chauhan, Ganesh A1 - van Buchem, Mark A A1 - Cushman, Mary A1 - Royle, Natalie A A1 - Bryan, R Nick A1 - Niessen, Wiro J A1 - Windham, Beverly G A1 - DeStefano, Anita L A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Palmer, Nicholette D A1 - Lewis, Cora E A1 - Eiriksdottir, Gudny A1 - Maillard, Pauline A1 - Mathias, Rasika A A1 - Homuth, Georg A1 - Valdés-Hernández, Maria Del C A1 - Divers, Jasmin A1 - Beiser, Alexa S A1 - Langner, Sönke A1 - Rice, Kenneth M A1 - Bastin, Mark E A1 - Yang, Qiong A1 - Maldjian, Joseph A A1 - Starr, John M A1 - Sidney, Stephen A1 - Risacher, Shannon L A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur G A1 - Nauck, Matthias A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Mazoyer, Bernard A1 - von Sarnowski, Bettina A1 - Gottesman, Rebecca F A1 - Levy, Daniel A1 - Sigurdsson, Sigurdur A1 - Vernooij, Meike W A1 - Turner, Stephen T A1 - Schmidt, Reinhold A1 - Wardlaw, Joanna M A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - DeCarli, Charles S A1 - Saykin, Andrew J A1 - Bowden, Donald W A1 - Becker, Diane M A1 - Deary, Ian J A1 - Schmidt, Helena A1 - Kardia, Sharon L R A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Grabe, Hans J A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Fornage, Myriam AB -

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

ER - TY - JOUR T1 - ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. JF - Circ Genom Precis Med Y1 - 2018 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Warren, Helen R A1 - Lin, Honghuang A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Marten, Jonathan A1 - Radmanesh, Farid A1 - Hall, Leanne M A1 - Grarup, Niels A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Huffman, Jennifer E A1 - Verweij, Niek A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Li-Gao, Ruifang A1 - van den Berg, Marten A1 - Weiss, Stefan A1 - Prins, Bram P A1 - van Setten, Jessica A1 - Haessler, Jeffrey A1 - Lyytikäinen, Leo-Pekka A1 - Li, Man A1 - Alonso, Alvaro A1 - Soliman, Elsayed Z A1 - Bis, Joshua C A1 - Austin, Tom A1 - Chen, Yii-Der Ida A1 - Psaty, Bruce M A1 - Harrris, Tamara B A1 - Launer, Lenore J A1 - Padmanabhan, Sandosh A1 - Dominiczak, Anna A1 - Huang, Paul L A1 - Xie, Zhijun A1 - Ellinor, Patrick T A1 - Kors, Jan A A1 - Campbell, Archie A1 - Murray, Alison D A1 - Nelson, Christopher P A1 - Tobin, Martin D A1 - Bork-Jensen, Jette A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Linneberg, Allan A1 - Sinner, Moritz F A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Kolcic, Ivana A1 - Rudan, Igor A1 - de Boer, Rudolf A A1 - van der Meer, Peter A1 - Lin, Henry J A1 - Taylor, Kent D A1 - de Mutsert, Renée A1 - Trompet, Stella A1 - Jukema, J Wouter A1 - Maan, Arie C A1 - Stricker, Bruno H C A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Völker, Uwe A1 - Homuth, Georg A1 - Völzke, Henry A1 - Felix, Stephan B A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Bots, Michiel L A1 - Perez, Marco A1 - Raitakari, Olli T A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Gudnason, Vilmundur A1 - Munroe, Patricia B A1 - Lubitz, Steven A A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher H A1 - Hayward, Caroline A1 - Rosand, Jonathan A1 - Samani, Nilesh J A1 - Kanters, Jørgen K A1 - Wilson, James G A1 - Kääb, Stefan A1 - Polasek, Ozren A1 - van der Harst, Pim A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Eijgelsheim, Mark A1 - Dörr, Marcus A1 - Jamshidi, Yalda A1 - Asselbergs, Folkert W A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

VL - 11 IS - 1 ER - TY - JOUR T1 - Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. JF - PLoS Med Y1 - 2018 A1 - Imamura, Fumiaki A1 - Fretts, Amanda A1 - Marklund, Matti A1 - Ardisson Korat, Andres V A1 - Yang, Wei-Sin A1 - Lankinen, Maria A1 - Qureshi, Waqas A1 - Helmer, Catherine A1 - Chen, Tzu-An A1 - Wong, Kerry A1 - Bassett, Julie K A1 - Murphy, Rachel A1 - Tintle, Nathan A1 - Yu, Chaoyu Ian A1 - Brouwer, Ingeborg A A1 - Chien, Kuo-Liong A1 - Frazier-Wood, Alexis C A1 - Del Gobbo, Liana C A1 - Djoussé, Luc A1 - Geleijnse, Johanna M A1 - Giles, Graham G A1 - de Goede, Janette A1 - Gudnason, Vilmundur A1 - Harris, William S A1 - Hodge, Allison A1 - Hu, Frank A1 - Koulman, Albert A1 - Laakso, Markku A1 - Lind, Lars A1 - Lin, Hung-Ju A1 - McKnight, Barbara A1 - Rajaobelina, Kalina A1 - Riserus, Ulf A1 - Robinson, Jennifer G A1 - Samieri, Cecilia A1 - Siscovick, David S A1 - Soedamah-Muthu, Sabita S A1 - Sotoodehnia, Nona A1 - Sun, Qi A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wagenknecht, Lynne E A1 - Wareham, Nick J A1 - Wu, Jason HY A1 - Micha, Renata A1 - Forouhi, Nita G A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Australia KW - Biomarkers KW - Dairy Products KW - Diabetes Mellitus, Type 2 KW - Dietary Fats KW - Europe KW - Fatty Acids KW - Fatty Acids, Monounsaturated KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Sex Factors KW - Taiwan KW - United States AB -

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

VL - 15 IS - 10 ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stephanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - Borst, Martin H de A1 - Geus, Eco J de A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Jarvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

VL - 50 IS - 10 ER - TY - JOUR T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, Rene A1 - Zhu, Gu A1 - Mace, Aurelien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michèle M A1 - Chen, Yii-der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - Lachance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

VL - 103 IS - 5 ER - TY - JOUR T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. JF - Nat Commun Y1 - 2018 A1 - Teumer, Alexander A1 - Chaker, Layal A1 - Groeneweg, Stefan A1 - Li, Yong A1 - Di Munno, Celia A1 - Barbieri, Caterina A1 - Schultheiss, Ulla T A1 - Traglia, Michela A1 - Ahluwalia, Tarunveer S A1 - Akiyama, Masato A1 - Appel, Emil Vincent R A1 - Arking, Dan E A1 - Arnold, Alice A1 - Astrup, Arne A1 - Beekman, Marian A1 - Beilby, John P A1 - Bekaert, Sofie A1 - Boerwinkle, Eric A1 - Brown, Suzanne J A1 - De Buyzere, Marc A1 - Campbell, Purdey J A1 - Ceresini, Graziano A1 - Cerqueira, Charlotte A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Deelen, Joris A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Eriksson, Johan G A1 - Ferrrucci, Luigi A1 - Fiers, Tom A1 - Fiorillo, Edoardo A1 - Ford, Ian A1 - Fox, Caroline S A1 - Fuchsberger, Christian A1 - Galesloot, Tessel E A1 - Gieger, Christian A1 - Gögele, Martin A1 - De Grandi, Alessandro A1 - Grarup, Niels A1 - Greiser, Karin Halina A1 - Haljas, Kadri A1 - Hansen, Torben A1 - Harris, Sarah E A1 - van Heemst, Diana A1 - den Heijer, Martin A1 - Hicks, Andrew A A1 - den Hollander, Wouter A1 - Homuth, Georg A1 - Hui, Jennie A1 - Ikram, M Arfan A1 - Ittermann, Till A1 - Jensen, Richard A A1 - Jing, Jiaojiao A1 - Jukema, J Wouter A1 - Kajantie, Eero A1 - Kamatani, Yoichiro A1 - Kasbohm, Elisa A1 - Kaufman, Jean-Marc A1 - Kiemeney, Lambertus A A1 - Kloppenburg, Margreet A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Lahti, Jari A1 - Lapauw, Bruno A1 - Li, Shuo A1 - Liewald, David C M A1 - Lim, Ee Mun A1 - Linneberg, Allan A1 - Marina, Michela A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Medenwald, Daniel A1 - Meisinger, Christa A1 - Meulenbelt, Ingrid A1 - De Meyer, Tim A1 - Meyer zu Schwabedissen, Henriette E A1 - Mikolajczyk, Rafael A1 - Moed, Matthijs A1 - Netea-Maier, Romana T A1 - Nolte, Ilja M A1 - Okada, Yukinori A1 - Pala, Mauro A1 - Pattaro, Cristian A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Porcu, Eleonora A1 - Postmus, Iris A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Ramos, Yolande F M A1 - Rawal, Rajesh A1 - Redmond, Paul A1 - Richards, J Brent A1 - Rietzschel, Ernst R A1 - Rivadeneira, Fernando A1 - Roef, Greet A1 - Rotter, Jerome I A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Selvin, Elizabeth A1 - Slagboom, P Eline A1 - Soranzo, Nicole A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Starr, John M A1 - Stott, David J A1 - Taes, Youri A1 - Taliun, Daniel A1 - Tanaka, Toshiko A1 - Thuesen, Betina A1 - Tiller, Daniel A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Visser, W Edward A1 - Walsh, John P A1 - Wilson, Scott G A1 - Wolffenbuttel, Bruce H R A1 - Yang, Qiong A1 - Zheng, Hou-Feng A1 - Cappola, Anne A1 - Peeters, Robin P A1 - Naitza, Silvia A1 - Völzke, Henry A1 - Sanna, Serena A1 - Köttgen, Anna A1 - Visser, Theo J A1 - Medici, Marco AB -

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy. JF - Sci Rep Y1 - 2018 A1 - Napier, Melanie D A1 - Franceschini, Nora A1 - Gondalia, Rahul A1 - Stewart, James D A1 - Méndez-Giráldez, Rául A1 - Sitlani, Colleen M A1 - Seyerle, Amanda A A1 - Highland, Heather M A1 - Li, Yun A1 - Wilhelmsen, Kirk C A1 - Yan, Song A1 - Duan, Qing A1 - Roach, Jeffrey A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - North, Kari E A1 - Reiner, Alexander P A1 - Zhang, Zhu-Ming A1 - Tinker, Lesley F A1 - Liao, Duanping A1 - Laurie, Cathy C A1 - Gogarten, Stephanie M A1 - Lin, Henry J A1 - Brody, Jennifer A A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Whitsel, Eric A AB -

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10) and multi-trait analysis (P = 2.9 × 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

VL - 8 IS - 1 ER - TY - JOUR T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JF - Nat Commun Y1 - 2018 A1 - Jiang, Xia A1 - O'Reilly, Paul F A1 - Aschard, Hugues A1 - Hsu, Yi-Hsiang A1 - Richards, J Brent A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Karasik, David A1 - Pilz, Stefan A1 - Berry, Diane A1 - Kestenbaum, Bryan A1 - Zheng, Jusheng A1 - Luan, Jianan A1 - Sofianopoulou, Eleni A1 - Streeten, Elizabeth A A1 - Albanes, Demetrius A1 - Lutsey, Pamela L A1 - Yao, Lu A1 - Tang, Weihong A1 - Econs, Michael J A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Zhou, Ang A1 - Power, Chris A1 - McCarthy, Mark I A1 - Michos, Erin D A1 - Boerwinkle, Eric A1 - Weinstein, Stephanie J A1 - Freedman, Neal D A1 - Huang, Wen-Yi A1 - van Schoor, Natasja M A1 - van der Velde, Nathalie A1 - Groot, Lisette C P G M de A1 - Enneman, Anke A1 - Cupples, L Adrienne A1 - Booth, Sarah L A1 - Vasan, Ramachandran S A1 - Liu, Ching-Ti A1 - Zhou, Yanhua A1 - Ripatti, Samuli A1 - Ohlsson, Claes A1 - Vandenput, Liesbeth A1 - Lorentzon, Mattias A1 - Eriksson, Johan G A1 - Shea, M Kyla A1 - Houston, Denise K A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Ferrucci, Luigi A1 - Peacock, Munro A1 - Gieger, Christian A1 - Beekman, Marian A1 - Slagboom, Eline A1 - Deelen, Joris A1 - Heemst, Diana van A1 - Kleber, Marcus E A1 - März, Winfried A1 - de Boer, Ian H A1 - Wood, Alexis C A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Robinson-Cohen, Cassianne A1 - den Heijer, Martin A1 - Jarvelin, Marjo-Riitta A1 - Cavadino, Alana A1 - Joshi, Peter K A1 - Wilson, James F A1 - Hayward, Caroline A1 - Lind, Lars A1 - Michaëlsson, Karl A1 - Trompet, Stella A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Broer, Linda A1 - Zgaga, Lina A1 - Campbell, Harry A1 - Theodoratou, Evropi A1 - Farrington, Susan M A1 - Timofeeva, Maria A1 - Dunlop, Malcolm G A1 - Valdes, Ana M A1 - Tikkanen, Emmi A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Mikkilä, Vera A1 - Ikram, M Arfan A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Forouhi, Nita G A1 - Gundersen, Thomas E A1 - Khaw, Kay-Tee A1 - Butterworth, Adam S A1 - Danesh, John A1 - Spector, Timothy A1 - Wang, Thomas J A1 - Hyppönen, Elina A1 - Kraft, Peter A1 - Kiel, Douglas P AB -

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. JF - Nat Commun Y1 - 2018 A1 - Vojinovic, Dina A1 - Adams, Hieab H A1 - Jian, Xueqiu A1 - Yang, Qiong A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Teumer, Alexander A1 - Scholz, Markus A1 - Armstrong, Nicola J A1 - Hofer, Edith A1 - Saba, Yasaman A1 - Luciano, Michelle A1 - Bernard, Manon A1 - Trompet, Stella A1 - Yang, Jingyun A1 - Gillespie, Nathan A A1 - van der Lee, Sven J A1 - Neumann, Alexander A1 - Ahmad, Shahzad A1 - Andreassen, Ole A A1 - Ames, David A1 - Amin, Najaf A1 - Arfanakis, Konstantinos A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Beiser, Alexa S A1 - Beyer, Frauke A1 - Brodaty, Henry A1 - Bryan, R Nick A1 - Bülow, Robin A1 - Dale, Anders M A1 - De Jager, Philip L A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Fleischman, Debra A A1 - Gottesman, Rebecca F A1 - van der Grond, Jeroen A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Homuth, Georg A1 - Knopman, David S A1 - Kwok, John B A1 - Lewis, Cora E A1 - Li, Shuo A1 - Loeffler, Markus A1 - Lopez, Oscar L A1 - Maillard, Pauline A1 - El Marroun, Hanan A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Muetzel, Ryan L A1 - Nauck, Matthias A1 - Nyquist, Paul A A1 - Panizzon, Matthew S A1 - Pausova, Zdenka A1 - Psaty, Bruce M A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Royle, Natalie A1 - Satizabal, Claudia L A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Stott, David J A1 - Thalamuthu, Anbupalam A1 - Uitterlinden, André G A1 - Valdés Hernández, Maria C A1 - Vernooij, Meike W A1 - Wen, Wei A1 - White, Tonya A1 - Witte, A Veronica A1 - Wittfeld, Katharina A1 - Wright, Margaret J A1 - Yanek, Lisa R A1 - Tiemeier, Henning A1 - Kremen, William S A1 - Bennett, David A A1 - Jukema, J Wouter A1 - Paus, Tomáš A1 - Wardlaw, Joanna M A1 - Schmidt, Helena A1 - Sachdev, Perminder S A1 - Villringer, Arno A1 - Grabe, Hans Jörgen A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Fornage, Myriam AB -

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. JF - Circulation Y1 - 2018 A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Marten, Jonathan A1 - Mastrangelo, Michael A A1 - Song, Ci A1 - Pankratz, Nathan A1 - Ward-Caviness, Cavin K A1 - Yanek, Lisa R A1 - Trompet, Stella A1 - Delgado, Graciela E A1 - Guo, Xiuqing A1 - Bartz, Traci M A1 - Martinez-Perez, Angel A1 - Germain, Marine A1 - de Haan, Hugoline G A1 - Ozel, Ayse B A1 - Polasek, Ozren A1 - Smith, Albert V A1 - Eicher, John D A1 - Reiner, Alex P A1 - Tang, Weihong A1 - Davies, Neil M A1 - Stott, David J A1 - Rotter, Jerome I A1 - Tofler, Geoffrey H A1 - Boerwinkle, Eric A1 - de Maat, Moniek P M A1 - Kleber, Marcus E A1 - Welsh, Paul A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Vaidya, Dhananjay A1 - Soria, José Manuel A1 - Suchon, Pierre A1 - van Hylckama Vlieg, Astrid A1 - Desch, Karl C A1 - Kolcic, Ivana A1 - Joshi, Peter K A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Campbell, Harry A1 - Rudan, Igor A1 - Becker, Diane M A1 - Li, Jun Z A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Morange, Pierre-Emmanuel A1 - McKnight, Barbara A1 - Chong, Michael R A1 - Fernandez-Cadenas, Israel A1 - Rosand, Jonathan A1 - Lindgren, Arne A1 - Gudnason, Vilmundur A1 - Wilson, James F A1 - Hayward, Caroline A1 - Ginsburg, David A1 - Fornage, Myriam A1 - Rosendaal, Frits R A1 - Souto, Juan Carlos A1 - Becker, Lewis C A1 - Jenny, Nancy S A1 - März, Winfried A1 - Jukema, J Wouter A1 - Dehghan, Abbas A1 - Trégouët, David-Alexandre A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Strachan, David P A1 - Lowenstein, Charles J A1 - Smith, Nicholas L AB -

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

ER - TY - JOUR T1 - Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. JF - PLoS Genet Y1 - 2018 A1 - Suri, Pradeep A1 - Palmer, Melody R A1 - Tsepilov, Yakov A A1 - Freidin, Maxim B A1 - Boer, Cindy G A1 - Yau, Michelle S A1 - Evans, Daniel S A1 - Gelemanovic, Andrea A1 - Bartz, Traci M A1 - Nethander, Maria A1 - Arbeeva, Liubov A1 - Karssen, Lennart A1 - Neogi, Tuhina A1 - Campbell, Archie A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Marshall, Lynn M A1 - Orwoll, Eric A1 - Uitterlinden, Andre A1 - Rotter, Jerome I A1 - Lauc, Gordan A1 - Psaty, Bruce M A1 - Karlsson, Magnus K A1 - Lane, Nancy E A1 - Jarvik, Gail P A1 - Polasek, Ozren A1 - Hochberg, Marc A1 - Jordan, Joanne M A1 - van Meurs, Joyce B J A1 - Jackson, Rebecca A1 - Nielson, Carrie M A1 - Mitchell, Braxton D A1 - Smith, Blair H A1 - Hayward, Caroline A1 - Smith, Nicholas L A1 - Aulchenko, Yurii S A1 - Williams, Frances M K AB -

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

VL - 14 IS - 9 ER - TY - JOUR T1 - Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study. JF - Am J Epidemiol Y1 - 2018 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Cassano, Patricia A A1 - Couper, David A1 - Enright, Paul L A1 - Folsom, Aaron R A1 - Hankinson, John A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kaplan, Robert A1 - Kronmal, Richard A1 - Lange, Leslie A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Navas Acien, Ana A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Lewis J A1 - Yeh, Fawn A1 - Zhang, Yiyi A1 - Moran, Andrew E A1 - Mwasongwe, Stanford A1 - White, Wendy B A1 - Yende, Sachin A1 - Barr, R Graham AB -

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

VL - 187 IS - 11 ER - TY - JOUR T1 - Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study. JF - SAGE Open Med Y1 - 2018 A1 - Delaney, Joseph Ac A1 - Yin, Xiaoyan A1 - Fontes, João Daniel A1 - Wallace, Erin R A1 - Skinner, Asheley A1 - Wang, Na A1 - Hammill, Bradley G A1 - Benjamin, Emelia J A1 - Curtis, Lesley H A1 - Heckbert, Susan R AB -

Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs.

Methods and Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234).

Conclusion: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities.

VL - 6 ER - TY - JOUR T1 - Impact of lung-function measures on cardiovascular disease events in older adults with metabolic syndrome and diabetes. JF - Clin Cardiol Y1 - 2018 A1 - Lee, Hwa Mu A1 - Zhao, Yanglu A1 - Liu, Michael A A1 - Yanez, David A1 - Carnethon, Mercedes A1 - Graham Barr, R A1 - Wong, Nathan D AB -

BACKGROUND: Individuals with metabolic syndrome (MetS) and diabetes (DM) are more likely to have decreased lung function and are at greater risk of cardiovascular disease (CVD).

HYPOTHESIS: Lung-function measures can predict CVD events in older persons with MetS, DM, and neither condition.

METHODS: We followed 4114 participants age ≥ 65 years with and without MetS or DM in the Cardiovascular Health Study. Cox regression examined the association of forced vital capacity (FVC) and 1-second forced expiratory volume (FEV ; percent of predicted values) with incident coronary heart disease and CVD events over 12.9 years.

RESULTS: DM was present in 537 (13.1%) and MetS in 1277 (31.0%) participants. Comparing fourth vs first quartiles for FVC, risk of CVD events was 16% (HR: 0.84, 95% CI: 0.59-1.18), 23% (HR: 0.77, 95% CI: 0.60-0.99), and 30% (HR: 0.70, 95% CI: 0.58-0.84) lower in DM, MetS, and neither disease groups, respectively. For FEV , CVD risk was lower by 2% (HR: 0.98, 95% CI: 0.70-1.37), 26% (HR: 0.74, 95% CI: 0.59-0.93), and 31% (HR: 0.69, 95% CI: 0.57-0.82) in DM. Findings were strongest for predicting congestive heart failure (CHF) in all disease groups. C-statistics increased significantly with addition of FEV or FVC over risk factors for CVD and CHF among those with neither MetS nor DM.

CONCLUSIONS: FEV and FVC are inversely related to CVD in older adults with and without MetS, but not DM (except for CHF); however, their value in incremental risk prediction beyond standard risk factors is limited mainly to metabolically healthier persons.

VL - 41 IS - 7 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

VL - 102 IS - 3 ER - TY - JOUR T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. JF - Nat Commun Y1 - 2018 A1 - Tin, Adrienne A1 - Li, Yong A1 - Brody, Jennifer A A1 - Nutile, Teresa A1 - Chu, Audrey Y A1 - Huffman, Jennifer E A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Robinson-Cohen, Cassianne A1 - Mace, Aurelien A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Sorice, Rossella A1 - Sedaghat, Sanaz A1 - Swen, Melody A1 - Yu, Bing A1 - Ghasemi, Sahar A1 - Teumer, Alexanda A1 - Vollenweider, Peter A1 - Ciullo, Marina A1 - Li, Meng A1 - Uitterlinden, André G A1 - Kraaij, Robert A1 - Amin, Najaf A1 - van Rooij, Jeroen A1 - Kutalik, Zoltán A1 - Dehghan, Abbas A1 - McKnight, Barbara A1 - van Duijn, Cornelia M A1 - Morrison, Alanna A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fox, Caroline S A1 - Woodward, Owen M A1 - Köttgen, Anna KW - Exome KW - Genetic Predisposition to Disease KW - Glucose Transport Proteins, Facilitative KW - Humans KW - Kidney Function Tests KW - Meta-Analysis as Topic KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Protein Structure, Secondary KW - Uric Acid AB -

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

VL - 9 IS - 1 ER - TY - JOUR T1 - Left atrial diameter and vascular brain injury on MRI: The Cardiovascular Health Study. JF - Neurology Y1 - 2018 A1 - Yaghi, Shadi A1 - Bartz, Traci M A1 - Kronmal, Richard A1 - Kamel, Hooman A1 - Gottdiener, John A1 - Longstreth, W T A1 - Elkind, Mitchell S V AB -

OBJECTIVE: To determine the association left atrial diameter (LAD) and vascular brain injury on brain MRI.

METHODS: We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort of community-dwelling adults ≥65 years old. LAD was measured from 2-dimensional transthoracic echocardiograms. Among CHS participants who underwent brain MRI, we examined associations of LAD with brain infarcts and leukoaraiosis. Primary outcomes (number for analysis) were prevalent infarcts (2,327) and degree of leukoaraiosis on initial MRI (2,315). Secondary outcomes were prevalent nonlacunar infarcts (2,327), incident infarcts (939), incident nonlacunar infarcts (1,185), and degree of leukoaraiosis on follow-up MRI adjusted for initial MRI (1,158). Relative risk (RR) and linear regression models were adjusted for demographics, vascular risk factors, and potential confounders.

RESULTS: Mean age of the 2,335 participants with initial brain MRI was 72.0 ± 4.8 years; 38.7% were men; and 29.0% participants had prevalent infarcts. In multivariable, fully adjusted models, LAD was associated with prevalent infarcts (RR 1.20, 95% confidence interval [CI] 1.08-1.34) and prevalent nonlacunar infarcts (RR 1.28, 95% CI 1.06-1.54) but not with leukoaraiosis (-0.08, 95% CI -0.17 to 0.07), incident infarcts (RR 1.00, 95% CI 0.78-1.29), nonlacunar infarcts (RR 0.98, 95% CI 0.67-1.42), or worsening leukoaraiosis (-0.04, 95% CI -0.10 to 0.02).

CONCLUSION: LAD is independently associated with prevalent brain infarcts, particularly nonlacunar infarcts, but not leukoaraiosis. Larger studies are needed to determine associations with incident infarct risk and whether this risk in patients with left atrial enlargement can be reduced with anticoagulant agents.

ER - TY - JOUR T1 - Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. JF - Nat Genet Y1 - 2018 A1 - Demenais, Florence A1 - Margaritte-Jeannin, Patricia A1 - Barnes, Kathleen C A1 - Cookson, William O C A1 - Altmüller, Janine A1 - Ang, Wei A1 - Barr, R Graham A1 - Beaty, Terri H A1 - Becker, Allan B A1 - Beilby, John A1 - Bisgaard, Hans A1 - Bjornsdottir, Unnur Steina A1 - Bleecker, Eugene A1 - Bønnelykke, Klaus A1 - Boomsma, Dorret I A1 - Bouzigon, Emmanuelle A1 - Brightling, Christopher E A1 - Brossard, Myriam A1 - Brusselle, Guy G A1 - Burchard, Esteban A1 - Burkart, Kristin M A1 - Bush, Andrew A1 - Chan-Yeung, Moira A1 - Chung, Kian Fan A1 - Couto Alves, Alexessander A1 - Curtin, John A A1 - Custovic, Adnan A1 - Daley, Denise A1 - de Jongste, Johan C A1 - Del-Rio-Navarro, Blanca E A1 - Donohue, Kathleen M A1 - Duijts, Liesbeth A1 - Eng, Celeste A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Fedorova, Yuliya A1 - Feenstra, Bjarke A1 - Ferreira, Manuel A A1 - Freidin, Maxim B A1 - Gajdos, Zofia A1 - Gauderman, Jim A1 - Gehring, Ulrike A1 - Geller, Frank A1 - Genuneit, Jon A1 - Gharib, Sina A A1 - Gilliland, Frank A1 - Granell, Raquel A1 - Graves, Penelope E A1 - Gudbjartsson, Daniel F A1 - Haahtela, Tari A1 - Heckbert, Susan R A1 - Heederik, Dick A1 - Heinrich, Joachim A1 - Heliövaara, Markku A1 - Henderson, John A1 - Himes, Blanca E A1 - Hirose, Hiroshi A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Holt, Patrick A1 - Hottenga, Jouke A1 - Hudson, Thomas J A1 - Hui, Jennie A1 - Imboden, Medea A1 - Ivanov, Vladimir A1 - Jaddoe, Vincent W V A1 - James, Alan A1 - Janson, Christer A1 - Jarvelin, Marjo-Riitta A1 - Jarvis, Deborah A1 - Jones, Graham A1 - Jonsdottir, Ingileif A1 - Jousilahti, Pekka A1 - Kabesch, Michael A1 - Kähönen, Mika A1 - Kantor, David B A1 - Karunas, Alexandra S A1 - Khusnutdinova, Elza A1 - Koppelman, Gerard H A1 - Kozyrskyj, Anita L A1 - Kreiner, Eskil A1 - Kubo, Michiaki A1 - Kumar, Rajesh A1 - Kumar, Ashish A1 - Kuokkanen, Mikko A1 - Lahousse, Lies A1 - Laitinen, Tarja A1 - Laprise, Catherine A1 - Lathrop, Mark A1 - Lau, Susanne A1 - Lee, Young-Ae A1 - Lehtimäki, Terho A1 - Letort, Sébastien A1 - Levin, Albert M A1 - Li, Guo A1 - Liang, Liming A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Loth, Daan W A1 - Manichaikul, Ani A1 - Marenholz, Ingo A1 - Martinez, Fernando J A1 - Matheson, Melanie C A1 - Mathias, Rasika A A1 - Matsumoto, Kenji A1 - Mbarek, Hamdi A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Melén, Erik A1 - Meyers, Deborah A1 - Michel, Sven A1 - Mohamdi, Hamida A1 - Musk, Arthur W A1 - Myers, Rachel A A1 - Nieuwenhuis, Maartje A E A1 - Noguchi, Emiko A1 - O'Connor, George T A1 - Ogorodova, Ludmila M A1 - Palmer, Cameron D A1 - Palotie, Aarno A1 - Park, Julie E A1 - Pennell, Craig E A1 - Pershagen, Göran A1 - Polonikov, Alexey A1 - Postma, Dirkje S A1 - Probst-Hensch, Nicole A1 - Puzyrev, Valery P A1 - Raby, Benjamin A A1 - Raitakari, Olli T A1 - Ramasamy, Adaikalavan A1 - Rich, Stephen S A1 - Robertson, Colin F A1 - Romieu, Isabelle A1 - Salam, Muhammad T A1 - Salomaa, Veikko A1 - Schlünssen, Vivi A1 - Scott, Robert A1 - Selivanova, Polina A A1 - Sigsgaard, Torben A1 - Simpson, Angela A1 - Siroux, Valérie A1 - Smith, Lewis J A1 - Solodilova, Maria A1 - Standl, Marie A1 - Stefansson, Kari A1 - Strachan, David P A1 - Stricker, Bruno H A1 - Takahashi, Atsushi A1 - Thompson, Philip J A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiesler, Carla M T A1 - Torgerson, Dara G A1 - Tsunoda, Tatsuhiko A1 - Uitterlinden, André G A1 - van der Valk, Ralf J P A1 - Vaysse, Amaury A1 - Vedantam, Sailaja A1 - von Berg, Andrea A1 - von Mutius, Erika A1 - Vonk, Judith M A1 - Waage, Johannes A1 - Wareham, Nick J A1 - Weiss, Scott T A1 - White, Wendy B A1 - Wickman, Magnus A1 - Widen, Elisabeth A1 - Willemsen, Gonneke A1 - Williams, L Keoki A1 - Wouters, Inge M A1 - Yang, James J A1 - Zhao, Jing Hua A1 - Moffatt, Miriam F A1 - Ober, Carole A1 - Nicolae, Dan L AB -

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

VL - 50 IS - 1 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

VL - 50 IS - 9 ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

VL - 13 IS - 6 ER - TY - JOUR T1 - Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. JF - Environ Int Y1 - 2018 A1 - Wong, Jason Y Y A1 - Margolis, Helene G A1 - Machiela, Mitchell A1 - Zhou, Weiyin A1 - Odden, Michelle C A1 - Psaty, Bruce M A1 - Robbins, John A1 - Jones, Rena R A1 - Rotter, Jerome I A1 - Chanock, Stephen J A1 - Rothman, Nathaniel A1 - Lan, Qing A1 - Lee, Jennifer S AB -

BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.

OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.

METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 μm (PM), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.

RESULTS: Increased PM was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 μg/m), the middle (28.5-31.0 μg/m; β = -0.0044, p = 0.09) and highest (≥31 μg/m; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.

CONCLUSIONS: PM may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

VL - 116 ER - TY - JOUR T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JF - Nat Commun Y1 - 2018 A1 - van Setten, Jessica A1 - Brody, Jennifer A A1 - Jamshidi, Yalda A1 - Swenson, Brenton R A1 - Butler, Anne M A1 - Campbell, Harry A1 - Del Greco, Fabiola M A1 - Evans, Daniel S A1 - Gibson, Quince A1 - Gudbjartsson, Daniel F A1 - Kerr, Kathleen F A1 - Krijthe, Bouwe P A1 - Lyytikäinen, Leo-Pekka A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Ritchie, Marylyn D A1 - Robino, Antonietta A1 - Smith, Albert V A1 - Steri, Maristella A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Ulivi, Sheila A1 - Verweij, Niek A1 - Yin, Xiaoyan A1 - Arnar, David O A1 - Asselbergs, Folkert W A1 - Bader, Joel S A1 - Barnard, John A1 - Bis, Josh A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Bradford, Yuki A1 - Buckley, Brendan M A1 - Chung, Mina K A1 - Crawford, Dana A1 - den Hoed, Marcel A1 - Denny, Josh C A1 - Dominiczak, Anna F A1 - Ehret, Georg B A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Franke, Lude A1 - Harris, Tamara B A1 - Holm, Hilma A1 - Ilaria, Gandin A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kolcic, Ivana A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Launer, Lenore J A1 - Lin, Honghuang A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - Leach, Irene Mateo A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Münzel, Thomas A1 - Papanicolaou, George J A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Silva Aldana, Claudia T A1 - Sinner, Moritz F A1 - Smith, Jonathan D A1 - Snieder, Harold A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stott, David J A1 - Strauch, Konstantin A1 - Tarasov, Kirill V A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Jan Westra, Harm A1 - Wild, Philipp S A1 - Zeller, Tanja A1 - Alonso, Alvaro A1 - Avery, Christy L A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Cucca, Francesco A1 - Dörr, Marcus A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Munroe, Patricia B A1 - Parsa, Afshin A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Schnabel, Renate B A1 - Sinagra, Gianfranco A1 - Stefansson, Kari A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Wilson, James F A1 - Gharib, Sina A A1 - de Bakker, Paul I W A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

VL - 9 IS - 1 ER - TY - JOUR T1 - Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration. JF - PLoS One Y1 - 2018 A1 - Lorenz, Matthias W A1 - Gao, Lu A1 - Ziegelbauer, Kathrin A1 - Norata, Giuseppe Danilo A1 - Empana, Jean Philippe A1 - Schmidtmann, Irene A1 - Lin, Hung-Ju A1 - McLachlan, Stela A1 - Bokemark, Lena A1 - Ronkainen, Kimmo A1 - Amato, Mauro A1 - Schminke, Ulf A1 - Srinivasan, Sathanur R A1 - Lind, Lars A1 - Okazaki, Shuhei A1 - Stehouwer, Coen D A A1 - Willeit, Peter A1 - Polak, Joseph F A1 - Steinmetz, Helmuth A1 - Sander, Dirk A1 - Poppert, Holger A1 - Desvarieux, Moïse A1 - Ikram, M Arfan A1 - Johnsen, Stein Harald A1 - Staub, Daniel A1 - Sirtori, Cesare R A1 - Iglseder, Bernhard A1 - Beloqui, Oscar A1 - Engström, Gunnar A1 - Friera, Alfonso A1 - Rozza, Francesco A1 - Xie, Wuxiang A1 - Parraga, Grace A1 - Grigore, Liliana A1 - Plichart, Matthieu A1 - Blankenberg, Stefan A1 - Su, Ta-Chen A1 - Schmidt, Caroline A1 - Tuomainen, Tomi-Pekka A1 - Veglia, Fabrizio A1 - Völzke, Henry A1 - Nijpels, Giel A1 - Willeit, Johann A1 - Sacco, Ralph L A1 - Franco, Oscar H A1 - Uthoff, Heiko A1 - Hedblad, Bo A1 - Suarez, Carmen A1 - Izzo, Raffaele A1 - Zhao, Dong A1 - Wannarong, Thapat A1 - Catapano, Alberico A1 - Ducimetiere, Pierre A1 - Espinola-Klein, Christine A1 - Chien, Kuo-Liong A1 - Price, Jackie F A1 - Bergström, Göran A1 - Kauhanen, Jussi A1 - Tremoli, Elena A1 - Dörr, Marcus A1 - Berenson, Gerald A1 - Kitagawa, Kazuo A1 - Dekker, Jacqueline M A1 - Kiechl, Stefan A1 - Sitzer, Matthias A1 - Bickel, Horst A1 - Rundek, Tatjana A1 - Hofman, Albert A1 - Mathiesen, Ellisiv B A1 - Castelnuovo, Samuela A1 - Landecho, Manuel F A1 - Rosvall, Maria A1 - Gabriel, Rafael A1 - de Luca, Nicola A1 - Liu, Jing A1 - Baldassarre, Damiano A1 - Kavousi, Maryam A1 - de Groot, Eric A1 - Bots, Michiel L A1 - Yanez, David N A1 - Thompson, Simon G KW - Aged KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Female KW - Humans KW - Intersectoral Collaboration KW - Male KW - Middle Aged KW - Prognosis KW - Risk Factors AB -

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.

METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.

CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

VL - 13 IS - 4 ER - TY - JOUR T1 - Protein and glycomic plasma markers for early detection of adenoma and colon cancer. JF - Gut Y1 - 2018 A1 - Rho, Jung-Hyun A1 - Ladd, Jon J A1 - Li, Christopher I A1 - Potter, John D A1 - Zhang, Yuzheng A1 - Shelley, David A1 - Shibata, David A1 - Coppola, Domenico A1 - Yamada, Hiroyuki A1 - Toyoda, Hidenori A1 - Tada, Toshifumi A1 - Kumada, Takashi A1 - Brenner, Dean E A1 - Hanash, Samir M A1 - Lampe, Paul D KW - Adaptor Proteins, Signal Transducing KW - Adenoma KW - Adult KW - Aged KW - Aged, 80 and over KW - Biomarkers, Tumor KW - CA-19-9 Antigen KW - Case-Control Studies KW - Colonic Neoplasms KW - Cytokine Receptor gp130 KW - Early Detection of Cancer KW - ErbB Receptors KW - Female KW - Humans KW - Hyaluronan Receptors KW - Lewis X Antigen KW - Male KW - Middle Aged KW - Oligosaccharides KW - Protein Array Analysis KW - von Willebrand Factor AB -

OBJECTIVE: To discover and confirm blood-based colon cancer early-detection markers.

DESIGN: We created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.

RESULTS: In the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.

CONCLUSIONS: A panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.

VL - 67 IS - 3 ER - TY - JOUR T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. JF - Nat Genet Y1 - 2018 A1 - Mahajan, Anubha A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Zhao, Wei A1 - Robertson, Neil R A1 - Chu, Audrey Y A1 - Gan, Wei A1 - Kitajima, Hidetoshi A1 - Taliun, Daniel A1 - Rayner, N William A1 - Guo, Xiuqing A1 - Lu, Yingchang A1 - Li, Man A1 - Jensen, Richard A A1 - Hu, Yao A1 - Huo, Shaofeng A1 - Lohman, Kurt K A1 - Zhang, Weihua A1 - Cook, James P A1 - Prins, Bram Peter A1 - Flannick, Jason A1 - Grarup, Niels A1 - Trubetskoy, Vassily Vladimirovich A1 - Kravic, Jasmina A1 - Kim, Young Jin A1 - Rybin, Denis V A1 - Yaghootkar, Hanieh A1 - Müller-Nurasyid, Martina A1 - Meidtner, Karina A1 - Li-Gao, Ruifang A1 - Varga, Tibor V A1 - Marten, Jonathan A1 - Li, Jin A1 - Smith, Albert Vernon A1 - An, Ping A1 - Ligthart, Symen A1 - Gustafsson, Stefan A1 - Malerba, Giovanni A1 - Demirkan, Ayse A1 - Tajes, Juan Fernandez A1 - Steinthorsdottir, Valgerdur A1 - Wuttke, Matthias A1 - Lecoeur, Cécile A1 - Preuss, Michael A1 - Bielak, Lawrence F A1 - Graff, Marielisa A1 - Highland, Heather M A1 - Justice, Anne E A1 - Liu, Dajiang J A1 - Marouli, Eirini A1 - Peloso, Gina Marie A1 - Warren, Helen R A1 - Afaq, Saima A1 - Afzal, Shoaib A1 - Ahlqvist, Emma A1 - Almgren, Peter A1 - Amin, Najaf A1 - Bang, Lia B A1 - Bertoni, Alain G A1 - Bombieri, Cristina A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Burtt, Noel P A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Cho, Yoon Shin A1 - Christensen, Cramer A1 - Eastwood, Sophie V A1 - Eckardt, Kai-Uwe A1 - Fischer, Krista A1 - Gambaro, Giovanni A1 - Giedraitis, Vilmantas A1 - Grove, Megan L A1 - de Haan, Hugoline G A1 - Hackinger, Sophie A1 - Hai, Yang A1 - Han, Sohee A1 - Tybjærg-Hansen, Anne A1 - Hivert, Marie-France A1 - Isomaa, Bo A1 - Jäger, Susanne A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Käräjämäki, AnneMari A1 - Kim, Bong-Jo A1 - Kim, Sung Soo A1 - Koistinen, Heikki A A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Jung-Jin A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Lin, Keng-Hung A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jun A1 - Loh, Marie A1 - Mägi, Reedik A1 - Mamakou, Vasiliki A1 - McKean-Cowdin, Roberta A1 - Nadkarni, Girish A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Ntalla, Ioanna A1 - Peyser, Patricia A A1 - Rathmann, Wolfgang A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rode, Line A1 - Rolandsson, Olov A1 - Schönherr, Sebastian A1 - Selvin, Elizabeth A1 - Small, Kerrin S A1 - Stančáková, Alena A1 - Surendran, Praveen A1 - Taylor, Kent D A1 - Teslovich, Tanya M A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tin, Adrienne A1 - Tönjes, Anke A1 - Varbo, Anette A1 - Witte, Daniel R A1 - Wood, Andrew R A1 - Yajnik, Pranav A1 - Yao, Jie A1 - Yengo, Loic A1 - Young, Robin A1 - Amouyel, Philippe A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Chowdhury, Rajiv A1 - Collins, Francis S A1 - Dedoussis, George A1 - Dehghan, Abbas A1 - Deloukas, Panos A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Florez, Jose C A1 - Frossard, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Howson, Joanna M M A1 - Ingelsson, Martin A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lindgren, Cecilia M A1 - Männistö, Satu A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Moitry, Marie A1 - Morris, Andrew D A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Orho-Melander, Marju A1 - Owen, Katharine R A1 - Perola, Markus A1 - Peters, Annette A1 - Province, Michael A A1 - Rasheed, Asif A1 - Ridker, Paul M A1 - Rivadineira, Fernando A1 - Rosendaal, Frits R A1 - Rosengren, Anders H A1 - Salomaa, Veikko A1 - Sheu, Wayne H-H A1 - Sladek, Rob A1 - Smith, Blair H A1 - Strauch, Konstantin A1 - Uitterlinden, André G A1 - Varma, Rohit A1 - Willer, Cristen J A1 - Blüher, Matthias A1 - Butterworth, Adam S A1 - Chambers, John Campbell A1 - Chasman, Daniel I A1 - Danesh, John A1 - van Duijn, Cornelia A1 - Dupuis, Josée A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Grallert, Harald A1 - Groop, Leif A1 - Han, Bok-Ghee A1 - Hansen, Torben A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal Singh A1 - Köttgen, Anna A1 - Kuulasmaa, Kari A1 - Laakso, Markku A1 - Lin, Xu A1 - Lind, Lars A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Marchini, Jonathan A1 - Metspalu, Andres A1 - Mook-Kanamori, Dennis A1 - Nordestgaard, Børge G A1 - Palmer, Colin N A A1 - Pankow, James S A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Rauramaa, Rainer A1 - Sattar, Naveed A1 - Schulze, Matthias B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Thorsteinsdottir, Unnur A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Zeggini, Eleftheria A1 - Scott, Robert A A1 - Barroso, Inês A1 - Frayling, Timothy M A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Boehnke, Michael A1 - Saleheen, Danish A1 - Morris, Andrew P A1 - Rotter, Jerome I A1 - McCarthy, Mark I AB -

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

VL - 50 IS - 4 ER - TY - JOUR T1 - Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. JF - Lancet Y1 - 2018 A1 - Wood, Angela M A1 - Kaptoge, Stephen A1 - Butterworth, Adam S A1 - Willeit, Peter A1 - Warnakula, Samantha A1 - Bolton, Thomas A1 - Paige, Ellie A1 - Paul, Dirk S A1 - Sweeting, Michael A1 - Burgess, Stephen A1 - Bell, Steven A1 - Astle, William A1 - Stevens, David A1 - Koulman, Albert A1 - Selmer, Randi M A1 - Verschuren, W M Monique A1 - Sato, Shinichi A1 - Njølstad, Inger A1 - Woodward, Mark A1 - Salomaa, Veikko A1 - Nordestgaard, Børge G A1 - Yeap, Bu B A1 - Fletcher, Astrid A1 - Melander, Olle A1 - Kuller, Lewis H A1 - Balkau, Beverley A1 - Marmot, Michael A1 - Koenig, Wolfgang A1 - Casiglia, Edoardo A1 - Cooper, Cyrus A1 - Arndt, Volker A1 - Franco, Oscar H A1 - Wennberg, Patrik A1 - Gallacher, John A1 - de la Cámara, Agustin Gómez A1 - Völzke, Henry A1 - Dahm, Christina C A1 - Dale, Caroline E A1 - Bergmann, Manuela M A1 - Crespo, Carlos J A1 - van der Schouw, Yvonne T A1 - Kaaks, Rudolf A1 - Simons, Leon A A1 - Lagiou, Pagona A1 - Schoufour, Josje D A1 - Boer, Jolanda M A A1 - Key, Timothy J A1 - Rodriguez, Beatriz A1 - Moreno-Iribas, Conchi A1 - Davidson, Karina W A1 - Taylor, James O A1 - Sacerdote, Carlotta A1 - Wallace, Robert B A1 - Quiros, J Ramon A1 - Tumino, Rosario A1 - Blazer, Dan G A1 - Linneberg, Allan A1 - Daimon, Makoto A1 - Panico, Salvatore A1 - Howard, Barbara A1 - Skeie, Guri A1 - Strandberg, Timo A1 - Weiderpass, Elisabete A1 - Nietert, Paul J A1 - Psaty, Bruce M A1 - Kromhout, Daan A1 - Salamanca-Fernandez, Elena A1 - Kiechl, Stefan A1 - Krumholz, Harlan M A1 - Grioni, Sara A1 - Palli, Domenico A1 - Huerta, José M A1 - Price, Jackie A1 - Sundström, Johan A1 - Arriola, Larraitz A1 - Arima, Hisatomi A1 - Travis, Ruth C A1 - Panagiotakos, Demosthenes B A1 - Karakatsani, Anna A1 - Trichopoulou, Antonia A1 - Kühn, Tilman A1 - Grobbee, Diederick E A1 - Barrett-Connor, Elizabeth A1 - van Schoor, Natasja A1 - Boeing, Heiner A1 - Overvad, Kim A1 - Kauhanen, Jussi A1 - Wareham, Nick A1 - Langenberg, Claudia A1 - Forouhi, Nita A1 - Wennberg, Maria A1 - Després, Jean-Pierre A1 - Cushman, Mary A1 - Cooper, Jackie A A1 - Rodriguez, Carlos J A1 - Sakurai, Masaru A1 - Shaw, Jonathan E A1 - Knuiman, Matthew A1 - Voortman, Trudy A1 - Meisinger, Christa A1 - Tjønneland, Anne A1 - Brenner, Hermann A1 - Palmieri, Luigi A1 - Dallongeville, Jean A1 - Brunner, Eric J A1 - Assmann, Gerd A1 - Trevisan, Maurizio A1 - Gillum, Richard F A1 - Ford, Ian A1 - Sattar, Naveed A1 - Lazo, Mariana A1 - Thompson, Simon G A1 - Ferrari, Pietro A1 - Leon, David A A1 - Smith, George Davey A1 - Peto, Richard A1 - Jackson, Rod A1 - Banks, Emily A1 - Di Angelantonio, Emanuele A1 - Danesh, John AB -

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

VL - 391 IS - 10129 ER - TY - JOUR T1 - Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. JF - Aging (Albany NY) Y1 - 2018 A1 - Kulminski, Alexander M A1 - Huang, Jian A1 - Loika, Yury A1 - Arbeev, Konstantin G A1 - Bagley, Olivia A1 - Yashkin, Arseniy A1 - Duan, Matt A1 - Culminskaya, Irina KW - Aging KW - Computational Biology KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Polymorphism, Single Nucleotide AB -

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

VL - 10 IS - 3 ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

VL - 9 IS - 1 ER - TY - JOUR T1 - Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. JF - Diabetologia Y1 - 2018 A1 - McKeown, Nicola M A1 - Dashti, Hassan S A1 - Ma, Jiantao A1 - Haslam, Danielle E A1 - Kiefte-de Jong, Jessica C A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Lemaitre, Rozenn N A1 - Rybin, Denis A1 - Sonestedt, Emily A1 - Frazier-Wood, Alexis C A1 - Mook-Kanamori, Dennis O A1 - Li, Yanping A1 - Wang, Carol A A1 - Leermakers, Elisabeth T M A1 - Mikkilä, Vera A1 - Young, Kristin L A1 - Mukamal, Kenneth J A1 - Cupples, L Adrienne A1 - Schulz, Christina-Alexandra A1 - Chen, Tzu-An A1 - Li-Gao, Ruifang A1 - Huang, Tao A1 - Oddy, Wendy H A1 - Raitakari, Olli A1 - Rice, Kenneth A1 - Meigs, James B A1 - Ericson, Ulrika A1 - Steffen, Lyn M A1 - Rosendaal, Frits R A1 - Hofman, Albert A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Brunkwall, Louise A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Siscovick, David S A1 - Seppälä, Ilkka A1 - North, Kari E A1 - Mozaffarian, Dariush A1 - Dupuis, Josée A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - de Mutsert, Renée A1 - Qi, Lu A1 - Pennell, Craig E A1 - Franco, Oscar H A1 - Lehtimäki, Terho A1 - Herman, Mark A AB -

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

VL - 61 IS - 2 ER - TY - JOUR T1 - Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. JF - Int J Obes (Lond) Y1 - 2018 A1 - Gong, J A1 - Nishimura, K K A1 - Fernandez-Rhodes, L A1 - Haessler, J A1 - Bien, S A1 - Graff, M A1 - Lim, U A1 - Lu, Y A1 - Gross, M A1 - Fornage, M A1 - Yoneyama, S A1 - Isasi, C R A1 - Bůžková, P A1 - Daviglus, M A1 - Lin, D-Y A1 - Tao, R A1 - Goodloe, R A1 - Bush, W S A1 - Farber-Eger, E A1 - Boston, J A1 - Dilks, H H A1 - Ehret, G A1 - Gu, C C A1 - Lewis, C E A1 - Nguyen, K-D H A1 - Cooper, R A1 - Leppert, M A1 - Irvin, M R A1 - Bottinger, E P A1 - Wilkens, L R A1 - Haiman, C A A1 - Park, L A1 - Monroe, K R A1 - Cheng, I A1 - Stram, D O A1 - Carlson, C S A1 - Jackson, R A1 - Kuller, L A1 - Houston, D A1 - Kooperberg, C A1 - Buyske, S A1 - Hindorff, L A A1 - Crawford, D C A1 - Loos, R J F A1 - Le Marchand, L A1 - Matise, T C A1 - North, K E A1 - Peters, U AB -

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.

SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.

RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue.

CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

VL - 42 IS - 3 ER - TY - JOUR T1 - Validation of the REGARDS Severe Sepsis Risk Score. JF - J Clin Med Y1 - 2018 A1 - Wang, Henry E A1 - Donnelly, John P A1 - Yende, Sachin A1 - Levitan, Emily B A1 - Shapiro, Nathan I A1 - Dai, Yuling A1 - Zhao, Hong A1 - Heiss, Gerardo A1 - Odden, Michelle A1 - Newman, Anne A1 - Safford, Monika AB -

There are no validated systems for characterizing long-term risk of severe sepsis in community-dwelling adults. We tested the ability of the REasons for Geographic and Racial Differences in Stroke-Severe Sepsis Risk Score (REGARDS-SSRS) to predict 10-year severe sepsis risk in separate cohorts of community-dwelling adults. We internally tested the REGARDS-SSRS on the REGARDS-Medicare subcohort. We then externally validated the REGARDS-SSRS using (1) the Cardiovascular Health Study (CHS) and (2) the Atherosclerosis Risk in Communities (ARIC) cohorts. Participants included community-dwelling adults: REGARDS-Medicare, age ≥65 years, = 9522; CHS, age ≥65 years, = 5888; ARIC, age 45⁻64 years, = 11,584. The primary exposure was 10-year severe sepsis risk, predicted by the REGARDS-SSRS from participant sociodemographics, health behaviors, chronic medical conditions and select biomarkers. The primary outcome was first severe sepsis hospitalizations, defined as the concurrent presence of ICD-9 discharge diagnoses for a serious infection and organ dysfunction. Median SSRS in the cohorts were: REGARDS-Medicare 11 points (IQR 7⁻16), CHS 10 (IQR 6⁻15), ARIC 7 (IQR 5⁻10). Severe sepsis incidence rates were: REGARDS-Medicare 30.7 per 1000 person-years (95% CI: 29.2⁻32.2); CHS 11.9 (10.9⁻12.9); ARIC 6.8 (6.3⁻7.3). SSRS discrimination for first severe sepsis events were: REGARDS-Medicare C-statistic 0.704 (95% CI: 0.691⁻0.718), CHS 0.696 (0.675⁻0.716), ARIC 0.697 (0.677⁻0.716). The REGARDS-SRSS may potentially play a role in identifying community-dwelling adults at high severe sepsis risk.

VL - 7 IS - 12 ER - TY - JOUR T1 - Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. JF - Hum Mol Genet Y1 - 2019 A1 - Wang, Heming A1 - Cade, Brian E A1 - Sofer, Tamar A1 - Sands, Scott A A1 - Chen, Han A1 - Browning, Sharon R A1 - Stilp, Adrienne M A1 - Louie, Tin L A1 - Thornton, Timothy A A1 - Johnson, W Craig A1 - Below, Jennifer E A1 - Conomos, Matthew P A1 - Evans, Daniel S A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Wood, Alexis C A1 - Mei, Hao A1 - Yaffe, Kristine A1 - Loredo, Jose S A1 - Ramos, Alberto R A1 - Barrett-Connor, Elizabeth A1 - Ancoli-Israel, Sonia A1 - Zee, Phyllis C A1 - Arens, Raanan A1 - Shah, Neomi A A1 - Taylor, Kent D A1 - Tranah, Gregory J A1 - Stone, Katie L A1 - Hanis, Craig L A1 - Wilson, James G A1 - Gottlieb, Daniel J A1 - Patel, Sanjay R A1 - Rice, Ken A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Sunyaev, Shamil R A1 - Cai, Jianwen A1 - Lin, Xihong A1 - Purcell, Shaun M A1 - Laurie, Cathy C A1 - Saxena, Richa A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

VL - 28 IS - 4 ER - TY - JOUR T1 - Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study. JF - Am J Respir Crit Care Med Y1 - 2019 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Grams, Morgan E A1 - Cassano, Patricia A A1 - Jacobs, David R A1 - Barr, R Graham A1 - Burkart, Kristin M A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Loehr, Laura R A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Shlipak, Michael A1 - Tracy, Russell P A1 - Tsai, Michael Y A1 - White, Wendy A1 - Yende, Sachin AB -

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD.

OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs.

METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications.

MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease.

CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

VL - 199 IS - 3 ER - TY - JOUR T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. JF - Brain Y1 - 2019 A1 - Mishra, Aniket A1 - Chauhan, Ganesh A1 - Violleau, Marie-Helene A1 - Vojinovic, Dina A1 - Jian, Xueqiu A1 - Bis, Joshua C A1 - Li, Shuo A1 - Saba, Yasaman A1 - Grenier-Boley, Benjamin A1 - Yang, Qiong A1 - Bartz, Traci M A1 - Hofer, Edith A1 - Soumaré, Aïcha A1 - Peng, Fen A1 - Duperron, Marie-Gabrielle A1 - Foglio, Mario A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Psaty, Bruce M A1 - Launer, Lenore J A1 - Boerwinkle, Eric A1 - Zhu, Yicheng A1 - Mazoyer, Bernard A1 - Lathrop, Mark A1 - Bellenguez, Céline A1 - van Duijn, Cornelia M A1 - Ikram, M Arfan A1 - Schmidt, Helena A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Seshadri, Sudha A1 - Joutel, Anne A1 - Tzourio, Christophe A1 - Debette, Stephanie AB -

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

ER - TY - JOUR T1 - Associations of autozygosity with a broad range of human phenotypes. JF - Nat Commun Y1 - 2019 A1 - Clark, David W A1 - Okada, Yukinori A1 - Moore, Kristjan H S A1 - Mason, Dan A1 - Pirastu, Nicola A1 - Gandin, Ilaria A1 - Mattsson, Hannele A1 - Barnes, Catriona L K A1 - Lin, Kuang A1 - Zhao, Jing Hua A1 - Deelen, Patrick A1 - Rohde, Rebecca A1 - Schurmann, Claudia A1 - Guo, Xiuqing A1 - Giulianini, Franco A1 - Zhang, Weihua A1 - Medina-Gómez, Carolina A1 - Karlsson, Robert A1 - Bao, Yanchun A1 - Bartz, Traci M A1 - Baumbach, Clemens A1 - Biino, Ginevra A1 - Bixley, Matthew J A1 - Brumat, Marco A1 - Chai, Jin-Fang A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Dekker, Annelot M A1 - Eccles, David A A1 - van Eijk, Kristel R A1 - Fuchsberger, Christian A1 - Gao, He A1 - Germain, Marine A1 - Gordon, Scott D A1 - de Haan, Hugoline G A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Huerta-Chagoya, Alicia A1 - Igartua, Catherine A1 - Jansen, Iris E A1 - Jia, Yucheng A1 - Kacprowski, Tim A1 - Karlsson, Torgny A1 - Kleber, Marcus E A1 - Li, Shengchao Alfred A1 - Li-Gao, Ruifang A1 - Mahajan, Anubha A1 - Matsuda, Koichi A1 - Meidtner, Karina A1 - Meng, Weihua A1 - Montasser, May E A1 - van der Most, Peter J A1 - Munz, Matthias A1 - Nutile, Teresa A1 - Palviainen, Teemu A1 - Prasad, Gauri A1 - Prasad, Rashmi B A1 - Priyanka, Tallapragada Divya Sri A1 - Rizzi, Federica A1 - Salvi, Erika A1 - Sapkota, Bishwa R A1 - Shriner, Daniel A1 - Skotte, Line A1 - Smart, Melissa C A1 - Smith, Albert Vernon A1 - van der Spek, Ashley A1 - Spracklen, Cassandra N A1 - Strawbridge, Rona J A1 - Tajuddin, Salman M A1 - Trompet, Stella A1 - Turman, Constance A1 - Verweij, Niek A1 - Viberti, Clara A1 - Wang, Lihua A1 - Warren, Helen R A1 - Wootton, Robyn E A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yousri, Noha A A1 - Zhao, Wei A1 - Adeyemo, Adebowale A A1 - Afaq, Saima A1 - Aguilar-Salinas, Carlos Alberto A1 - Akiyama, Masato A1 - Albert, Matthew L A1 - Allison, Matthew A A1 - Alver, Maris A1 - Aung, Tin A1 - Azizi, Fereidoun A1 - Bentley, Amy R A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Borja, Judith B A1 - de Borst, Gert J A1 - Bottinger, Erwin P A1 - Broer, Linda A1 - Campbell, Harry A1 - Chanock, Stephen A1 - Chee, Miao-Li A1 - Chen, Guanjie A1 - Chen, Yii-der I A1 - Chen, Zhengming A1 - Chiu, Yen-Feng A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Concas, Maria Pina A1 - Corley, Janie A1 - Cugliari, Giovanni A1 - van Dam, Rob M A1 - Damulina, Anna A1 - Daneshpour, Maryam S A1 - Day, Felix R A1 - Delgado, Graciela E A1 - Dhana, Klodian A1 - Doney, Alexander S F A1 - Dörr, Marcus A1 - Doumatey, Ayo P A1 - Dzimiri, Nduna A1 - Ebenesersdóttir, S Sunna A1 - Elliott, Joshua A1 - Elliott, Paul A1 - Ewert, Ralf A1 - Felix, Janine F A1 - Fischer, Krista A1 - Freedman, Barry I A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gögele, Martin A1 - Goodarzi, Mark O A1 - Graff, Mariaelisa A1 - Granot-Hershkovitz, Einat A1 - Grodstein, Francine A1 - Guarrera, Simonetta A1 - Gudbjartsson, Daniel F A1 - Guity, Kamran A1 - Gunnarsson, Bjarni A1 - Guo, Yu A1 - Hagenaars, Saskia P A1 - Haiman, Christopher A A1 - Halevy, Avner A1 - Harris, Tamara B A1 - Hedayati, Mehdi A1 - van Heel, David A A1 - Hirata, Makoto A1 - Höfer, Imo A1 - Hsiung, Chao Agnes A1 - Huang, Jinyan A1 - Hung, Yi-Jen A1 - Ikram, M Arfan A1 - Jagadeesan, Anuradha A1 - Jousilahti, Pekka A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerrison, Nicola D A1 - Kessler, Thorsten A1 - Khaw, Kay-Tee A1 - Khor, Chiea Chuen A1 - de Kleijn, Dominique P V A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Krämer, Bernhard K A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lawlor, Deborah A A1 - Lee, I-Te A1 - Lee, Wen-Jane A1 - Lerch, Markus M A1 - Li, Liming A1 - Liu, Jianjun A1 - Loh, Marie A1 - London, Stephanie J A1 - Loomis, Stephanie A1 - Lu, Yingchang A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - Manunta, Paolo A1 - Másson, Gísli A1 - Matoba, Nana A1 - Mei, Xue W A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Mezzavilla, Massimo A1 - Milani, Lili A1 - Millwood, Iona Y A1 - Momozawa, Yukihide A1 - Moore, Amy A1 - Morange, Pierre-Emmanuel A1 - Moreno-Macias, Hortensia A1 - Mori, Trevor A A1 - Morrison, Alanna C A1 - Muka, Taulant A1 - Murakami, Yoshinori A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Mychaleckyj, Josyf C A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Neville, Matt J A1 - Nolte, Ilja M A1 - Ong, Ken K A1 - Orozco, Lorena A1 - Padmanabhan, Sandosh A1 - Pálsson, Gunnar A1 - Pankow, James S A1 - Pattaro, Cristian A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Quintana-Murci, Lluis A1 - Räikkönen, Katri A1 - Ralhan, Sarju A1 - Rao, Dabeeru C A1 - van Rheenen, Wouter A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rietveld, Cornelius A A1 - Robino, Antonietta A1 - van Rooij, Frank J A A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Sabater-Lleal, Maria A1 - Sala, Cinzia Felicita A1 - Salomaa, Veikko A1 - Sandow, Kevin A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sedaghati-Khayat, Bahareh A1 - Sennblad, Bengt A1 - van Setten, Jessica A1 - Sever, Peter J A1 - Sheu, Wayne H-H A1 - Shi, Yuan A1 - Shrestha, Smeeta A1 - Shukla, Sharvari Rahul A1 - Sigurdsson, Jon K A1 - Sikka, Timo Tonis A1 - Singh, Jai Rup A1 - Smith, Blair H A1 - Stančáková, Alena A1 - Stanton, Alice A1 - Starr, John M A1 - Stefansdottir, Lilja A1 - Straker, Leon A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Swertz, Morris A A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Terzikhan, Natalie A1 - Tham, Yih-Chung A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tillander, Annika A1 - Tracy, Russell P A1 - Tusié-Luna, Teresa A1 - Tzoulaki, Ioanna A1 - Vaccargiu, Simona A1 - Vangipurapu, Jagadish A1 - Veldink, Jan H A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vuoksimaa, Eero A1 - Wakil, Salma M A1 - Waldenberger, Melanie A1 - Wander, Gurpreet S A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Wild, Sarah A1 - Yajnik, Chittaranjan S A1 - Yuan, Jian-Min A1 - Zeng, Lingyao A1 - Zhang, Liang A1 - Zhou, Jie A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Becker, Diane M A1 - Lehne, Benjamin A1 - Bennett, David A A1 - van den Berg, Leonard H A1 - Berndt, Sonja I A1 - Bharadwaj, Dwaipayan A1 - Bielak, Lawrence F A1 - Bochud, Murielle A1 - Boehnke, Mike A1 - Bouchard, Claude A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carmi, Shai A1 - Caulfield, Mark J A1 - Cesarini, David A1 - Chambers, John C A1 - Chandak, Giriraj Ratan A1 - Cheng, Ching-Yu A1 - Ciullo, Marina A1 - Cornelis, Marilyn A1 - Cusi, Daniele A1 - Smith, George Davey A1 - Deary, Ian J A1 - Dorajoo, Rajkumar A1 - van Duijn, Cornelia M A1 - Ellinghaus, David A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Evans, Michele K A1 - Faul, Jessica D A1 - Feenstra, Bjarke A1 - Feitosa, Mary A1 - Foisy, Sylvain A1 - Franke, Andre A1 - Friedlander, Yechiel A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Gonzalez, Clicerio A1 - Goyette, Philippe A1 - Grant, Struan F A A1 - Griffiths, Lyn R A1 - Groop, Leif A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hakonarson, Hakon A1 - Hamsten, Anders A1 - van der Harst, Pim A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hochner, Hagit A1 - Huikuri, Heikki A1 - Hunt, Steven C A1 - Jaddoe, Vincent W V A1 - De Jager, Philip L A1 - Johannesson, Magnus A1 - Johansson, Asa A1 - Jonas, Jost B A1 - Jukema, J Wouter A1 - Junttila, Juhani A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kumari, Meena A1 - Laakso, Markku A1 - van der Laan, Sander W A1 - Lahti, Jari A1 - Laudes, Matthias A1 - Lea, Rodney A A1 - Lieb, Wolfgang A1 - Lumley, Thomas A1 - Martin, Nicholas G A1 - März, Winfried A1 - Matullo, Giuseppe A1 - McCarthy, Mark I A1 - Medland, Sarah E A1 - Merriman, Tony R A1 - Metspalu, Andres A1 - Meyer, Brian F A1 - Mohlke, Karen L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis A1 - Munroe, Patricia B A1 - North, Kari E A1 - Nyholt, Dale R A1 - O'Connell, Jeffery R A1 - Ober, Carole A1 - Oldehinkel, Albertine J A1 - Palmas, Walter A1 - Palmer, Colin A1 - Pasterkamp, Gerard G A1 - Patin, Etienne A1 - Pennell, Craig E A1 - Perusse, Louis A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polderman, Tinca J C A1 - Porteous, David J A1 - Posthuma, Danielle A1 - Psaty, Bruce M A1 - Rioux, John D A1 - Rivadeneira, Fernando A1 - Rotimi, Charles A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - den Ruijter, Hester M A1 - Sanghera, Dharambir K A1 - Sattar, Naveed A1 - Schmidt, Reinhold A1 - Schulze, Matthias B A1 - Schunkert, Heribert A1 - Scott, Robert A A1 - Shuldiner, Alan R A1 - Sim, Xueling A1 - Small, Neil A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Tai, E-Shyong A1 - Teumer, Alexander A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Trégouët, David-Alexandre A1 - Tuomi, Tiinamaija A1 - Vollenweider, Peter A1 - Wang, Carol A A1 - Weir, David R A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wong, Tien-Yin A1 - Wright, John A1 - Yang, Jingyun A1 - Yu, Lei A1 - Zemel, Babette S A1 - Zonderman, Alan B A1 - Perola, Markus A1 - Magnusson, Patrik K E A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Chasman, Daniel I A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Franke, Lude A1 - Haley, Chris S A1 - Hayward, Caroline A1 - Walters, Robin G A1 - Perry, John R B A1 - Esko, Tõnu A1 - Helgason, Agnar A1 - Stefansson, Kari A1 - Joshi, Peter K A1 - Kubo, Michiaki A1 - Wilson, James F AB -

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

VL - 10 IS - 1 ER - TY - JOUR T1 - {Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: a pooled analysis of prospective cohort studies JF - Am. J. Clin. Nutr. Y1 - 2019 A1 - Fretts, A. M. A1 - Imamura, F. A1 - Marklund, M. A1 - Micha, R. A1 - Wu, J. H. Y. A1 - Murphy, R. A. A1 - Chien, K. L. A1 - McKnight, B. A1 - Tintle, N. A1 - Forouhi, N. G. A1 - Qureshi, W. T. A1 - Virtanen, J. K. A1 - Wong, K. A1 - Wood, A. C. A1 - Lankinen, M. A1 - Rajaobelina, K. A1 - Harris, T. B. A1 - Djouss?, L. A1 - Harris, B. A1 - Wareham, N. J. A1 - Steffen, L. M. A1 - Laakso, M. A1 - Veenstra, J. A1 - Samieri, C. A1 - Brouwer, I. A. A1 - Yu, C. I. A1 - Koulman, A. A1 - Steffen, B. T. A1 - Helmer, C. A1 - Sotoodehnia, N. A1 - Siscovick, D. A1 - Gudnason, V. A1 - Wagenknecht, L. A1 - Voutilainen, S. A1 - Tsai, M. Y. A1 - Uusitupa, M. A1 - Kalsbeek, A. A1 - Berr, C. A1 - Mozaffarian, D. A1 - Lemaitre, R. N. AB - Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.\ We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.\ Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.\ There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.\ Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes. VL - 109 ER - TY - JOUR T1 - Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. JF - PLoS Genet Y1 - 2019 A1 - Cade, Brian E A1 - Chen, Han A1 - Stilp, Adrienne M A1 - Louie, Tin A1 - Ancoli-Israel, Sonia A1 - Arens, Raanan A1 - Barfield, Richard A1 - Below, Jennifer E A1 - Cai, Jianwen A1 - Conomos, Matthew P A1 - Evans, Daniel S A1 - Frazier-Wood, Alexis C A1 - Gharib, Sina A A1 - Gleason, Kevin J A1 - Gottlieb, Daniel J A1 - Hillman, David R A1 - Johnson, W Craig A1 - Lederer, David J A1 - Lee, Jiwon A1 - Loredo, Jose S A1 - Mei, Hao A1 - Mukherjee, Sutapa A1 - Patel, Sanjay R A1 - Post, Wendy S A1 - Purcell, Shaun M A1 - Ramos, Alberto R A1 - Reid, Kathryn J A1 - Rice, Ken A1 - Shah, Neomi A A1 - Sofer, Tamar A1 - Taylor, Kent D A1 - Thornton, Timothy A A1 - Wang, Heming A1 - Yaffe, Kristine A1 - Zee, Phyllis C A1 - Hanis, Craig L A1 - Palmer, Lyle J A1 - Rotter, Jerome I A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Wilson, James G A1 - Sunyaev, Shamil R A1 - Laurie, Cathy C A1 - Zhu, Xiaofeng A1 - Saxena, Richa A1 - Lin, Xihong A1 - Redline, Susan KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cell Adhesion Molecules, Neuronal KW - Computational Biology KW - Extracellular Matrix Proteins KW - Female KW - Gene Regulatory Networks KW - Genetic Variation KW - Genome-Wide Association Study KW - Hexokinase KW - Humans KW - Hypoxia KW - Interleukin-18 Receptor alpha Subunit KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - NLR Family, Pyrin Domain-Containing 3 Protein KW - Oxygen KW - Oxyhemoglobins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Serine Endopeptidases KW - Sleep KW - Sleep Apnea Syndromes KW - Young Adult AB -

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

VL - 15 IS - 4 ER - TY - JOUR T1 - Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality. JF - Circulation Y1 - 2019 A1 - Marklund, Matti A1 - Wu, Jason H Y A1 - Imamura, Fumiaki A1 - Del Gobbo, Liana C A1 - Fretts, Amanda A1 - de Goede, Janette A1 - Shi, Peilin A1 - Tintle, Nathan A1 - Wennberg, Maria A1 - Aslibekyan, Stella A1 - Chen, Tzu-An A1 - de Oliveira Otto, Marcia C A1 - Hirakawa, Yoichiro A1 - Eriksen, Helle Højmark A1 - Kröger, Janine A1 - Laguzzi, Federica A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Prem, Kiesha A1 - Samieri, Cecilia A1 - Virtanen, Jyrki A1 - Wood, Alexis C A1 - Wong, Kerry A1 - Yang, Wei-Sin A1 - Zhou, Xia A1 - Baylin, Ana A1 - Boer, Jolanda M A A1 - Brouwer, Ingeborg A A1 - Campos, Hannia A1 - Chaves, Paulo H M A1 - Chien, Kuo-Liong A1 - de Faire, Ulf A1 - Djoussé, Luc A1 - Eiriksdottir, Gudny A1 - El-Abbadi, Naglaa A1 - Forouhi, Nita G A1 - Michael Gaziano, J A1 - Geleijnse, Johanna M A1 - Gigante, Bruna A1 - Giles, Graham A1 - Guallar, Eliseo A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Harris, William S A1 - Helmer, Catherine A1 - Hellenius, Mai-Lis A1 - Hodge, Allison A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Jansson, Jan-Håkan A1 - Kalsbeek, Anya A1 - Khaw, Kay-Tee A1 - Koh, Woon-Puay A1 - Laakso, Markku A1 - Leander, Karin A1 - Lin, Hung-Ju A1 - Lind, Lars A1 - Luben, Robert A1 - Luo, Juhua A1 - McKnight, Barbara A1 - Mursu, Jaakko A1 - Ninomiya, Toshiharu A1 - Overvad, Kim A1 - Psaty, Bruce M A1 - Rimm, Eric A1 - Schulze, Matthias B A1 - Siscovick, David A1 - Skjelbo Nielsen, Michael A1 - Smith, Albert V A1 - Steffen, Brian T A1 - Steffen, Lyn A1 - Sun, Qi A1 - Sundström, Johan A1 - Tsai, Michael Y A1 - Tunstall-Pedoe, Hugh A1 - Uusitupa, Matti I J A1 - van Dam, Rob M A1 - Veenstra, Jenna A1 - Monique Verschuren, W M A1 - Wareham, Nick A1 - Willett, Walter A1 - Woodward, Mark A1 - Yuan, Jian-Min A1 - Micha, Renata A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush A1 - Riserus, Ulf AB -

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.

METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).

RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.

CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

VL - 139 IS - 21 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

VL - 51 IS - 6 ER - TY - JOUR T1 - Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality. JF - JAMA Y1 - 2019 A1 - Bhatt, Surya P A1 - Balte, Pallavi P A1 - Schwartz, Joseph E A1 - Cassano, Patricia A A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - O'Connor, George T A1 - Yende, Sachin A1 - Sanders, Jason L A1 - Umans, Jason G A1 - Dransfield, Mark T A1 - Chaves, Paulo H A1 - White, Wendy B A1 - Oelsner, Elizabeth C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Hospitalization KW - Humans KW - Male KW - Middle Aged KW - Prognosis KW - Proportional Hazards Models KW - Pulmonary Disease, Chronic Obstructive KW - Risk Assessment KW - Vital Capacity AB -

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.

Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.

Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).

Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.

Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.

Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

VL - 321 IS - 24 ER - TY - JOUR T1 - Disentangling the genetics of lean mass. JF - Am J Clin Nutr Y1 - 2019 A1 - Karasik, David A1 - Zillikens, M Carola A1 - Hsu, Yi-Hsiang A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Bochud, Murielle A1 - Borecki, Ingrid B A1 - Broer, Linda A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos-Obando, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Chambers, John C A1 - Chen, Zhao A1 - Cho, Nam H A1 - Choi, Hyung Jin A1 - Chou, Wen-Chi A1 - Cummings, Steven R A1 - de Groot, Lisette C P G M A1 - De Jager, Phillip L A1 - Demuth, Ilja A1 - Diatchenko, Luda A1 - Econs, Michael J A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Eriksson, Joel A1 - Eriksson, Johan G A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Gieger, Christian A1 - Grallert, Harald A1 - Gudnason, Vilmundur A1 - Lenore, Launer J A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Johnson, Toby A1 - Biffar, Reiner A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koller, Daniel L A1 - Kooner, Jaspal S A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kutalik, Zoltán A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lill, Christina A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Livshits, Gregory A1 - Ljunggren, Osten A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Luan, Jian'an A1 - Luben, Robert N A1 - Malkin, Ida A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Nethander, Maria A1 - Newman, Anne B A1 - O'Connell, Jeffery R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Prince, Richard L A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schipf, Sabine A1 - Shin, Chan Soo A1 - Smith, Albert V A1 - Smith, Shad B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stančáková, Alena A1 - Stefansson, Kari A1 - Steinhagen-Thiessen, Elisabeth A1 - Stolk, Lisette A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - Vandenput, Liesbeth A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - J Wareham, Nicholas A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Yerges-Armstrong, Laura M A1 - Yu, Lei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhou, Yanhua A1 - Nielson, Carrie M A1 - Harris, Tamara B A1 - Demissie, Serkalem A1 - Kiel, Douglas P A1 - Ohlsson, Claes AB -

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

VL - 109 IS - 2 ER - TY - JOUR T1 - {Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies JF - Eur Heart J Y1 - 2019 A1 - Pennells, L. A1 - Kaptoge, S. A1 - Wood, A. A1 - Sweeting, M. A1 - Zhao, X. A1 - White, I. A1 - Burgess, S. A1 - Willeit, P. A1 - Bolton, T. A1 - Moons, K. G. M. A1 - van der Schouw, Y. T. A1 - Selmer, R. A1 - Khaw, K. T. A1 - Gudnason, V. A1 - Assmann, G. A1 - Amouyel, P. A1 - Salomaa, V. A1 - Kivimaki, M. A1 - Nordestgaard, B. G. A1 - Blaha, M. J. A1 - Kuller, L. H. A1 - Brenner, H. A1 - Gillum, R. F. A1 - Meisinger, C. A1 - Ford, I. A1 - Knuiman, M. W. A1 - Rosengren, A. A1 - Lawlor, D. A. A1 - V?lzke, H. A1 - Cooper, C. A1 - Mar?n Iba?ez, A. A1 - Casiglia, E. A1 - Kauhanen, J. A1 - Cooper, J. A. A1 - Rodriguez, B. A1 - Sundstr?m, J. A1 - Barrett-Connor, E. A1 - Dankner, R. A1 - Nietert, P. J. A1 - Davidson, K. W. A1 - Wallace, R. B. A1 - Blazer, D. G. A1 - Bj?rkelund, C. A1 - Donfrancesco, C. A1 - Krumholz, H. M. A1 - Nissinen, A. A1 - Davis, B. R. A1 - Coady, S. A1 - Whincup, P. H. A1 - J?rgensen, T. A1 - Ducimetiere, P. A1 - Trevisan, M. A1 - Engstr?m, G. A1 - Crespo, C. J. A1 - Meade, T. W. A1 - Visser, M. A1 - Kromhout, D. A1 - Kiechl, S. A1 - Daimon, M. A1 - Price, J. F. A1 - G?mez de la C?mara, A. A1 - Wouter Jukema, J. A1 - Lamarche, B. A1 - Onat, A. A1 - Simons, L. A. A1 - Kavousi, M. A1 - Ben-Shlomo, Y. A1 - Gallacher, J. A1 - Dekker, J. M. A1 - Arima, H. A1 - Shara, N. A1 - Tipping, R. W. A1 - Roussel, R. A1 - Brunner, E. J. A1 - Koenig, W. A1 - Sakurai, M. A1 - Pavlovic, J. A1 - Gansevoort, R. T. A1 - Nagel, D. A1 - Goldbourt, U. A1 - Barr, E. L. M. A1 - Palmieri, L. A1 - Nj?lstad, I. A1 - Sato, S. A1 - Monique Verschuren, W. M. A1 - Varghese, C. V. A1 - Graham, I. A1 - Onuma, O. A1 - Greenland, P. A1 - Woodward, M. A1 - Ezzati, M. A1 - Psaty, B. M. A1 - Sattar, N. A1 - Jackson, R. A1 - Ridker, P. M. A1 - Cook, N. R. A1 - D'Agostino, R. B. A1 - Thompson, S. G. A1 - Danesh, J. A1 - Di Angelantonio, E. A1 - Tipping, R. W. A1 - Simpson, L. M. A1 - Pressel, S. L. A1 - Couper, D. J. A1 - Nambi, V. A1 - Matsushita, K. A1 - Folsom, A. R. A1 - Shaw, J. E. A1 - Magliano, D. J. A1 - Zimmet, P. Z. A1 - Knuiman, M. W. A1 - Whincup, P. H. A1 - Wannamethee, S. G. A1 - Willeit, J. A1 - Santer, P. A1 - Egger, G. A1 - Casas, J. P. A1 - Amuzu, A. A1 - Ben-Shlomo, Y. A1 - Gallacher, J. A1 - Tikhonoff, V. A1 - Casiglia, E. A1 - Sutherland, S. E. A1 - Nietert, P. J. A1 - Cushman, M. A1 - Psaty, B. M. A1 - S?gaard, A. J. A1 - H?heim, L. L. A1 - Ariansen, I. A1 - Tybj?rg-Hansen, A. A1 - Jensen, G. B. A1 - Schnohr, P. A1 - Giampaoli, S. A1 - Vanuzzo, D. A1 - Panico, S. A1 - Palmieri, L. A1 - Balkau, B. A1 - Bonnet, F. A1 - Marre, M. A1 - de la C?mara, A. G. A1 - Rubio Herrera, M. A. A1 - Friedlander, Y. A1 - McCallum, J. A1 - McLachlan, S. A1 - Guralnik, J. A1 - Phillips, C. L. A1 - Khaw, K. T. A1 - Wareham, N. A1 - Sch?ttker, B. A1 - Saum, K. U. A1 - Holleczek, B. A1 - Nissinen, A. A1 - Tolonen, H. A1 - Giampaoli, S. A1 - Donfrancesco, C. A1 - Vartiainen, E. A1 - Jousilahti, P. A1 - Harald, K. A1 - D?Agostino, R. B. A1 - Massaro, J. M. A1 - Pencina, M. A1 - Vasan, R. A1 - Kayama, T. A1 - Kato, T. A1 - Oizumi, T. A1 - Jespersen, J. A1 - M?ller, L. A1 - Bladbjerg, E. M. A1 - Chetrit, A. A1 - Rosengren, A. A1 - Wilhelmsen, L. A1 - Bj?rkelund, C. A1 - Lissner, L. A1 - Nagel, D. A1 - Dennison, E. A1 - Kiyohara, Y. A1 - Ninomiya, T. A1 - Doi, Y. A1 - Rodriguez, B. A1 - Nijpels, G. A1 - Stehouwer, C. D. A. A1 - Sato, S. A1 - Kazumasa, Y. A1 - Iso, H. A1 - Goldbourt, U. A1 - Salomaa, V. A1 - Vartiainen, E. A1 - Kurl, S. A1 - Tuomainen, T. P. A1 - Salonen, J. T. A1 - Visser, M. A1 - Deeg, D. J. H. A1 - Meade, T. W. A1 - Nilsson, P. M. A1 - Hedblad, B. A1 - Melander, O. A1 - De Boer, I. H. A1 - DeFilippis, A. P. A1 - Verschuren, W. M. M. A1 - Sattar, N. A1 - Watt, G. A1 - Meisinger, C. A1 - Koenig, W. A1 - Rosengren, A. A1 - Kuller, L. H. A1 - Tverdal, A. A1 - Gillum, R. F. A1 - Cooper, J. A. A1 - Kirkland, S. A1 - Shimbo, D. A1 - Shaffer, J. A1 - Sato, S. A1 - Kazumasa, Y. A1 - Iso, H. A1 - Ducimetiere, P. A1 - Bakker, S. J. L. A1 - van der Harst, P. A1 - Hillege, H. L. A1 - Crespo, C. J. A1 - Amouyel, P. A1 - Dallongeville, J. A1 - Assmann, G. A1 - Schulte, H. A1 - Trompet, S. A1 - Smit, R. A. J. A1 - Stott, D. J. A1 - van der Schouw, Y. T. A1 - Despr?s, J. P. A1 - Cantin, B. A1 - Dagenais, G. R. A1 - Laughlin, G. A1 - Wingard, D. A1 - Trevisan, M. A1 - Aspelund, T. A1 - Eiriksdottir, G. A1 - Gudmundsson, E. F. A1 - Ikram, A. A1 - van Rooij, F. J. A. A1 - Franco, O. H. A1 - Rueda-Ochoa, O. L. A1 - Muka, T. A1 - Glisic, M. A1 - Tunstall-Pedoe, H. A1 - V?lzke, H. A1 - Howard, B. V. A1 - Zhang, Y. A1 - Jolly, S. A1 - Gallacher, J. A1 - Davey-Smith, G. A1 - Can, G. A1 - Y?ksel, H. A1 - Nakagawa, H. A1 - Morikawa, Y. A1 - Miura, K. A1 - Nj?lstad, I. A1 - Ingelsson, M. A1 - Giedraitis, V. A1 - Ridker, P. M. A1 - Gaziano, J. M. A1 - Kivimaki, M. A1 - Shipley, M. A1 - Brunner, E. J. A1 - Arndt, V. A1 - Brenner, H. A1 - Cook, N. A1 - Ridker, P. M. A1 - Ford, I. A1 - Sattar, N. A1 - Iba?ez, A. M. A1 - Geleijnse, J. M. AB - There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.\ Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.\ Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. VL - 40 ER - TY - JOUR T1 - {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology JF - Am J Hum Genet Y1 - 2019 A1 - Spracklen, C. N. A1 - Karaderi, T. A1 - Yaghootkar, H. A1 - Schurmann, C. A1 - Fine, R. S. A1 - Kutalik, Z. A1 - Preuss, M. H. A1 - Lu, Y. A1 - Wittemans, L. B. L. A1 - Adair, L. S. A1 - Allison, M. A1 - Amin, N. A1 - Auer, P. L. A1 - Bartz, T. M. A1 - her, M. A1 - Boehnke, M. A1 - Borja, J. B. A1 - Bork-Jensen, J. A1 - Broer, L. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Chirstofidou, P. A1 - Demirkan, A. A1 - van Duijn, C. M. A1 - Feitosa, M. F. A1 - Garcia, M. E. A1 - Graff, M. A1 - Grallert, H. A1 - Grarup, N. A1 - Guo, X. A1 - Haesser, J. A1 - Hansen, T. A1 - Harris, T. B. A1 - Highland, H. M. A1 - Hong, J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jackson, R. A1 - Jousilahti, P. A1 - nen, M. A1 - Kizer, J. R. A1 - Kovacs, P. A1 - Kriebel, J. A1 - Laakso, M. A1 - Lange, L. A. A1 - ki, T. A1 - Li, J. A1 - Li-Gao, R. A1 - Lind, L. A1 - Luan, J. A1 - inen, L. P. A1 - MacGregor, S. A1 - Mackey, D. A. A1 - Mahajan, A. A1 - Mangino, M. A1 - ö, S. A1 - McCarthy, M. I. A1 - McKnight, B. A1 - Medina-Gomez, C. A1 - Meigs, J. B. A1 - Molnos, S. A1 - Mook-Kanamori, D. A1 - Morris, A. P. A1 - de Mutsert, R. A1 - Nalls, M. A. A1 - Nedeljkovic, I. A1 - North, K. E. A1 - Pennell, C. E. A1 - Pradhan, A. D. A1 - Province, M. A. A1 - Raitakari, O. T. A1 - Raulerson, C. K. A1 - Reiner, A. P. A1 - Ridker, P. M. A1 - Ripatti, S. A1 - Roberston, N. A1 - Rotter, J. I. A1 - Salomaa, V. A1 - rate, A. A. A1 - Sitlani, C. M. A1 - Spector, T. D. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Taylor, K. D. A1 - Thuesen, B. A1 - njes, A. A1 - Uitterlinden, A. G. A1 - Venturini, C. A1 - Walker, M. A1 - Wang, C. A. A1 - Wang, S. A1 - Wareham, N. J. A1 - Willems, S. M. A1 - Willems van Dijk, K. A1 - Wilson, J. G. A1 - Wu, Y. A1 - Yao, J. A1 - Young, K. L. A1 - Langenberg, C. A1 - Frayling, T. M. A1 - inen, T. O. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. AB - ) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels. VL - 105 ER - TY - JOUR T1 - {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology JF - Am J Hum Genet Y1 - 2019 A1 - Spracklen, C. N. A1 - Karaderi, T. A1 - Yaghootkar, H. A1 - Schurmann, C. A1 - Fine, R. S. A1 - Kutalik, Z. A1 - Preuss, M. H. A1 - Lu, Y. A1 - Wittemans, L. B. L. A1 - Adair, L. S. A1 - Allison, M. A1 - Amin, N. A1 - Auer, P. L. A1 - Bartz, T. M. A1 - her, M. A1 - Boehnke, M. A1 - Borja, J. B. A1 - Bork-Jensen, J. A1 - Broer, L. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Chirstofidou, P. A1 - Demirkan, A. A1 - van Duijn, C. M. A1 - Feitosa, M. F. A1 - Garcia, M. E. A1 - Graff, M. A1 - Grallert, H. A1 - Grarup, N. A1 - Guo, X. A1 - Haesser, J. A1 - Hansen, T. A1 - Harris, T. B. A1 - Highland, H. M. A1 - Hong, J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jackson, R. A1 - Jousilahti, P. A1 - nen, M. A1 - Kizer, J. R. A1 - Kovacs, P. A1 - Kriebel, J. A1 - Laakso, M. A1 - Lange, L. A. A1 - ki, T. A1 - Li, J. A1 - Li-Gao, R. A1 - Lind, L. A1 - Luan, J. A1 - inen, L. P. A1 - MacGregor, S. A1 - Mackey, D. A. A1 - Mahajan, A. A1 - Mangino, M. A1 - ö, S. A1 - McCarthy, M. I. A1 - McKnight, B. A1 - Medina-Gomez, C. A1 - Meigs, J. B. A1 - Molnos, S. A1 - Mook-Kanamori, D. A1 - Morris, A. P. A1 - de Mutsert, R. A1 - Nalls, M. A. A1 - Nedeljkovic, I. A1 - North, K. E. A1 - Pennell, C. E. A1 - Pradhan, A. D. A1 - Province, M. A. A1 - Raitakari, O. T. A1 - Raulerson, C. K. A1 - Reiner, A. P. A1 - Ridker, P. M. A1 - Ripatti, S. A1 - Roberston, N. A1 - Rotter, J. I. A1 - Salomaa, V. A1 - rate, A. A. A1 - Sitlani, C. M. A1 - Spector, T. D. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Taylor, K. D. A1 - Thuesen, B. A1 - njes, A. A1 - Uitterlinden, A. G. A1 - Venturini, C. A1 - Walker, M. A1 - Wang, C. A. A1 - Wang, S. A1 - Wareham, N. J. A1 - Willems, S. M. A1 - Willems van Dijk, K. A1 - Wilson, J. G. A1 - Wu, Y. A1 - Yao, J. A1 - Young, K. L. A1 - Langenberg, C. A1 - Frayling, T. M. A1 - inen, T. O. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. VL - 105 ER - TY - JOUR T1 - Genetic architecture of subcortical brain structures in 38,851 individuals. JF - Nat Genet Y1 - 2019 A1 - Satizabal, Claudia L A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - White, Charles C A1 - Knol, Maria J A1 - Stein, Jason L A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Jahanshad, Neda A1 - Roshchupkin, Gennady V A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Luciano, Michelle A1 - Hofer, Edith A1 - Teumer, Alexander A1 - van der Lee, Sven J A1 - Yang, Jingyun A1 - Yanek, Lisa R A1 - Lee, Tom V A1 - Li, Shuo A1 - Hu, Yanhui A1 - Koh, Jia Yu A1 - Eicher, John D A1 - Desrivières, Sylvane A1 - Arias-Vasquez, Alejandro A1 - Chauhan, Ganesh A1 - Athanasiu, Lavinia A1 - Rentería, Miguel E A1 - Kim, Sungeun A1 - Hoehn, David A1 - Armstrong, Nicola J A1 - Chen, Qiang A1 - Holmes, Avram J A1 - den Braber, Anouk A1 - Kloszewska, Iwona A1 - Andersson, Micael A1 - Espeseth, Thomas A1 - Grimm, Oliver A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Milaneschi, Yuri A1 - Papmeyer, Martina A1 - Axelsson, Tomas A1 - Ehrlich, Stefan A1 - Roiz-Santiañez, Roberto A1 - Kraemer, Bernd A1 - Håberg, Asta K A1 - Jones, Hannah J A1 - Pike, G Bruce A1 - Stein, Dan J A1 - Stevens, Allison A1 - Bralten, Janita A1 - Vernooij, Meike W A1 - Harris, Tamara B A1 - Filippi, Irina A1 - Witte, A Veronica A1 - Guadalupe, Tulio A1 - Wittfeld, Katharina A1 - Mosley, Thomas H A1 - Becker, James T A1 - Doan, Nhat Trung A1 - Hagenaars, Saskia P A1 - Saba, Yasaman A1 - Cuellar-Partida, Gabriel A1 - Amin, Najaf A1 - Hilal, Saima A1 - Nho, Kwangsik A1 - Mirza-Schreiber, Nazanin A1 - Arfanakis, Konstantinos A1 - Becker, Diane M A1 - Ames, David A1 - Goldman, Aaron L A1 - Lee, Phil H A1 - Boomsma, Dorret I A1 - Lovestone, Simon A1 - Giddaluru, Sudheer A1 - Le Hellard, Stephanie A1 - Mattheisen, Manuel A1 - Bohlken, Marc M A1 - Kasperaviciute, Dalia A1 - Schmaal, Lianne A1 - Lawrie, Stephen M A1 - Agartz, Ingrid A1 - Walton, Esther A1 - Tordesillas-Gutierrez, Diana A1 - Davies, Gareth E A1 - Shin, Jean A1 - Ipser, Jonathan C A1 - Vinke, Louis N A1 - Hoogman, Martine A1 - Jia, Tianye A1 - Burkhardt, Ralph A1 - Klein, Marieke A1 - Crivello, Fabrice A1 - Janowitz, Deborah A1 - Carmichael, Owen A1 - Haukvik, Unn K A1 - Aribisala, Benjamin S A1 - Schmidt, Helena A1 - Strike, Lachlan T A1 - Cheng, Ching-Yu A1 - Risacher, Shannon L A1 - Pütz, Benno A1 - Fleischman, Debra A A1 - Assareh, Amelia A A1 - Mattay, Venkata S A1 - Buckner, Randy L A1 - Mecocci, Patrizia A1 - Dale, Anders M A1 - Cichon, Sven A1 - Boks, Marco P A1 - Matarin, Mar A1 - Penninx, Brenda W J H A1 - Calhoun, Vince D A1 - Chakravarty, M Mallar A1 - Marquand, Andre F A1 - Macare, Christine A1 - Kharabian Masouleh, Shahrzad A1 - Oosterlaan, Jaap A1 - Amouyel, Philippe A1 - Hegenscheid, Katrin A1 - Rotter, Jerome I A1 - Schork, Andrew J A1 - Liewald, David C M A1 - de Zubicaray, Greig I A1 - Wong, Tien Yin A1 - Shen, Li A1 - Sämann, Philipp G A1 - Brodaty, Henry A1 - Roffman, Joshua L A1 - de Geus, Eco J C A1 - Tsolaki, Magda A1 - Erk, Susanne A1 - van Eijk, Kristel R A1 - Cavalleri, Gianpiero L A1 - van der Wee, Nic J A A1 - McIntosh, Andrew M A1 - Gollub, Randy L A1 - Bulayeva, Kazima B A1 - Bernard, Manon A1 - Richards, Jennifer S A1 - Himali, Jayandra J A1 - Loeffler, Markus A1 - Rommelse, Nanda A1 - Hoffmann, Wolfgang A1 - Westlye, Lars T A1 - Valdés Hernández, Maria C A1 - Hansell, Narelle K A1 - van Erp, Theo G M A1 - Wolf, Christiane A1 - Kwok, John B J A1 - Vellas, Bruno A1 - Heinz, Andreas A1 - Olde Loohuis, Loes M A1 - Delanty, Norman A1 - Ho, Beng-Choon A1 - Ching, Christopher R K A1 - Shumskaya, Elena A1 - Singh, Baljeet A1 - Hofman, Albert A1 - van der Meer, Dennis A1 - Homuth, Georg A1 - Psaty, Bruce M A1 - Bastin, Mark E A1 - Montgomery, Grant W A1 - Foroud, Tatiana M A1 - Reppermund, Simone A1 - Hottenga, Jouke-Jan A1 - Simmons, Andrew A1 - Meyer-Lindenberg, Andreas A1 - Cahn, Wiepke A1 - Whelan, Christopher D A1 - van Donkelaar, Marjolein M J A1 - Yang, Qiong A1 - Hosten, Norbert A1 - Green, Robert C A1 - Thalamuthu, Anbupalam A1 - Mohnke, Sebastian A1 - Hulshoff Pol, Hilleke E A1 - Lin, Honghuang A1 - Jack, Clifford R A1 - Schofield, Peter R A1 - Mühleisen, Thomas W A1 - Maillard, Pauline A1 - Potkin, Steven G A1 - Wen, Wei A1 - Fletcher, Evan A1 - Toga, Arthur W A1 - Gruber, Oliver A1 - Huentelman, Matthew A1 - Davey Smith, George A1 - Launer, Lenore J A1 - Nyberg, Lars A1 - Jönsson, Erik G A1 - Crespo-Facorro, Benedicto A1 - Koen, Nastassja A1 - Greve, Douglas N A1 - Uitterlinden, André G A1 - Weinberger, Daniel R A1 - Steen, Vidar M A1 - Fedko, Iryna O A1 - Groenewold, Nynke A A1 - Niessen, Wiro J A1 - Toro, Roberto A1 - Tzourio, Christophe A1 - Longstreth, William T A1 - Ikram, M Kamran A1 - Smoller, Jordan W A1 - van Tol, Marie-Jose A1 - Sussmann, Jessika E A1 - Paus, Tomáš A1 - Lemaître, Hervé A1 - Schroeter, Matthias L A1 - Mazoyer, Bernard A1 - Andreassen, Ole A A1 - Holsboer, Florian A1 - Depondt, Chantal A1 - Veltman, Dick J A1 - Turner, Jessica A A1 - Pausova, Zdenka A1 - Schumann, Gunter A1 - van Rooij, Daan A1 - Djurovic, Srdjan A1 - Deary, Ian J A1 - McMahon, Katie L A1 - Müller-Myhsok, Bertram A1 - Brouwer, Rachel M A1 - Soininen, Hilkka A1 - Pandolfo, Massimo A1 - Wassink, Thomas H A1 - Cheung, Joshua W A1 - Wolfers, Thomas A1 - Martinot, Jean-Luc A1 - Zwiers, Marcel P A1 - Nauck, Matthias A1 - Melle, Ingrid A1 - Martin, Nicholas G A1 - Kanai, Ryota A1 - Westman, Eric A1 - Kahn, René S A1 - Sisodiya, Sanjay M A1 - White, Tonya A1 - Saremi, Arvin A1 - van Bokhoven, Hans A1 - Brunner, Han G A1 - Völzke, Henry A1 - Wright, Margaret J A1 - van 't Ent, Dennis A1 - Nöthen, Markus M A1 - Ophoff, Roel A A1 - Buitelaar, Jan K A1 - Fernández, Guillén A1 - Sachdev, Perminder S A1 - Rietschel, Marcella A1 - van Haren, Neeltje E M A1 - Fisher, Simon E A1 - Beiser, Alexa S A1 - Francks, Clyde A1 - Saykin, Andrew J A1 - Mather, Karen A A1 - Romanczuk-Seiferth, Nina A1 - Hartman, Catharina A A1 - DeStefano, Anita L A1 - Heslenfeld, Dirk J A1 - Weiner, Michael W A1 - Walter, Henrik A1 - Hoekstra, Pieter J A1 - Nyquist, Paul A A1 - Franke, Barbara A1 - Bennett, David A A1 - Grabe, Hans J A1 - Johnson, Andrew D A1 - Chen, Christopher A1 - van Duijn, Cornelia M A1 - Lopez, Oscar L A1 - Fornage, Myriam A1 - Wardlaw, Joanna M A1 - Schmidt, Reinhold A1 - DeCarli, Charles A1 - De Jager, Philip L A1 - Villringer, Arno A1 - Debette, Stephanie A1 - Gudnason, Vilmundur A1 - Medland, Sarah E A1 - Shulman, Joshua M A1 - Thompson, Paul M A1 - Seshadri, Sudha A1 - Ikram, M Arfan AB -

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

VL - 51 IS - 11 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

VL - 51 IS - 3 ER - TY - JOUR T1 - {Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria JF - Nat Commun Y1 - 2019 A1 - Teumer, A. A1 - Li, Y. A1 - Ghasemi, S. A1 - Prins, B. P. A1 - Wuttke, M. A1 - Hermle, T. A1 - Giri, A. A1 - Sieber, K. B. A1 - Qiu, C. A1 - Kirsten, H. A1 - Tin, A. A1 - Chu, A. Y. A1 - Bansal, N. A1 - Feitosa, M. F. A1 - Wang, L. A1 - Chai, J. F. A1 - Cocca, M. A1 - Fuchsberger, C. A1 - Gorski, M. A1 - Hoppmann, A. A1 - Horn, K. A1 - Li, M. A1 - Marten, J. A1 - Noce, D. A1 - Nutile, T. A1 - Sedaghat, S. A1 - Sveinbjornsson, G. A1 - Tayo, B. O. A1 - van der Most, P. J. A1 - Xu, Y. A1 - Yu, Z. A1 - Gerstner, L. A1 - ?rnl?v, J. A1 - Bakker, S. J. L. A1 - Baptista, D. A1 - Biggs, M. L. A1 - Boerwinkle, E. A1 - Brenner, H. A1 - Burkhardt, R. A1 - Carroll, R. J. A1 - Chee, M. L. A1 - Chee, M. L. A1 - Chen, M. A1 - Cheng, C. Y. A1 - Cook, J. P. A1 - Coresh, J. A1 - Corre, T. A1 - Danesh, J. A1 - de Borst, M. H. A1 - De Grandi, A. A1 - de Mutsert, R. A1 - de Vries, A. P. J. A1 - Degenhardt, F. A1 - Dittrich, K. A1 - Divers, J. A1 - Eckardt, K. U. A1 - Ehret, G. A1 - Endlich, K. A1 - Felix, J. F. A1 - Franco, O. H. A1 - Franke, A. A1 - Freedman, B. I. A1 - Freitag-Wolf, S. A1 - Gansevoort, R. T. A1 - Giedraitis, V. A1 - G?gele, M. A1 - Grundner-Culemann, F. A1 - Gudbjartsson, D. F. A1 - Gudnason, V. A1 - Hamet, P. A1 - Harris, T. B. A1 - Hicks, A. A. A1 - Holm, H. A1 - Foo, V. H. X. A1 - Hwang, S. J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jaddoe, V. W. V. A1 - Jakobsdottir, J. A1 - Josyula, N. S. A1 - Jung, B. A1 - K?h?nen, M. A1 - Khor, C. C. A1 - Kiess, W. A1 - Koenig, W. A1 - K?rner, A. A1 - Kovacs, P. A1 - Kramer, H. A1 - Kr?mer, B. K. A1 - Kronenberg, F. A1 - Lange, L. A. A1 - Langefeld, C. D. A1 - Lee, J. J. A1 - Lehtim?ki, T. A1 - Lieb, W. A1 - Lim, S. C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - Liu, J. A1 - Loeffler, M. A1 - Lyytik?inen, L. P. A1 - Mahajan, A. A1 - Maranville, J. C. A1 - Mascalzoni, D. A1 - McMullen, B. A1 - Meisinger, C. A1 - Meitinger, T. A1 - Miliku, K. A1 - Mook-Kanamori, D. O. A1 - M?ller-Nurasyid, M. A1 - Mychaleckyj, J. C. A1 - Nauck, M. A1 - Nikus, K. A1 - Ning, B. A1 - Noordam, R. A1 - Connell, J. O. A1 - Olafsson, I. A1 - Palmer, N. D. A1 - Peters, A. A1 - Podgornaia, A. I. A1 - Ponte, B. A1 - Poulain, T. A1 - Pramstaller, P. P. A1 - Rabelink, T. J. A1 - Raffield, L. M. A1 - Reilly, D. F. A1 - Rettig, R. A1 - Rheinberger, M. A1 - Rice, K. M. A1 - Rivadeneira, F. A1 - Runz, H. A1 - Ryan, K. A. A1 - Sabanayagam, C. A1 - Saum, K. U. A1 - Sch?ttker, B. A1 - Shaffer, C. M. A1 - Shi, Y. A1 - Smith, A. V. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Sun, B. B. A1 - Szymczak, S. A1 - Tai, E. S. A1 - Tan, N. Y. Q. A1 - Taylor, K. D. A1 - Teren, A. A1 - Tham, Y. C. A1 - Thiery, J. A1 - Thio, C. H. L. A1 - Thomsen, H. A1 - Thorsteinsdottir, U. A1 - T?njes, A. A1 - Tremblay, J. A1 - Uitterlinden, A. G. A1 - van der Harst, P. A1 - Verweij, N. A1 - Vogelezang, S. A1 - V?lker, U. A1 - Waldenberger, M. A1 - Wang, C. A1 - Wilson, O. D. A1 - Wong, C. A1 - Wong, T. Y. A1 - Yang, Q. A1 - Yasuda, M. A1 - Akilesh, S. A1 - Bochud, M. A1 - B?ger, C. A. A1 - Devuyst, O. A1 - Edwards, T. L. A1 - Ho, K. A1 - Morris, A. P. A1 - Parsa, A. A1 - Pendergrass, S. A. A1 - Psaty, B. M. A1 - Rotter, J. I. A1 - Stefansson, K. A1 - Wilson, J. G. A1 - Susztak, K. A1 - Snieder, H. A1 - Heid, I. M. A1 - Scholz, M. A1 - Butterworth, A. S. A1 - Hung, A. M. A1 - Pattaro, C. A1 - K?ttgen, A. AB - Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. VL - 10 ER - TY - JOUR T1 - {A genome-wide association study identifies genetic loci associated with specific lobar brain volumes JF - Commun Biol Y1 - 2019 A1 - van der Lee, S. J. A1 - Knol, M. J. A1 - Chauhan, G. A1 - Satizabal, C. L. A1 - Smith, A. V. A1 - Hofer, E. A1 - Bis, J. C. A1 - Hibar, D. P. A1 - Hilal, S. A1 - van den Akker, E. B. A1 - Arfanakis, K. A1 - Bernard, M. A1 - Yanek, L. R. A1 - Amin, N. A1 - Crivello, F. A1 - Cheung, J. W. A1 - Harris, T. B. A1 - Saba, Y. A1 - Lopez, O. L. A1 - Li, S. A1 - van der Grond, J. A1 - Yu, L. A1 - Paus, T. A1 - Roshchupkin, G. V. A1 - Amouyel, P. A1 - Jahanshad, N. A1 - Taylor, K. D. A1 - Yang, Q. A1 - Mathias, R. A. A1 - Boehringer, S. A1 - Mazoyer, B. A1 - Rice, K. A1 - Cheng, C. Y. A1 - Maillard, P. A1 - van Heemst, D. A1 - Wong, T. Y. A1 - Niessen, W. J. A1 - Beiser, A. S. A1 - Beekman, M. A1 - Zhao, W. A1 - Nyquist, P. A. A1 - Chen, C. A1 - Launer, L. J. A1 - Psaty, B. M. A1 - Ikram, M. K. A1 - Vernooij, M. W. A1 - Schmidt, H. A1 - Pausova, Z. A1 - Becker, D. M. A1 - De Jager, P. L. A1 - Thompson, P. M. A1 - van Duijn, C. M. A1 - Bennett, D. A. A1 - Slagboom, P. E. A1 - Schmidt, R. A1 - Longstreth, W. T. A1 - Ikram, M. A. A1 - Seshadri, S. A1 - Debette, S. A1 - Gudnason, V. A1 - Adams, H. H. H. A1 - DeCarli, C. AB - Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes. VL - 2 ER - TY - JOUR T1 - {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group JF - Am J Hypertens Y1 - 2019 A1 - Irvin, M. R. A1 - Sitlani, C. M. A1 - Floyd, J. S. A1 - Psaty, B. M. A1 - Bis, J. C. A1 - Wiggins, K. L. A1 - Whitsel, E. A. A1 - Sturmer, T. A1 - Stewart, J. A1 - Raffield, L. A1 - Sun, F. A1 - Liu, C. T. A1 - Xu, H. A1 - Cupples, A. L. A1 - Tanner, R. M. A1 - Rossing, P. A1 - Smith, A. A1 - Zilh?o, N. R. A1 - Launer, L. J. A1 - Noordam, R. A1 - Rotter, J. I. A1 - Yao, J. A1 - Li, X. A1 - Guo, X. A1 - Limdi, N. A1 - Sundaresan, A. A1 - Lange, L. A1 - Correa, A. A1 - Stott, D. J. A1 - Ford, I. A1 - Jukema, J. W. A1 - Gudnason, V. A1 - Mook-Kanamori, D. O. A1 - Trompet, S. A1 - Palmas, W. A1 - Warren, H. R. A1 - Hellwege, J. N. A1 - Giri, A. A1 - O'Donnell, C. A1 - Hung, A. M. A1 - Edwards, T. L. A1 - Ahluwalia, T. S. A1 - Arnett, D. K. A1 - Avery, C. L. AB - {Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.\ We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931 VL - 32 ER - TY - JOUR T1 - Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. JF - Am J Hypertens Y1 - 2019 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Stewart, James A1 - Raffield, Laura A1 - Sun, Fangui A1 - Liu, Ching-Ti A1 - Xu, Hanfei A1 - Cupples, Adrienne L A1 - Tanner, Rikki M A1 - Rossing, Peter A1 - Smith, Albert A1 - Zilhão, Nuno R A1 - Launer, Lenore J A1 - Noordam, Raymond A1 - Rotter, Jerome I A1 - Yao, Jie A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Limdi, Nita A1 - Sundaresan, Aishwarya A1 - Lange, Leslie A1 - Correa, Adolfo A1 - Stott, David J A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Gudnason, Vilmundur A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Palmas, Walter A1 - Warren, Helen R A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - O'donnell, Christopher A1 - Hung, Adriana M A1 - Edwards, Todd L A1 - Ahluwalia, Tarunveer S A1 - Arnett, Donna K A1 - Avery, Christy L KW - Aged KW - Antihypertensive Agents KW - Black or African American KW - Blood Pressure KW - Case-Control Studies KW - DNA (Cytosine-5-)-Methyltransferases KW - DNA Methyltransferase 3A KW - DNA-Binding Proteins KW - Drug Resistance KW - Dystrophin-Associated Proteins KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myosin Heavy Chains KW - Myosin Type V KW - Neuropeptides KW - Pharmacogenetics KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Risk Factors KW - Transcription Factors KW - United States KW - White People AB -

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

VL - 32 IS - 12 ER - TY - JOUR T1 - {Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels JF - Circulation Y1 - 2019 A1 - Sabater-Lleal, M. A1 - Huffman, J. E. A1 - de Vries, P. S. A1 - Marten, J. A1 - Mastrangelo, M. A. A1 - Song, C. A1 - Pankratz, N. A1 - Ward-Caviness, C. K. A1 - Yanek, L. R. A1 - Trompet, S. A1 - Delgado, G. E. A1 - Guo, X. A1 - Bartz, T. M. A1 - Martinez-Perez, A. A1 - Germain, M. A1 - de Haan, H. G. A1 - Ozel, A. B. A1 - Polasek, O. A1 - Smith, A. V. A1 - Eicher, J. D. A1 - Reiner, A. P. A1 - Tang, W. A1 - Davies, N. M. A1 - Stott, D. J. A1 - Rotter, J. I. A1 - Tofler, G. H. A1 - Boerwinkle, E. A1 - de Maat, M. P. M. A1 - Kleber, M. E. A1 - Welsh, P. A1 - Brody, J. A. A1 - Chen, M. H. A1 - Vaidya, D. A1 - Soria, J. M. A1 - Suchon, P. A1 - van Hylckama Vlieg, A. A1 - Desch, K. C. A1 - Kolcic, I. A1 - Joshi, P. K. A1 - Launer, L. J. A1 - Harris, T. B. A1 - Campbell, H. A1 - Rudan, I. A1 - Becker, D. M. A1 - Li, J. Z. A1 - Rivadeneira, F. A1 - Uitterlinden, A. G. A1 - Hofman, A. A1 - Franco, O. H. A1 - Cushman, M. A1 - Psaty, B. M. A1 - Morange, P. E. A1 - McKnight, B. A1 - Chong, M. R. A1 - Fernandez-Cadenas, I. A1 - Rosand, J. A1 - Lindgren, A. A1 - Gudnason, V. A1 - Wilson, J. F. A1 - Hayward, C. A1 - Ginsburg, D. A1 - Fornage, M. A1 - Rosendaal, F. R. A1 - Souto, J. C. A1 - Becker, L. C. A1 - Jenny, N. S. A1 - M?rz, W. A1 - Jukema, J. W. A1 - Dehghan, A. A1 - Tr?gou?t, D. A. A1 - Morrison, A. C. A1 - Johnson, A. D. A1 - O'Donnell, C. J. A1 - Strachan, D. P. A1 - Lowenstein, C. J. A1 - Smith, N. L. AB - Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.\ We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.\ We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.\ The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events. VL - 139 ER - TY - JOUR T1 - Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. JF - Elife Y1 - 2019 A1 - Timmers, Paul Rhj A1 - Mounier, Ninon A1 - Läll, Kristi A1 - Fischer, Krista A1 - Ning, Zheng A1 - Feng, Xiao A1 - Bretherick, Andrew D A1 - Clark, David W A1 - Agbessi, M A1 - Ahsan, H A1 - Alves, I A1 - Andiappan, A A1 - Awadalla, P A1 - Battle, A A1 - Bonder, M J A1 - Boomsma, D A1 - Christiansen, M A1 - Claringbould, A A1 - Deelen, P A1 - van Dongen, J A1 - Esko, T A1 - Favé, M A1 - Franke, L A1 - Frayling, T A1 - Gharib, S A A1 - Gibson, G A1 - Hemani, G A1 - Jansen, R A1 - Kalnapenkis, A A1 - Kasela, S A1 - Kettunen, J A1 - Kim, Y A1 - Kirsten, H A1 - Kovacs, P A1 - Krohn, K A1 - Kronberg-Guzman, J A1 - Kukushkina, V A1 - Kutalik, Z A1 - Kähönen, M A1 - Lee, B A1 - Lehtimäki, T A1 - Loeffler, M A1 - Marigorta, U A1 - Metspalu, A A1 - van Meurs, J A1 - Milani, L A1 - Müller-Nurasyid, M A1 - Nauck, M A1 - Nivard, M A1 - Penninx, B A1 - Perola, M A1 - Pervjakova, N A1 - Pierce, B A1 - Powell, J A1 - Prokisch, H A1 - Psaty, B M A1 - Raitakari, O A1 - Ring, S A1 - Ripatti, S A1 - Rotzschke, O A1 - Ruëger, S A1 - Saha, A A1 - Scholz, M A1 - Schramm, K A1 - Seppälä, I A1 - Stumvoll, M A1 - Sullivan, P A1 - Teumer, A A1 - Thiery, J A1 - Tong, L A1 - Tönjes, A A1 - Verlouw, J A1 - Visscher, P M A1 - Võsa, U A1 - Völker, U A1 - Yaghootkar, H A1 - Yang, J A1 - Zeng, B A1 - Zhang, F A1 - Agbessi, M A1 - Ahsan, H A1 - Alves, I A1 - Andiappan, A A1 - Awadalla, P A1 - Battle, A A1 - Bonder, M J A1 - Boomsma, D A1 - Christiansen, M A1 - Claringbould, A A1 - Deelen, P A1 - van Dongen, J A1 - Esko, T A1 - Favé, M A1 - Franke, L A1 - Frayling, T A1 - Gharib, S A A1 - Gibson, G A1 - Hemani, G A1 - Jansen, R A1 - Kalnapenkis, A A1 - Kasela, S A1 - Kettunen, J A1 - Kim, Y A1 - Kirsten, H A1 - Kovacs, P A1 - Krohn, K A1 - Kronberg-Guzman, J A1 - Kukushkina, V A1 - Kutalik, Z A1 - Kähönen, M A1 - Lee, B A1 - Lehtimäki, T A1 - Loeffler, M A1 - Marigorta, U A1 - Metspalu, A A1 - van Meurs, J A1 - Milani, L A1 - Müller-Nurasyid, M A1 - Nauck, M A1 - Nivard, M A1 - Penninx, B A1 - Perola, M A1 - Pervjakova, N A1 - Pierce, B A1 - Powell, J A1 - Prokisch, H A1 - Psaty, B M A1 - Raitakari, O A1 - Ring, S A1 - Ripatti, S A1 - Rotzschke, O A1 - Ruëger, S A1 - Saha, A A1 - Scholz, M A1 - Schramm, K A1 - Seppälä, I A1 - Stumvoll, M A1 - Sullivan, P A1 - Teumer, A A1 - Thiery, J A1 - Tong, L A1 - Tönjes, A A1 - Verlouw, J A1 - Visscher, P M A1 - Võsa, U A1 - Völker, U A1 - Yaghootkar, H A1 - Yang, J A1 - Zeng, B A1 - Zhang, F A1 - Shen, Xia A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F A1 - Joshi, Peter K AB -

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

VL - 8 ER - TY - JOUR T1 - {The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE) JF - PLoS One Y1 - 2019 A1 - Wolters, F. J. A1 - Yang, Q. A1 - Biggs, M. L. A1 - Jakobsdottir, J. A1 - Li, S. A1 - Evans, D. S. A1 - Bis, J. C. A1 - Harris, T. B. A1 - Vasan, R. S. A1 - Zilhao, N. R. A1 - Ghanbari, M. A1 - Ikram, M. A. A1 - Launer, L. A1 - Psaty, B. M. A1 - Tranah, G. J. A1 - Kulminski, A. M. A1 - Gudnason, V. A1 - Seshadri, S. AB - Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive.\ We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population.\ During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90-1.01), but attenuated for APOE-ε4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1-16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities.\ Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease. VL - 14 ER - TY - JOUR T1 - Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. JF - PLoS One Y1 - 2019 A1 - Ward-Caviness, Cavin K A1 - de Vries, Paul S A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Giulianini, Franco A1 - Guo, Xiuqing A1 - Kleber, Marcus E A1 - Kacprowski, Tim A1 - Groß, Stefan A1 - Petersman, Astrid A1 - Davey Smith, George A1 - Hartwig, Fernando P A1 - Bowden, Jack A1 - Hemani, Gibran A1 - Müller-Nuraysid, Martina A1 - Strauch, Konstantin A1 - Koenig, Wolfgang A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Pankratz, Nathan A1 - Boerwinkle, Eric A1 - Tang, Weihong A1 - Fu, Yi-Ping A1 - Johnson, Andrew D A1 - Song, Ci A1 - de Maat, Moniek P M A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Brody, Jennifer A A1 - McKnight, Barbara A1 - Chen, Yii-Der Ida A1 - Psaty, Bruce M A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Peyser, Patricia A A1 - Smith, Jennifer A A1 - Bielinski, Suzette J A1 - Ridker, Paul M A1 - Taylor, Kent D A1 - Yao, Jie A1 - Tracy, Russell A1 - Delgado, Graciela A1 - Trompet, Stella A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - März, Winfried A1 - Dörr, Marcus A1 - Chasman, Daniel I A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Morrison, Alanna C AB -

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

VL - 14 IS - 5 ER - TY - JOUR T1 - {A meta-analysis of genome-wide association studies identifies multiple longevity genes JF - Nat Commun Y1 - 2019 A1 - Deelen, J. A1 - Evans, D. S. A1 - Arking, D. E. A1 - Tesi, N. A1 - Nygaard, M. A1 - Liu, X. A1 - Wojczynski, M. K. A1 - Biggs, M. L. A1 - van der Spek, A. A1 - Atzmon, G. A1 - Ware, E. B. A1 - Sarnowski, C. A1 - Smith, A. V. A1 - Sepp?l?, I. A1 - Cordell, H. J. A1 - Dose, J. A1 - Amin, N. A1 - Arnold, A. M. A1 - Ayers, K. L. A1 - Barzilai, N. A1 - Becker, E. J. A1 - Beekman, M. A1 - Blanch?, H. A1 - Christensen, K. A1 - Christiansen, L. A1 - Collerton, J. C. A1 - Cubaynes, S. A1 - Cummings, S. R. A1 - Davies, K. A1 - Debrabant, B. A1 - Deleuze, J. F. A1 - Duncan, R. A1 - Faul, J. D. A1 - Franceschi, C. A1 - Galan, P. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Huisman, M. A1 - Hurme, M. A. A1 - Jagger, C. A1 - Jansen, I. A1 - Jylh?, M. A1 - K?h?nen, M. A1 - Karasik, D. A1 - Kardia, S. L. R. A1 - Kingston, A. A1 - Kirkwood, T. B. L. A1 - Launer, L. J. A1 - Lehtim?ki, T. A1 - Lieb, W. A1 - Lyytik?inen, L. P. A1 - Martin-Ruiz, C. A1 - Min, J. A1 - Nebel, A. A1 - Newman, A. B. A1 - Nie, C. A1 - Nohr, E. A. A1 - Orwoll, E. S. A1 - Perls, T. T. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Reinders, M. J. T. A1 - Robine, J. M. A1 - Rotter, J. I. A1 - Sebastiani, P. A1 - Smith, J. A1 - S?rensen, T. I. A. A1 - Taylor, K. D. A1 - Uitterlinden, A. G. A1 - van der Flier, W. A1 - van der Lee, S. J. A1 - van Duijn, C. M. A1 - van Heemst, D. A1 - Vaupel, J. W. A1 - Weir, D. A1 - Ye, K. A1 - Zeng, Y. A1 - Zheng, W. A1 - Holstege, H. A1 - Kiel, D. P. A1 - Lunetta, K. L. A1 - Slagboom, P. E. A1 - Murabito, J. M. AB - Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity. VL - 10 ER - TY - JOUR T1 - {A meta-analysis of genome-wide association studies identifies multiple longevity genes JF - Nat Commun Y1 - 2019 A1 - Deelen, J. A1 - Evans, D. S. A1 - Arking, D. E. A1 - Tesi, N. A1 - Nygaard, M. A1 - Liu, X. A1 - Wojczynski, M. K. A1 - Biggs, M. L. A1 - van der Spek, A. A1 - Atzmon, G. A1 - Ware, E. B. A1 - Sarnowski, C. A1 - Smith, A. V. A1 - ä, I. A1 - Cordell, H. J. A1 - Dose, J. A1 - Amin, N. A1 - Arnold, A. M. A1 - Ayers, K. L. A1 - Barzilai, N. A1 - Becker, E. J. A1 - Beekman, M. A1 - é, H. A1 - Christensen, K. A1 - Christiansen, L. A1 - Collerton, J. C. A1 - Cubaynes, S. A1 - Cummings, S. R. A1 - Davies, K. A1 - Debrabant, B. A1 - Deleuze, J. F. A1 - Duncan, R. A1 - Faul, J. D. A1 - Franceschi, C. A1 - Galan, P. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Huisman, M. A1 - Hurme, M. A. A1 - Jagger, C. A1 - Jansen, I. A1 - ä, M. A1 - nen, M. A1 - Karasik, D. A1 - Kardia, S. L. R. A1 - Kingston, A. A1 - Kirkwood, T. B. L. A1 - Launer, L. J. A1 - ki, T. A1 - Lieb, W. A1 - inen, L. P. A1 - Martin-Ruiz, C. A1 - Min, J. A1 - Nebel, A. A1 - Newman, A. B. A1 - Nie, C. A1 - Nohr, E. A. A1 - Orwoll, E. S. A1 - Perls, T. T. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Reinders, M. J. T. A1 - Robine, J. M. A1 - Rotter, J. I. A1 - Sebastiani, P. A1 - Smith, J. A1 - rensen, T. I. A. A1 - Taylor, K. D. A1 - Uitterlinden, A. G. A1 - van der Flier, W. A1 - van der Lee, S. J. A1 - van Duijn, C. M. A1 - van Heemst, D. A1 - Vaupel, J. W. A1 - Weir, D. A1 - Ye, K. A1 - Zeng, Y. A1 - Zheng, W. A1 - Holstege, H. A1 - Kiel, D. P. A1 - Lunetta, K. L. A1 - Slagboom, P. E. A1 - Murabito, J. M. AB - 2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity. VL - 10 ER - TY - JOUR T1 - {Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry JF - J Bone Miner Res Y1 - 2019 A1 - Hsu, Y. H. A1 - Estrada, K. A1 - Evangelou, E. A1 - Ackert-Bicknell, C. A1 - Akesson, K. A1 - Beck, T. A1 - Brown, S. J. A1 - Capellini, T. A1 - Carbone, L. A1 - Cauley, J. A1 - Cheung, C. L. A1 - Cummings, S. R. A1 - Czerwinski, S. A1 - Demissie, S. A1 - Econs, M. A1 - Evans, D. A1 - Farber, C. A1 - Gautvik, K. A1 - Harris, T. A1 - Kammerer, C. A1 - Kemp, J. A1 - Koller, D. L. A1 - Kung, A. A1 - Lawlor, D. A1 - Lee, M. A1 - Lorentzon, M. A1 - McGuigan, F. A1 - Medina-Gomez, C. A1 - Mitchell, B. A1 - Newman, A. A1 - Nielson, C. A1 - Ohlsson, C. A1 - Peacock, M. A1 - Reppe, S. A1 - Richards, J. B. A1 - Robbins, J. A1 - Sigurdsson, G. A1 - Spector, T. D. A1 - Stefansson, K. A1 - Streeten, E. A1 - Styrkarsdottir, U. A1 - Tobias, J. A1 - Trajanoska, K. A1 - Uitterlinden, A. A1 - Vandenput, L. A1 - Wilson, S. G. A1 - Yerges-Armstrong, L. A1 - Young, M. A1 - Zillikens, M. C. A1 - Rivadeneira, F. A1 - Kiel, D. P. A1 - Karasik, D. AB - Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research. VL - 34 ER - TY - JOUR T1 - Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. JF - Am J Epidemiol Y1 - 2019 A1 - de Vries, Paul S A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Kraja, Aldi T A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Deng, Xuan A1 - Dorajoo, Rajkumar A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Evangelou, Evangelos A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lee, Joseph H A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Riaz, Muhammad A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Connell, John M A1 - de Faire, Ulf A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Ding, Jingzhong A1 - Dominiczak, Anna F A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Grove, Megan L A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Steve B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lemaitre, Rozenn N A1 - Li, Yize A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Mukamal, Kenneth J A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tan, Nicholas A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Yujie A1 - Wang, Zhe A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Penninx, Brenda A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Zheng, Wei A1 - Elliott, Paul A1 - North, Kari E A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Kardia, Sharon L R A1 - Zhu, Xiaofeng A1 - Rotimi, Charles N A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Liu, Jingmin A1 - Rotter, Jerome I A1 - Gauderman, W James A1 - Province, Michael A A1 - Munroe, Patricia B A1 - Rice, Kenneth A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Morrison, Alanna C AB -

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. JF - Nat Genet Y1 - 2019 A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Brown, Michael R A1 - Winkler, Thomas W A1 - Kraja, Aldi T A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Chasman, Daniel I A1 - Lim, Elise A1 - Deng, Xuan A1 - Guo, Xiuqing A1 - Liu, Jingmin A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Baker, Jenna A1 - Chen, Guanjie A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Ding, Jingzhong A1 - Dorajoo, Rajkumar A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Zhao, Wei A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Hung, Yi-Jen A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lin, Keng-Hung A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Prins, Bram A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Tzung-Dau A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Xiang, Yong-Bing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Adeyemo, Adebowale A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Arzumanyan, Zorayr A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Cade, Brian E A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Christensen, Kaare A1 - Concas, Maria Pina A1 - Connell, John M A1 - de Las Fuentes, Lisa A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Doumatey, Ayo A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Floyd, James S A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gharib, Sina A A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Ikram, M Arfan A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Liang, Jingjing A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Louie, Tin A1 - Luzzi, Anna A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Tiemeier, Henning A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Heming A1 - Wang, Lan A1 - Wang, Lihua A1 - Wei, Wen Bin A1 - Williams, Christine A A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Young, Kristin A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhou, Jie A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Cooper, Richard S A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Juang, Jyh-Ming Jimmy A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Redline, Susan A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Jun-Sing A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zeggini, Eleftheria A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Province, Michael A A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Rotimi, Charles N A1 - Cupples, L Adrienne AB -

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

VL - 51 IS - 4 ER - TY - JOUR T1 - {A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure JF - Hum. Mol. Genet. Y1 - 2019 A1 - Sung, Y. J. A1 - de Las Fuentes, L. A1 - Winkler, T. W. A1 - Chasman, D. I. A1 - Bentley, A. R. A1 - Kraja, A. T. A1 - Ntalla, I. A1 - Warren, H. R. A1 - Guo, X. A1 - Schwander, K. A1 - Manning, A. K. A1 - Brown, M. R. A1 - Aschard, H. A1 - Feitosa, M. F. A1 - Franceschini, N. A1 - Lu, Y. A1 - Cheng, C. Y. A1 - Sim, X. A1 - Vojinovic, D. A1 - Marten, J. A1 - Musani, S. K. A1 - Kilpel?inen, T. O. A1 - Richard, M. A. A1 - Aslibekyan, S. A1 - Bartz, T. M. A1 - Dorajoo, R. A1 - Li, C. A1 - Liu, Y. A1 - Rankinen, T. A1 - Smith, A. V. A1 - Tajuddin, S. M. A1 - Tayo, B. O. A1 - Zhao, W. A1 - Zhou, Y. A1 - Matoba, N. A1 - Sofer, T. A1 - Alver, M. A1 - Amini, M. A1 - Boissel, M. A1 - Chai, J. F. A1 - Chen, X. A1 - Divers, J. A1 - Gandin, I. A1 - Gao, C. A1 - Giulianini, F. A1 - Goel, A. A1 - Harris, S. E. A1 - Hartwig, F. P. A1 - He, M. A1 - Horimoto, A. R. V. R. A1 - Hsu, F. C. A1 - Jackson, A. U. A1 - Kammerer, C. M. A1 - Kasturiratne, A. A1 - Komulainen, P. A1 - K?hnel, B. A1 - Leander, K. A1 - Lee, W. J. A1 - Lin, K. H. A1 - Luan, J. A1 - Lyytik?inen, L. P. A1 - McKenzie, C. A. A1 - Nelson, C. P. A1 - Noordam, R. A1 - Scott, R. A. A1 - Sheu, W. H. H. A1 - Stan??kov?, A. A1 - Takeuchi, F. A1 - van der Most, P. J. A1 - Varga, T. V. A1 - Waken, R. J. A1 - Wang, H. A1 - Wang, Y. A1 - Ware, E. B. A1 - Weiss, S. A1 - Wen, W. A1 - Yanek, L. R. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Afaq, S. A1 - Alfred, T. A1 - Amin, N. A1 - Arking, D. E. A1 - Aung, T. A1 - Barr, R. G. A1 - Bielak, L. F. A1 - Boerwinkle, E. A1 - Bottinger, E. P. A1 - Braund, P. S. A1 - Brody, J. A. A1 - Broeckel, U. A1 - Cade, B. A1 - Campbell, A. A1 - Canouil, M. A1 - Chakravarti, A. A1 - Cocca, M. A1 - Collins, F. S. A1 - Connell, J. M. A1 - de Mutsert, R. A1 - de Silva, H. J. A1 - D?rr, M. A1 - Duan, Q. A1 - Eaton, C. B. A1 - Ehret, G. A1 - Evangelou, E. A1 - Faul, J. D. A1 - Forouhi, N. G. A1 - Franco, O. H. A1 - Friedlander, Y. A1 - Gao, H. A1 - Gigante, B. A1 - Gu, C. C. A1 - Gupta, P. A1 - Hagenaars, S. P. A1 - Harris, T. B. A1 - He, J. A1 - Heikkinen, S. A1 - Heng, C. K. A1 - Hofman, A. A1 - Howard, B. V. A1 - Hunt, S. C. A1 - Irvin, M. R. A1 - Jia, Y. A1 - Katsuya, T. A1 - Kaufman, J. A1 - Kerrison, N. D. A1 - Khor, C. C. A1 - Koh, W. P. A1 - Koistinen, H. A. A1 - Kooperberg, C. B. A1 - Krieger, J. E. A1 - Kubo, M. A1 - Kutalik, Z. A1 - Kuusisto, J. A1 - Lakka, T. A. A1 - Langefeld, C. D. A1 - Langenberg, C. A1 - Launer, L. J. A1 - Lee, J. H. A1 - Lehne, B. A1 - Levy, D. A1 - Lewis, C. E. A1 - Li, Y. A1 - Lim, S. H. A1 - Liu, C. T. A1 - Liu, J. A1 - Liu, J. A1 - Liu, Y. A1 - Loh, M. A1 - Lohman, K. K. A1 - Louie, T. A1 - M?gi, R. A1 - Matsuda, K. A1 - Meitinger, T. A1 - Metspalu, A. A1 - Milani, L. A1 - Momozawa, Y. A1 - Mosley, T. H. A1 - Nalls, M. A. A1 - Nasri, U. A1 - O'Connell, J. R. A1 - Ogunniyi, A. A1 - Palmas, W. R. A1 - Palmer, N. D. A1 - Pankow, J. S. A1 - Pedersen, N. L. A1 - Peters, A. A1 - Peyser, P. A. A1 - Polasek, O. A1 - Porteous, D. A1 - Raitakari, O. T. A1 - Renstr?m, F. A1 - Rice, T. K. A1 - Ridker, P. M. A1 - Robino, A. A1 - Robinson, J. G. A1 - Rose, L. M. A1 - Rudan, I. A1 - Sabanayagam, C. A1 - Salako, B. L. A1 - Sandow, K. A1 - Schmidt, C. O. A1 - Schreiner, P. J. A1 - Scott, W. R. A1 - Sever, P. A1 - Sims, M. A1 - Sitlani, C. M. A1 - Smith, B. H. A1 - Smith, J. A. A1 - Snieder, H. A1 - Starr, J. M. A1 - Strauch, K. A1 - Tang, H. A1 - Taylor, K. D. A1 - Teo, Y. Y. A1 - Tham, Y. C. A1 - Uitterlinden, A. G. A1 - Waldenberger, M. A1 - Wang, L. A1 - Wang, Y. X. A1 - Wei, W. B. A1 - Wilson, G. A1 - Wojczynski, M. K. A1 - Xiang, Y. B. A1 - Yao, J. A1 - Yuan, J. M. A1 - Zonderman, A. B. A1 - Becker, D. M. A1 - Boehnke, M. A1 - Bowden, D. W. A1 - Chambers, J. C. A1 - Chen, Y. I. A1 - Weir, D. R. A1 - de Faire, U. A1 - Deary, I. J. A1 - Esko, T. A1 - Farrall, M. A1 - Forrester, T. A1 - Freedman, B. I. A1 - Froguel, P. A1 - Gasparini, P. A1 - Gieger, C. A1 - Horta, B. L. A1 - Hung, Y. J. A1 - Jonas, J. B. A1 - Kato, N. A1 - Kooner, J. S. A1 - Laakso, M. A1 - Lehtim?ki, T. A1 - Liang, K. W. A1 - Magnusson, P. K. E. A1 - Oldehinkel, A. J. A1 - Pereira, A. C. A1 - Perls, T. A1 - Rauramaa, R. A1 - Redline, S. A1 - Rettig, R. A1 - Samani, N. J. A1 - Scott, J. A1 - Shu, X. O. A1 - van der Harst, P. A1 - Wagenknecht, L. E. A1 - Wareham, N. J. A1 - Watkins, H. A1 - Wickremasinghe, A. R. A1 - Wu, T. A1 - Kamatani, Y. A1 - Laurie, C. C. A1 - Bouchard, C. A1 - Cooper, R. S. A1 - Evans, M. K. A1 - Gudnason, V. A1 - Hixson, J. A1 - Kardia, S. L. R. A1 - Kritchevsky, S. B. A1 - Psaty, B. M. A1 - van Dam, R. M. A1 - Arnett, D. K. A1 - Mook-Kanamori, D. O. A1 - Fornage, M. A1 - Fox, E. R. A1 - Hayward, C. A1 - van Duijn, C. M. A1 - Tai, E. S. A1 - Wong, T. Y. A1 - Loos, R. J. F. A1 - Reiner, A. P. A1 - Rotimi, C. N. A1 - Bierut, L. J. A1 - Zhu, X. A1 - Cupples, L. A. A1 - Province, M. A. A1 - Rotter, J. I. A1 - Franks, P. W. A1 - Rice, K. A1 - Elliott, P. A1 - Caulfield, M. J. A1 - Gauderman, W. J. A1 - Munroe, P. B. A1 - Rao, D. C. A1 - Morrison, A. C. AB - Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings. ER - TY - JOUR T1 - Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. JF - Nat Commun Y1 - 2019 A1 - Noordam, Raymond A1 - Bos, Maxime M A1 - Wang, Heming A1 - Winkler, Thomas W A1 - Bentley, Amy R A1 - Kilpeläinen, Tuomas O A1 - de Vries, Paul S A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Cade, Brian E A1 - Manning, Alisa A1 - Aschard, Hugues A1 - Brown, Michael R A1 - Chen, Han A1 - Franceschini, Nora A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - de Las Fuentes, Lisa A1 - Feitosa, Mary A1 - Horimoto, Andrea R A1 - Ilkov, Marjan A1 - Kho, Minjung A1 - Kraja, Aldi A1 - Li, Changwei A1 - Lim, Elise A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Rankinen, Tuomo A1 - Tajuddin, Salman M A1 - van der Spek, Ashley A1 - Wang, Zhe A1 - Marten, Jonathan A1 - Laville, Vincent A1 - Alver, Maris A1 - Evangelou, Evangelos A1 - Graff, Maria E A1 - He, Meian A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Marques-Vidal, Pedro A1 - Nolte, Ilja M A1 - Palmer, Nicholette D A1 - Rauramaa, Rainer A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Adolfo, Correa A1 - Ballantyne, Christie A1 - Bielak, Larry A1 - Biermasz, Nienke R A1 - Boerwinkle, Eric A1 - Dimou, Niki A1 - Eiriksdottir, Gudny A1 - Gao, Chuan A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Haba-Rubio, José A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heinzer, Raphael A1 - Hixson, James E A1 - Homuth, Georg A1 - Ikram, M Arfan A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Lee, Jiwon A1 - Liu, Jingmin A1 - Lohman, Kurt K A1 - Luik, Annemarie I A1 - Mägi, Reedik A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Nalls, Mike A A1 - O'Connell, Jeff A1 - Peters, Annette A1 - Peyser, Patricia A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rensen, Patrick C N A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Roenneberg, Till A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Shikany, James A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Sofer, Tamar A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wallance, Robert B A1 - van Dijk, Ko Willems A1 - Yu, Caizheng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Penninx, Brenda W J H A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Xiang, Yong-Bing A1 - Zheng, Wei A1 - Arnett, Donna K A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Loos, Ruth J F A1 - Pereira, Alexandre C A1 - Province, Mike A1 - Psaty, Bruce M A1 - Rotimi, Charles A1 - Zhu, Xiaofeng A1 - Amin, Najaf A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin F A1 - Guo, Xiuqing A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Kooperberg, Charles A1 - Munroe, Patricia B A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - van Heemst, Diana A1 - Redline, Susan AB -

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nat Commun Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Jakupović, Hermina A1 - Chasman, Daniel I A1 - Manning, Alisa A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Wang, Heming A1 - Wang, Zhe A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Lohman, Kurt K A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Zhao, Jing Hua A1 - Kraja, Aldi T A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Stringham, Heather M A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Cade, Brian A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Eaton, Charles B A1 - Faul, Jessica D A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jonas, Jost B A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - O'Connell, Jeff A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poveda, Alaitz A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Risch, Neil A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Starr, John M A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - van Vliet-Ostaptchouk, Jana V A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Evans, Michele K A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Liu, Yongmei A1 - North, Kari E A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Kardia, Sharon L R A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Redline, Susan A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Kooperberg, Charles B A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Rotimi, Charles N A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Loos, Ruth J F KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic Americans KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Young Adult AB -

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. JF - Diabetes Y1 - 2019 A1 - Pollack, Samuela A1 - Igo, Robert P A1 - Jensen, Richard A A1 - Christiansen, Mark A1 - Li, Xiaohui A1 - Cheng, Ching-Yu A1 - Ng, Maggie C Y A1 - Smith, Albert V A1 - Rossin, Elizabeth J A1 - Segrè, Ayellet V A1 - Davoudi, Samaneh A1 - Tan, Gavin S A1 - Chen, Yii-Der Ida A1 - Kuo, Jane Z A1 - Dimitrov, Latchezar M A1 - Stanwyck, Lynn K A1 - Meng, Weihua A1 - Hosseini, S Mohsen A1 - Imamura, Minako A1 - Nousome, Darryl A1 - Kim, Jihye A1 - Hai, Yang A1 - Jia, Yucheng A1 - Ahn, Jeeyun A1 - Leong, Aaron A1 - Shah, Kaanan A1 - Park, Kyu Hyung A1 - Guo, Xiuqing A1 - Ipp, Eli A1 - Taylor, Kent D A1 - Adler, Sharon G A1 - Sedor, John R A1 - Freedman, Barry I A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Kubo, Michiaki A1 - Takahashi, Atsushi A1 - Hadjadj, Samy A1 - Marre, Michel A1 - Trégouët, David-Alexandre A1 - McKean-Cowdin, Roberta A1 - Varma, Rohit A1 - McCarthy, Mark I A1 - Groop, Leif A1 - Ahlqvist, Emma A1 - Lyssenko, Valeriya A1 - Agardh, Elisabet A1 - Morris, Andrew A1 - Doney, Alex S F A1 - Colhoun, Helen M A1 - Toppila, Iiro A1 - Sandholm, Niina A1 - Groop, Per-Henrik A1 - Maeda, Shiro A1 - Hanis, Craig L A1 - Penman, Alan A1 - Chen, Ching J A1 - Hancock, Heather A1 - Mitchell, Paul A1 - Craig, Jamie E A1 - Chew, Emily Y A1 - Paterson, Andrew D A1 - Grassi, Michael A A1 - Palmer, Colin A1 - Bowden, Donald W A1 - Yaspan, Brian L A1 - Siscovick, David A1 - Cotch, Mary Frances A1 - Wang, Jie Jin A1 - Burdon, Kathryn P A1 - Wong, Tien Y A1 - Klein, Barbara E K A1 - Klein, Ronald A1 - Rotter, Jerome I A1 - Iyengar, Sudha K A1 - Price, Alkes L A1 - Sobrin, Lucia AB -

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

VL - 68 IS - 2 ER - TY - JOUR T1 - {New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders JF - Nat Hum Behav Y1 - 2019 A1 - Evangelou, E. A1 - Gao, H. A1 - Chu, C. A1 - Ntritsos, G. A1 - Blakeley, P. A1 - Butts, A. R. A1 - Pazoki, R. A1 - Suzuki, H. A1 - Koskeridis, F. A1 - Yiorkas, A. M. A1 - Karaman, I. A1 - Elliott, J. A1 - Luo, Q. A1 - Aeschbacher, S. A1 - Bartz, T. M. A1 - Baumeister, S. E. A1 - Braund, P. S. A1 - Brown, M. R. A1 - Brody, J. A. A1 - Clarke, T. K. A1 - Dimou, N. A1 - Faul, J. D. A1 - Homuth, G. A1 - Jackson, A. U. A1 - Kentistou, K. A. A1 - Joshi, P. K. A1 - Lemaitre, R. N. A1 - Lind, P. A. A1 - Lyytik?inen, L. P. A1 - Mangino, M. A1 - Milaneschi, Y. A1 - Nelson, C. P. A1 - Nolte, I. M. A1 - Per?l?, M. M. A1 - Polasek, O. A1 - Porteous, D. A1 - Ratliff, S. M. A1 - Smith, J. A. A1 - Stan??kov?, A. A1 - Teumer, A. A1 - Tuominen, S. A1 - Th?riault, S. A1 - Vangipurapu, J. A1 - Whitfield, J. B. A1 - Wood, A. A1 - Yao, J. A1 - Yu, B. A1 - Zhao, W. A1 - Arking, D. E. A1 - Auvinen, J. A1 - Liu, C. A1 - M?nnikk?, M. A1 - Risch, L. A1 - Rotter, J. I. A1 - Snieder, H. A1 - Veijola, J. A1 - Blakemore, A. I. A1 - Boehnke, M. A1 - Campbell, H. A1 - Conen, D. A1 - Eriksson, J. G. A1 - Grabe, H. J. A1 - Guo, X. A1 - van der Harst, P. A1 - Hartman, C. A. A1 - Hayward, C. A1 - Heath, A. C. A1 - Jarvelin, M. R. A1 - K?h?nen, M. A1 - Kardia, S. L. R. A1 - K?hne, M. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Lahti, J. A1 - Lehtim?ki, T. A1 - McIntosh, A. M. A1 - Mohlke, K. L. A1 - Morrison, A. C. A1 - Martin, N. G. A1 - Oldehinkel, A. J. A1 - Penninx, B. W. J. H. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Rudan, I. A1 - Samani, N. J. A1 - Scott, L. J. A1 - Spector, T. D. A1 - Verweij, N. A1 - Weir, D. R. A1 - Wilson, J. F. A1 - Levy, D. A1 - Tzoulaki, I. A1 - Bell, J. D. A1 - Matthews, P. M. A1 - Rothenfluh, A. A1 - Desrivi?res, S. A1 - Schumann, G. A1 - Elliott, P. AB - Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia. VL - 3 ER - TY - JOUR T1 - Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. JF - PLoS One Y1 - 2019 A1 - Floyd, James S A1 - Bloch, Katarzyna M A1 - Brody, Jennifer A A1 - Maroteau, Cyrielle A1 - Siddiqui, Moneeza K A1 - Gregory, Richard A1 - Carr, Daniel F A1 - Molokhia, Mariam A1 - Liu, Xiaoming A1 - Bis, Joshua C A1 - Ahmed, Ammar A1 - Liu, Xuan A1 - Hallberg, Pär A1 - Yue, Qun-Ying A1 - Magnusson, Patrik K E A1 - Brisson, Diane A1 - Wiggins, Kerri L A1 - Morrison, Alanna C A1 - Khoury, Etienne A1 - McKeigue, Paul A1 - Stricker, Bruno H A1 - Lapeyre-Mestre, Maryse A1 - Heckbert, Susan R A1 - Gallagher, Arlene M A1 - Chinoy, Hector A1 - Gibbs, Richard A A1 - Bondon-Guitton, Emmanuelle A1 - Tracy, Russell A1 - Boerwinkle, Eric A1 - Gaudet, Daniel A1 - Conforti, Anita A1 - van Staa, Tjeerd A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Maitland-van der Zee, Anke-Hilse A1 - Wadelius, Mia A1 - Morris, Andrew P A1 - Pirmohamed, Munir A1 - Palmer, Colin A N A1 - Psaty, Bruce M A1 - Alfirevic, Ana AB -

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

VL - 14 IS - 6 ER - TY - JOUR T1 - {Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis JF - BMJ Y1 - 2019 A1 - Merino, J. A1 - Guasch-Ferr?, M. A1 - Ellervik, C. A1 - Dashti, H. S. A1 - Sharp, S. J. A1 - Wu, P. A1 - Overvad, K. A1 - Sarnowski, C. A1 - Kuokkanen, M. A1 - Lemaitre, R. N. A1 - Justice, A. E. A1 - Ericson, U. A1 - Braun, K. V. E. A1 - Mahendran, Y. A1 - Frazier-Wood, A. C. A1 - Sun, D. A1 - Chu, A. Y. A1 - Tanaka, T. A1 - Luan, J. A1 - Hong, J. A1 - Tj?nneland, A. A1 - Ding, M. A1 - Lundqvist, A. A1 - Mukamal, K. A1 - Rohde, R. A1 - Schulz, C. A. A1 - Franco, O. H. A1 - Grarup, N. A1 - Chen, Y. I. A1 - Bazzano, L. A1 - Franks, P. W. A1 - Buring, J. E. A1 - Langenberg, C. A1 - Liu, C. T. A1 - Hansen, T. A1 - Jensen, M. K. A1 - S??ksj?rvi, K. A1 - Psaty, B. M. A1 - Young, K. L. A1 - Hindy, G. A1 - Sandholt, C. H. A1 - Ridker, P. M. A1 - Ordovas, J. M. A1 - Meigs, J. B. A1 - Pedersen, O. A1 - Kraft, P. A1 - Perola, M. A1 - North, K. E. A1 - Orho-Melander, M. A1 - Voortman, T. A1 - Toft, U. A1 - Rotter, J. I. A1 - Qi, L. A1 - Forouhi, N. G. A1 - Mozaffarian, D. A1 - S?rensen, T. I. A. A1 - Stampfer, M. J. A1 - M?nnist?, S. A1 - Selvin, E. A1 - Imamura, F. A1 - Salomaa, V. A1 - Hu, F. B. A1 - Wareham, N. J. A1 - Dupuis, J. A1 - Smith, C. E. A1 - Kilpel?inen, T. O. A1 - Chasman, D. I. A1 - Florez, J. C. AB - {To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.\ Individual participant data meta-analysis.\ Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.\ Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.\ Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75 VL - 366 ER - TY - JOUR T1 - {Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium JF - Am J Kidney Dis Y1 - 2019 A1 - Inker, L. A. A1 - Grams, M. E. A1 - Levey, A. S. A1 - Coresh, J. A1 - Cirillo, M. A1 - Collins, J. F. A1 - Gansevoort, R. T. A1 - Gutierrez, O. M. A1 - Hamano, T. A1 - Heine, G. H. A1 - Ishikawa, S. A1 - Jee, S. H. A1 - Kronenberg, F. A1 - Landray, M. J. A1 - Miura, K. A1 - Nadkarni, G. N. A1 - Peralta, C. A. A1 - Rothenbacher, D. A1 - Schaeffner, E. A1 - Sedaghat, S. A1 - Shlipak, M. G. A1 - Zhang, L. A1 - van Zuilen, A. D. A1 - Hallan, S. I. A1 - Kovesdy, C. P. A1 - Woodward, M. A1 - Levin, A. A1 - Astor, B. A1 - Appel, L. A1 - Greene, T. A1 - Chen, T. A1 - Chalmers, J. A1 - Woodward, M. A1 - Arima, H. A1 - Perkovic, V. A1 - Yatsuya, H. A1 - Tamakoshi, K. A1 - Li, Y. A1 - Hirakawa, Y. A1 - Coresh, J. A1 - Matsushita, K. A1 - Grams, M. A1 - Sang, Y. A1 - Polkinghorne, K. A1 - Chadban, S. A1 - Atkins, R. A1 - Levin, A. A1 - Djurdjev, O. A1 - Zhang, L. A1 - Liu, L. A1 - Zhao, M. A1 - Wang, F. A1 - Wang, J. A1 - Schaeffner, E. A1 - Ebert, N. A1 - Martus, P. A1 - Levin, A. A1 - Djurdjev, O. A1 - Tang, M. A1 - Heine, G. A1 - Emrich, I. A1 - Seiler, S. A1 - Zawada, A. A1 - Nally, J. A1 - Navaneethan, S. A1 - Schold, J. A1 - Zhang, L. A1 - Zhao, M. A1 - Wang, F. A1 - Wang, J. A1 - Shlipak, M. A1 - Sarnak, M. A1 - Katz, R. A1 - Hiramoto, J. A1 - Iso, H. A1 - Yamagishi, K. A1 - Umesawa, M. A1 - Muraki, I. A1 - Fukagawa, M. A1 - Maruyama, S. A1 - Hamano, T. A1 - Hasegawa, T. A1 - Fujii, N. A1 - Wheeler, D. A1 - Emberson, J. A1 - Townend, J. A1 - Landray, M. A1 - Brenner, H. A1 - Sch?ttker, B. A1 - Saum, K. U. A1 - Rothenbacher, D. A1 - Fox, C. A1 - Hwang, S. J. A1 - K?ttgen, A. A1 - Kronenberg, F. A1 - Schneider, M. P. A1 - Eckardt, K. U. A1 - Green, J. A1 - Kirchner, H. L. A1 - Chang, A. R. A1 - Ho, K. A1 - Ito, S. A1 - Miyazaki, M. A1 - Nakayama, M. A1 - Yamada, G. A1 - Cirillo, M. A1 - Irie, F. A1 - Sairenchi, T. A1 - Ishikawa, S. A1 - Yano, Y. A1 - Kotani, K. A1 - Nakamura, T. A1 - Jee, S. H. A1 - Kimm, H. A1 - Mok, Y. A1 - Chodick, G. A1 - Shalev, V. A1 - Wetzels, J. F. M. A1 - Blankestijn, P. J. A1 - van Zuilen, A. D. A1 - van den Brand, J. A1 - Sarnak, M. A1 - Inker, L. A1 - Peralta, C. A1 - Hiramoto, J. A1 - Katz, R. A1 - Sarnak, M. A1 - Kronenberg, F. A1 - Kollerits, B. A1 - Ritz, E. A1 - Nitsch, D. A1 - Roderick, P. A1 - Fletcher, A. A1 - Bottinger, E. A1 - Nadkarni, G. N. A1 - Ellis, S. B. A1 - Nadukuru, R. A1 - Sang, Y. A1 - Ueshima, H. A1 - Okayama, A. A1 - Miura, K. A1 - Tanaka, S. A1 - Ueshima, H. A1 - Okamura, T. A1 - Miura, K. A1 - Tanaka, S. A1 - Miura, K. A1 - Okayama, A. A1 - Kadota, A. A1 - Tanaka, S. A1 - Kenealy, T. A1 - Elley, C. R. A1 - Collins, J. F. A1 - Drury, P. L. A1 - Ohkubo, T. A1 - Asayama, K. A1 - Metoki, H. A1 - Kikuya, M. A1 - Nakayama, M. A1 - Nelson, R. G. A1 - Knowler, W. C. A1 - Gansevoort, R. T. A1 - Bakker, S. J. A1 - Hak, E. A1 - Heerspink, H. J. L. A1 - Brunskill, N. A1 - Major, R. A1 - Shepherd, D. A1 - Medcalf, J. A1 - Jassal, S. K. A1 - Bergstrom, J. A1 - Ix, J. H. A1 - Barrett-Connor, E. A1 - Kovesdy, C. A1 - Kalantar-Zadeh, K. A1 - Sumida, K. A1 - Gutierrez, O. M. A1 - Muntner, P. A1 - Warnock, D. A1 - McClellan, W. A1 - Heerspink, H. J. L. A1 - de Zeeuw, D. A1 - Brenner, B. A1 - Sedaghat, S. A1 - Ikram, M. A. A1 - Hoorn, E. J. A1 - Dehghan, A. A1 - Carrero, J. J. A1 - Gasparini, A. A1 - Wettermark, B. A1 - Elinder, C. G. A1 - Wong, T. Y. A1 - Sabanayagam, C. A1 - Cheng, C. Y. A1 - Visseren, F. L. J. A1 - Evans, M. A1 - Segelmark, M. A1 - Stendahl, M. A1 - Sch?n, S. A1 - Tangri, N. A1 - Sud, M. A1 - Naimark, D. A1 - Wen, C. P. A1 - Tsao, C. K. A1 - Tsai, M. K. A1 - Chen, C. H. A1 - Konta, T. A1 - Hirayama, A. A1 - Ichikawa, K. A1 - Lannfelt, L. A1 - Larsson, A. A1 - ?rnl?v, J. A1 - Bilo, H. J. G. A1 - Landman, G. W. D. A1 - van Hateren, K. J. J. A1 - Kleefstra, N. A1 - Coresh Chair, J. A1 - Gansevoort, R. T. A1 - Grams, M. E. A1 - Hallan, S. A1 - Kovesdy, C. P. A1 - Levey, A. S. A1 - Matsushita, K. A1 - Shalev, V. A1 - Woodward, M. A1 - Ballew, S. H. A1 - Chen, J. A1 - Coresh, J. A1 - Grams, M. E. A1 - Kwak, L. A1 - Matsushita, K. A1 - Sang, Y. A1 - Surapaneni, A. A1 - Woodward, M. AB - Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.\ Cross-sectional individual participant-level analyses in a global consortium.\ 17 CKD and 38 general population and high-risk cohorts.\ Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.\ Data were obtained and analyzed between July 2015 and January 2018.\ We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.\ The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).\ Variations in study era, health care delivery system, typical diet, and laboratory assays.\ Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. VL - 73 ER - TY - JOUR T1 - Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. JF - Genome Biol Y1 - 2019 A1 - Ebbert, Mark T W A1 - Jensen, Tanner D A1 - Jansen-West, Karen A1 - Sens, Jonathon P A1 - Reddy, Joseph S A1 - Ridge, Perry G A1 - Kauwe, John S K A1 - Belzil, Veronique A1 - Pregent, Luc A1 - Carrasquillo, Minerva M A1 - Keene, Dirk A1 - Larson, Eric A1 - Crane, Paul A1 - Asmann, Yan W A1 - Ertekin-Taner, Nilufer A1 - Younkin, Steven G A1 - Ross, Owen A A1 - Rademakers, Rosa A1 - Petrucelli, Leonard A1 - Fryer, John D KW - Genetic Predisposition to Disease KW - Genome, Human KW - Humans KW - Mutation AB -

BACKGROUND: The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.

RESULTS: Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.

CONCLUSIONS: While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.

VL - 20 IS - 1 ER - TY - JOUR T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. JF - Nat Genet Y1 - 2019 A1 - Tin, Adrienne A1 - Marten, Jonathan A1 - Halperin Kuhns, Victoria L A1 - Li, Yong A1 - Wuttke, Matthias A1 - Kirsten, Holger A1 - Sieber, Karsten B A1 - Qiu, Chengxiang A1 - Gorski, Mathias A1 - Yu, Zhi A1 - Giri, Ayush A1 - Sveinbjornsson, Gardar A1 - Li, Man A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - O'Connor, Luke J A1 - Prins, Bram A1 - Nutile, Teresa A1 - Noce, Damia A1 - Akiyama, Masato A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - van der Most, Peter J A1 - Horn, Katrin A1 - Xu, Yizhe A1 - Fuchsberger, Christian A1 - Sedaghat, Sanaz A1 - Afaq, Saima A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Cusi, Daniele A1 - Felicita, Sala Cinzia A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Devuyst, Olivier A1 - Dittrich, Katalin A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Gansevoort, Ron T A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Holm, Hilma A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Lewis, Raychel M A1 - Ingelsson, Erik A1 - Jakobsdottir, Johanna A1 - Jonsdottir, Ingileif A1 - Jonsson, Helgi A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerr, Shona M A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - La Bianca, Martina A1 - Lange, Leslie A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liu, Jun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - O'Donnell, Christopher J A1 - Wilson, Otis D A1 - Gaziano, J Michael A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Müller-Nurasyid, Martina A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey R A1 - Olafsson, Isleifur A1 - Padmanabhan, Sandosh A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Peters, Annette A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Preuss, Michael H A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Krajcoviechova, Alena A1 - Cifkova, Renata A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Shaffer, Christian M A1 - Smith, Albert V A1 - Smith, Blair H A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Tajuddin, Salman M A1 - Teren, Andrej A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thorsteinsdottir, Unnur A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Yang, Qiong A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Bochud, Murielle A1 - Wilson, James G A1 - Pendergrass, Sarah A A1 - Ho, Kevin A1 - Parsa, Afshin A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Böger, Carsten A A1 - Snieder, Harold A1 - Butterworth, Adam S A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Stefansson, Kari A1 - Susztak, Katalin A1 - Scholz, Markus A1 - Heid, Iris M A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Pattaro, Cristian A1 - Woodward, Owen M A1 - Vitart, Veronique A1 - Köttgen, Anna AB -

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

VL - 51 IS - 10 ER - TY - JOUR T1 - Use of a pooled cohort to impute cardiovascular disease risk factors across the adult life course. JF - Int J Epidemiol Y1 - 2019 A1 - Zeki Al Hazzouri, Adina A1 - Vittinghoff, Eric A1 - Zhang, Yiyi A1 - Pletcher, Mark J A1 - Moran, Andrew E A1 - Bibbins-Domingo, Kirsten A1 - Golden, Sherita H A1 - Yaffe, Kristine AB -

BACKGROUND: In designing prevention strategies, it may be useful to understand how early and midlife cardiovascular disease risk factor (CVDRF) exposures affect outcomes that primarily occur in mid to late life. Few single US cohorts have followed participants from early adulthood to late life.

METHODS: We pooled four prospective cohorts that represent segments of the adult life course, and studied 15 001 White and Black adults aged 18 to 95 years at enrollment. We imputed early and midlife exposure to body mass index (BMI), glucose, lipids and blood pressure (BP). CVDRF trajectories were estimated using linear mixed models. Using the best linear unbiased predictions, we obtained person-specific estimates of CVDRF trajectories beginning at age 20 until each participant's end of follow-up. We then calculated for each CVDRF, summary measures of early and midlife exposure as time-weighted averages (TWAs).

RESULTS: In the pooled cohort, 33.7% were Black and 54.8% were female. CVDRF summary measures worsened in midlife compared with early life and varied by sex and race. In particular, systolic and diastolic BP were consistently higher over the adult life course among men, and BMI was higher among Blacks, particularly Black women. Simulation studies suggested acceptable imputation accuracy, especially for the younger cohorts. Correlations of true and imputed CVDRF summary measures ranged from 0.53 to 0.99, and agreement ranged from 67% to 99%.

CONCLUSIONS: These results suggest that imputed CVDRFs may be accurate enough to be useful in assessing the effects of early and midlife exposures on later life outcomes.

VL - 48 IS - 3 ER - TY - JOUR T1 - {Androgens In Men Study (AIMS): protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men JF - BMJ Open Y1 - 2020 A1 - Yeap, B. B. A1 - Marriott, R. J. A1 - Adams, R. J. A1 - Antonio, L. A1 - Ballantyne, C. M. A1 - Bhasin, S. A1 - Cawthon, P. M. A1 - Couper, D. J. A1 - Dobs, A. S. A1 - Flicker, L. A1 - Karlsson, M. A1 - Martin, S. A. A1 - Matsumoto, A. M. A1 - Mellstr?m, D. A1 - Norman, P. E. A1 - Ohlsson, C. A1 - Orwoll, E. S. A1 - O'Neill, T. W. A1 - Shores, M. M. A1 - Travison, T. G. A1 - Vanderschueren, D. A1 - Wittert, G. A. A1 - Wu, F. C. W. A1 - Murray, K. AB - This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.\ Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.\ Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.\ CRD42019139668. VL - 10 ER - TY - JOUR T1 - Association Between Blood Pressure and Later-Life Cognition Among Black and White Individuals. JF - JAMA Neurol Y1 - 2020 A1 - Levine, Deborah A A1 - Gross, Alden L A1 - Briceño, Emily M A1 - Tilton, Nicholas A1 - Kabeto, Mohammed U A1 - Hingtgen, Stephanie M A1 - Giordani, Bruno J A1 - Sussman, Jeremy B A1 - Hayward, Rodney A A1 - Burke, James F A1 - Elkind, Mitchell S V A1 - Manly, Jennifer J A1 - Moran, Andrew E A1 - Kulick, Erin R A1 - Gottesman, Rebecca F A1 - Walker, Keenan A A1 - Yano, Yuichiro A1 - Gaskin, Darrell J A1 - Sidney, Stephen A1 - Yaffe, Kristine A1 - Sacco, Ralph L A1 - Wright, Clinton B A1 - Roger, Veronique L A1 - Allen, Norrina Bai A1 - Galecki, Andrzej T AB -

Importance: Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain.

Objective: To determine whether cumulative BP levels explain racial differences in cognitive decline.

Design, Setting, and Participants: Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018.

Main Outcomes and Measures: The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function.

Exposures: Race (black vs white).

Results: Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (-0.03 points per year faster [95% CI, -0.05 to -0.01]; P = .004) and memory (-0.08 points per year faster [95% CI, -0.11 to -0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (-0.018 points per year faster per each 10-mm Hg increase [95% CI, -0.023 to -0.014]; P < .001), memory (-0.028 points per year faster per each 10-mm Hg increase [95% CI, -0.035 to -0.021]; P < .001), and executive function (-0.01 points per year faster per each 10-mm Hg increase [95% CI, -0.014 to -0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (-0.01 points per year [95% CI, -0.03 to 0.01]; P = .56) and memory (-0.06 points per year [95% CI, -0.08 to -0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001).

Conclusions and Relevance: These results suggest that black individuals' higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

ER - TY - JOUR T1 - Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies. JF - JAMA Netw Open Y1 - 2020 A1 - Arbeev, Konstantin G A1 - Verhulst, Simon A1 - Steenstrup, Troels A1 - Kark, Jeremy D A1 - Bagley, Olivia A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Fitzpatrick, Annette L A1 - Christensen, Kaare A1 - Yashin, Anatoliy I A1 - Aviv, Abraham AB -

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

Objective: To examine whether LTL is associated with the life span of contemporary humans.

Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).

Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

VL - 3 IS - 2 ER - TY - JOUR T1 - Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults. JF - JAMA Intern Med Y1 - 2020 A1 - Balte, Pallavi P A1 - Chaves, Paulo H M A1 - Couper, David J A1 - Enright, Paul A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kronmal, Richard A A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Benjamin M A1 - Smith, Lewis J A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Asthma KW - Bronchitis, Chronic KW - Female KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Prospective Studies KW - Respiratory Function Tests KW - Smokers KW - Smoking KW - Young Adult AB -

Importance: Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain.

Objective: To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers.

Design, Setting, and Participants: This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018.

Exposures: Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years.

Main Outcomes and Measures: Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis.

Results: Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes.

Conclusions and Relevance: The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.

VL - 180 IS - 5 ER - TY - JOUR T1 - {Cerebral small vessel disease genomics and its implications across the lifespan JF - Nat Commun Y1 - 2020 A1 - Sargurupremraj, M. A1 - Suzuki, H. A1 - Jian, X. A1 - Sarnowski, C. A1 - Evans, T. E. A1 - Bis, J. C. A1 - Eiriksdottir, G. A1 - Sakaue, S. A1 - Terzikhan, N. A1 - Habes, M. A1 - Zhao, W. A1 - Armstrong, N. J. A1 - Hofer, E. A1 - Yanek, L. R. A1 - Hagenaars, S. P. A1 - Kumar, R. B. A1 - van den Akker, E. B. A1 - McWhirter, R. E. A1 - Trompet, S. A1 - Mishra, A. A1 - Saba, Y. A1 - Satizabal, C. L. A1 - Beaudet, G. A1 - Petit, L. A1 - Tsuchida, A. A1 - Zago, L. A1 - Schilling, S. A1 - Sigurdsson, S. A1 - Gottesman, R. F. A1 - Lewis, C. E. A1 - Aggarwal, N. T. A1 - Lopez, O. L. A1 - Smith, J. A. A1 - Vald?s Hern?ndez, M. C. A1 - van der Grond, J. A1 - Wright, M. J. A1 - Knol, M. J. A1 - D?rr, M. A1 - Thomson, R. J. A1 - Bordes, C. A1 - Le Grand, Q. A1 - Duperron, M. G. A1 - Smith, A. V. A1 - Knopman, D. S. A1 - Schreiner, P. J. A1 - Evans, D. A. A1 - Rotter, J. I. A1 - Beiser, A. S. A1 - Maniega, S. M. A1 - Beekman, M. A1 - Trollor, J. A1 - Stott, D. J. A1 - Vernooij, M. W. A1 - Wittfeld, K. A1 - Niessen, W. J. A1 - Soumar?, A. A1 - Boerwinkle, E. A1 - Sidney, S. A1 - Turner, S. T. A1 - Davies, G. A1 - Thalamuthu, A. A1 - V?lker, U. A1 - van Buchem, M. A. A1 - Bryan, R. N. A1 - Dupuis, J. A1 - Bastin, M. E. A1 - Ames, D. A1 - Teumer, A. A1 - Amouyel, P. A1 - Kwok, J. B. A1 - B?low, R. A1 - Deary, I. J. A1 - Schofield, P. R. A1 - Brodaty, H. A1 - Jiang, J. A1 - Tabara, Y. A1 - Setoh, K. A1 - Miyamoto, S. A1 - Yoshida, K. A1 - Nagata, M. A1 - Kamatani, Y. A1 - Matsuda, F. A1 - Psaty, B. M. A1 - Bennett, D. A. A1 - De Jager, P. L. A1 - Mosley, T. H. A1 - Sachdev, P. S. A1 - Schmidt, R. A1 - Warren, H. R. A1 - Evangelou, E. A1 - Tr?gou?t, D. A. A1 - Ikram, M. A. A1 - Wen, W. A1 - DeCarli, C. A1 - Srikanth, V. K. A1 - Jukema, J. W. A1 - Slagboom, E. P. A1 - Kardia, S. L. R. A1 - Okada, Y. A1 - Mazoyer, B. A1 - Wardlaw, J. M. A1 - Nyquist, P. A. A1 - Mather, K. A. A1 - Grabe, H. J. A1 - Schmidt, H. A1 - van Duijn, C. M. A1 - Gudnason, V. A1 - Longstreth, W. T. A1 - Launer, L. J. A1 - Lathrop, M. A1 - Seshadri, S. A1 - Tzourio, C. A1 - Adams, H. H. A1 - Matthews, P. M. A1 - Fornage, M. A1 - Debette, S. A1 - Amouyel, P. A1 - de Andrade, M. A1 - Basu, S. A1 - Berr, C. A1 - Brody, J. A. A1 - Chasman, D. I. A1 - Dartigues, J. F. A1 - Folsom, A. R. A1 - Germain, M. A1 - de Haan, H. A1 - Heit, J. A1 - Houwing-Duitermaat, J. A1 - Kabrhel, C. A1 - Kraft, P. A1 - Legal, G. A1 - Lindstr?m, S. A1 - Monajemi, R. A1 - Morange, P. E. A1 - Psaty, B. M. A1 - Reitsma, P. H. A1 - Ridker, P. M. A1 - Rose, L. M. A1 - Rosendaal, F. R. A1 - Saut, N. A1 - Slagboom, E. A1 - Smadja, D. A1 - Smith, N. L. A1 - Suchon, P. A1 - Tang, W. A1 - Taylor, K. D. A1 - Tr?gou?t, D. A. A1 - Tzourio, C. A1 - de Visser, M. C. H. A1 - van Hylckama Vlieg, A. A1 - Weng, L. C. A1 - Wiggins, K. L. A1 - Gormley, P. A1 - Anttila, V. A1 - Winsvold, B. S. A1 - Palta, P. A1 - Esko, T. A1 - Pers, T. H. A1 - Farh, K. H. A1 - Cuenca-Leon, E. A1 - Muona, M. A1 - Furlotte, N. A. A1 - Kurth, T. A1 - Ingason, A. A1 - McMahon, G. A1 - Ligthart, L. A1 - Terwindt, G. M. A1 - Kallela, M. A1 - Freilinger, T. M. A1 - Ran, C. A1 - Gordon, S. G. A1 - Stam, A. H. A1 - Steinberg, S. A1 - Borck, G. A1 - Koiranen, M. A1 - Quaye, L. A1 - Adams, H. H. H. A1 - Lehtim?ki, T. A1 - Sarin, A. P. A1 - Wedenoja, J. A1 - Hinds, D. A. A1 - Buring, J. E. A1 - Sch?rks, M. A1 - Ridker, P. M. A1 - Gudlaug Hrafnsdottir, M. A1 - Stefansson, H. A1 - Ring, S. M. A1 - Hottenga, J. J. A1 - Penninx, B. W. J. H. A1 - F?rkkil?, M. A1 - Artto, V. A1 - Kaunisto, M. A1 - Veps?l?inen, S. A1 - Malik, R. A1 - Heath, A. C. A1 - Madden, P. A. F. A1 - Martin, N. G. A1 - Montgomery, G. W. A1 - Kurki, M. A1 - Kals, M. A1 - M?gi, R. A1 - P?rn, K. A1 - H?m?l?inen, E. A1 - Huang, H. A1 - Byrnes, A. E. A1 - Franke, L. A1 - Huang, J. A1 - Stergiakouli, E. A1 - Lee, P. H. A1 - Sandor, C. A1 - Webber, C. A1 - Cader, Z. A1 - Muller-Myhsok, B. A1 - Schreiber, S. A1 - Meitinger, T. A1 - Eriksson, J. G. A1 - Salomaa, V. A1 - Heikkil?, K. A1 - Loehrer, E. A1 - Uitterlinden, A. G. A1 - Hofman, A. A1 - van Duijn, C. M. A1 - Cherkas, L. A1 - Pedersen, L. M. A1 - Stubhaug, A. A1 - Nielsen, C. S. A1 - M?nnikk?, M. A1 - Mihailov, E. A1 - Milani, L. A1 - G?bel, H. A1 - Esserlind, A. L. A1 - Francke Christensen, A. A1 - Folkmann Hansen, T. A1 - Werge, T. A1 - Kaprio, J. A1 - Aromaa, A. J. A1 - Raitakari, O. A1 - Ikram, M. A. A1 - Spector, T. A1 - J?rvelin, M. R. A1 - Metspalu, A. A1 - Kubisch, C. A1 - Strachan, D. P. A1 - Ferrari, M. D. A1 - Belin, A. C. A1 - Dichgans, M. A1 - Wessman, M. A1 - van den Maagdenberg, A. M. J. M. A1 - Zwart, J. A. A1 - Boomsma, D. I. A1 - Davey Smith, G. A1 - Stefansson, K. A1 - Eriksson, N. A1 - Daly, M. J. A1 - Neale, B. M. A1 - Olesen, J. A1 - Chasman, D. I. A1 - Nyholt, D. R. A1 - Palotie, A. AB - White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. VL - 11 ER - TY - JOUR T1 - {Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals JF - Nat Genet Y1 - 2020 A1 - Surendran, P. A1 - Feofanova, E. V. A1 - Lahrouchi, N. A1 - Ntalla, I. A1 - Karthikeyan, S. A1 - Cook, J. A1 - Chen, L. A1 - Mifsud, B. A1 - Yao, C. A1 - Kraja, A. T. A1 - Cartwright, J. H. A1 - Hellwege, J. N. A1 - Giri, A. A1 - Tragante, V. A1 - Thorleifsson, G. A1 - Liu, D. J. A1 - Prins, B. P. A1 - Stewart, I. D. A1 - Cabrera, C. P. A1 - Eales, J. M. A1 - Akbarov, A. A1 - Auer, P. L. A1 - Bielak, L. F. A1 - Bis, J. C. A1 - Braithwaite, V. S. A1 - Brody, J. A. A1 - Daw, E. W. A1 - Warren, H. R. A1 - Drenos, F. A1 - Nielsen, S. F. A1 - Faul, J. D. A1 - Fauman, E. B. A1 - Fava, C. A1 - Ferreira, T. A1 - Foley, C. N. A1 - Franceschini, N. A1 - Gao, H. A1 - Giannakopoulou, O. A1 - Giulianini, F. A1 - Gudbjartsson, D. F. A1 - Guo, X. A1 - Harris, S. E. A1 - Havulinna, A. S. A1 - Helgadottir, A. A1 - Huffman, J. E. A1 - Hwang, S. J. A1 - Kanoni, S. A1 - Kontto, J. A1 - Larson, M. G. A1 - Li-Gao, R. A1 - Lindstr?m, J. A1 - Lotta, L. A. A1 - Lu, Y. A1 - Luan, J. A1 - Mahajan, A. A1 - Malerba, G. A1 - Masca, N. G. D. A1 - Mei, H. A1 - Menni, C. A1 - Mook-Kanamori, D. O. A1 - Mosen-Ansorena, D. A1 - M?ller-Nurasyid, M. A1 - Par?, G. A1 - Paul, D. S. A1 - Perola, M. A1 - Poveda, A. A1 - Rauramaa, R. A1 - Richard, M. A1 - Richardson, T. G. A1 - Sep?lveda, N. A1 - Sim, X. A1 - Smith, A. V. A1 - Smith, J. A. A1 - Staley, J. R. A1 - Stan?kov?, A. A1 - Sulem, P. A1 - Th?riault, S. A1 - Thorsteinsdottir, U. A1 - Trompet, S. A1 - Varga, T. V. A1 - Velez Edwards, D. R. A1 - Veronesi, G. A1 - Weiss, S. A1 - Willems, S. M. A1 - Yao, J. A1 - Young, R. A1 - Yu, B. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Zhao, W. A1 - Zhao, W. A1 - Evangelou, E. A1 - Aeschbacher, S. A1 - Asllanaj, E. A1 - Blankenberg, S. A1 - Bonnycastle, L. L. A1 - Bork-Jensen, J. A1 - Brandslund, I. A1 - Braund, P. S. A1 - Burgess, S. A1 - Cho, K. A1 - Christensen, C. A1 - Connell, J. A1 - Mutsert, R. A1 - Dominiczak, A. F. A1 - D?rr, M. A1 - Eiriksdottir, G. A1 - Farmaki, A. E. A1 - Gaziano, J. M. A1 - Grarup, N. A1 - Grove, M. L. A1 - Hallmans, G. A1 - Hansen, T. A1 - Have, C. T. A1 - Heiss, G. A1 - J?rgensen, M. E. A1 - Jousilahti, P. A1 - Kajantie, E. A1 - Kamat, M. A1 - K?r?j?m?ki, A. A1 - Karpe, F. A1 - Koistinen, H. A. A1 - Kovesdy, C. P. A1 - Kuulasmaa, K. A1 - Laatikainen, T. A1 - Lannfelt, L. A1 - Lee, I. T. A1 - Lee, W. J. A1 - Linneberg, A. A1 - Martin, L. W. A1 - Moitry, M. A1 - Nadkarni, G. A1 - Neville, M. J. A1 - Palmer, C. N. A. A1 - Papanicolaou, G. J. A1 - Pedersen, O. A1 - Peters, J. A1 - Poulter, N. A1 - Rasheed, A. A1 - Rasmussen, K. L. A1 - Rayner, N. W. A1 - M?gi, R. A1 - Renstr?m, F. A1 - Rettig, R. A1 - Rossouw, J. A1 - Schreiner, P. J. A1 - Sever, P. S. A1 - Sigurdsson, E. L. A1 - Skaaby, T. A1 - Sun, Y. V. A1 - Sundstrom, J. A1 - Thorgeirsson, G. A1 - Esko, T. A1 - Trabetti, E. A1 - Tsao, P. S. A1 - Tuomi, T. A1 - Turner, S. T. A1 - Tzoulaki, I. A1 - Vaartjes, I. A1 - Vergnaud, A. C. A1 - Willer, C. J. A1 - Wilson, P. W. F. A1 - Witte, D. R. A1 - Yonova-Doing, E. A1 - Zhang, H. A1 - Aliya, N. A1 - Almgren, P. A1 - Amouyel, P. A1 - Asselbergs, F. W. A1 - Barnes, M. R. A1 - Blakemore, A. I. A1 - Boehnke, M. A1 - Bots, M. L. A1 - Bottinger, E. P. A1 - Buring, J. E. A1 - Chambers, J. C. A1 - Chen, Y. I. A1 - Chowdhury, R. A1 - Conen, D. A1 - Correa, A. A1 - Davey Smith, G. A1 - Boer, R. A. A1 - Deary, I. J. A1 - Dedoussis, G. A1 - Deloukas, P. A1 - Di Angelantonio, E. A1 - Elliott, P. A1 - Felix, S. B. A1 - Ferri?res, J. A1 - Ford, I. A1 - Fornage, M. A1 - Franks, P. W. A1 - Franks, S. A1 - Frossard, P. A1 - Gambaro, G. A1 - Gaunt, T. R. A1 - Groop, L. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Hayward, C. A1 - Hennig, B. J. A1 - Herzig, K. H. A1 - Ingelsson, E. A1 - Tuomilehto, J. A1 - J?rvelin, M. R. A1 - Jukema, J. W. A1 - Kardia, S. L. R. A1 - Kee, F. A1 - Kooner, J. S. A1 - Kooperberg, C. A1 - Launer, L. J. A1 - Lind, L. A1 - Loos, R. J. F. A1 - Majumder, A. A. S. A1 - Laakso, M. A1 - McCarthy, M. I. A1 - Melander, O. A1 - Mohlke, K. L. A1 - Murray, A. D. A1 - Nordestgaard, B. G. A1 - Orho-Melander, M. A1 - Packard, C. J. A1 - Padmanabhan, S. A1 - Palmas, W. A1 - Polasek, O. A1 - Porteous, D. J. A1 - Prentice, A. M. A1 - Province, M. A. A1 - Relton, C. L. A1 - Rice, K. A1 - Ridker, P. M. A1 - Rolandsson, O. A1 - Rosendaal, F. R. A1 - Rotter, J. I. A1 - Rudan, I. A1 - Salomaa, V. A1 - Samani, N. J. A1 - Sattar, N. A1 - Sheu, W. H. A1 - Smith, B. H. A1 - Soranzo, N. A1 - Spector, T. D. A1 - Starr, J. M. A1 - Sebert, S. A1 - Taylor, K. D. A1 - Lakka, T. A. A1 - Timpson, N. J. A1 - Tobin, M. D. A1 - van der Harst, P. A1 - van der Meer, P. A1 - Ramachandran, V. S. A1 - Verweij, N. A1 - Virtamo, J. A1 - V?lker, U. A1 - Weir, D. R. A1 - Zeggini, E. A1 - Charchar, F. J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Tomaszewski, M. A1 - Butterworth, A. S. A1 - Caulfield, M. J. A1 - Danesh, J. A1 - Edwards, T. L. A1 - Holm, H. A1 - Hung, A. M. A1 - Lindgren, C. M. A1 - Liu, C. A1 - Manning, A. K. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - O'Donnell, C. J. A1 - Psaty, B. M. A1 - Saleheen, D. A1 - Stefansson, K. A1 - Boerwinkle, E. A1 - Chasman, D. I. A1 - Levy, D. A1 - Newton-Cheh, C. A1 - Munroe, P. B. A1 - Howson, J. M. M. A1 - de Boer, R. A. A1 - van der Harst, P. A1 - van der Meer, P. A1 - Verweij, N. A1 - Butterworth, A. S. A1 - Danesh, J. A1 - Langenberg, C. A1 - Deloukas, P. A1 - McCarthy, M. I. A1 - Franks, P. W. A1 - Rolandsson, O. A1 - Wareham, N. J. A1 - Prins, B. P. A1 - Zeggini, E. A1 - Hellwege, J. N. A1 - Giri, A. A1 - Edwards, D. R. V. A1 - Cho, K. A1 - Gaziano, J. M. A1 - Kovesdy, C. P. A1 - Sun, Y. V. A1 - Tsao, P. S. A1 - Wilson, P. W. F. A1 - Edwards, T. L. A1 - Hung, A. M. A1 - O'Donnell, C. J. AB - Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. VL - 52 ER - TY - JOUR T1 - A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline. JF - Am J Epidemiol Y1 - 2020 A1 - Cornelius, Talea A1 - Schwartz, Joseph E A1 - Balte, Pallavi A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Currow, David A1 - Jacobs, David R A1 - Johnson, Miriam A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Loehr, Laura A1 - O'Connor, George T A1 - Smith, Benjamin A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Aged KW - Body Mass Index KW - Cohort Studies KW - Humans KW - Linear Models KW - Lung KW - Middle Aged KW - Respiratory Function Tests KW - Weight Gain AB -

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

VL - 189 IS - 10 ER - TY - JOUR T1 - {Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale JF - Nat Genet Y1 - 2020 A1 - Li, X. A1 - Li, Z. A1 - Zhou, H. A1 - Gaynor, S. M. A1 - Liu, Y. A1 - Chen, H. A1 - Sun, R. A1 - Dey, R. A1 - Arnett, D. K. A1 - Aslibekyan, S. A1 - Ballantyne, C. M. A1 - Bielak, L. F. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bowden, D. W. A1 - Broome, J. G. A1 - Conomos, M. P. A1 - Correa, A. A1 - Cupples, L. A. A1 - Curran, J. E. A1 - Freedman, B. I. A1 - Guo, X. A1 - Hindy, G. A1 - Irvin, M. R. A1 - Kardia, S. L. R. A1 - Kathiresan, S. A1 - Khan, A. T. A1 - Kooperberg, C. L. A1 - Laurie, C. C. A1 - Liu, X. S. A1 - Mahaney, M. C. A1 - Manichaikul, A. W. A1 - Martin, L. W. A1 - Mathias, R. A. A1 - McGarvey, S. T. A1 - Mitchell, B. D. A1 - Montasser, M. E. A1 - Moore, J. E. A1 - Morrison, A. C. A1 - O'Connell, J. R. A1 - Palmer, N. D. A1 - Pampana, A. A1 - Peralta, J. M. A1 - Peyser, P. A. A1 - Psaty, B. M. A1 - Redline, S. A1 - Rice, K. M. A1 - Rich, S. S. A1 - Smith, J. A. A1 - Tiwari, H. K. A1 - Tsai, M. Y. A1 - Vasan, R. S. A1 - Wang, F. F. A1 - Weeks, D. E. A1 - Weng, Z. A1 - Wilson, J. G. A1 - Yanek, L. R. A1 - Neale, B. M. A1 - Sunyaev, S. R. A1 - Abecasis, G. R. A1 - Rotter, J. I. A1 - Willer, C. J. A1 - Peloso, G. M. A1 - Natarajan, P. A1 - Lin, X. A1 - Abe, N. A1 - Abecasis, G. R. A1 - Aguet, F. A1 - Albert, C. A1 - Almasy, L. A1 - Alonso, A. A1 - Ament, S. A1 - Anderson, P. A1 - Anugu, P. A1 - Applebaum-Bowden, D. A1 - Ardlie, K. A1 - Arking, D. A1 - Arnett, D. K. A1 - Ashley-Koch, A. A1 - Aslibekyan, S. A1 - Assimes, T. A1 - Auer, P. A1 - Avramopoulos, D. A1 - Barnard, J. A1 - Barnes, K. A1 - Barr, R. G. A1 - Barron-Casella, E. A1 - Barwick, L. A1 - Beaty, T. A1 - Beck, G. A1 - Becker, D. A1 - Becker, L. A1 - Beer, R. A1 - Beitelshees, A. A1 - Benjamin, E. A1 - Benos, T. A1 - Bezerra, M. A1 - Bielak, L. F. A1 - Bis, J. A1 - Blackwell, T. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bowden, D. W. A1 - Bowler, R. A1 - Brody, J. A1 - Broeckel, U. A1 - Broome, J. G. A1 - Bunting, K. A1 - Burchard, E. A1 - Bustamante, C. A1 - Buth, E. A1 - Cade, B. A1 - Cardwell, J. A1 - Carey, V. A1 - Carty, C. A1 - Casaburi, R. A1 - Casella, J. A1 - Castaldi, P. A1 - Chaffin, M. A1 - Chang, C. A1 - Chang, Y. C. A1 - Chasman, D. A1 - Chavan, S. A1 - Chen, B. J. A1 - Chen, W. M. A1 - Chen, Y. I. A1 - Cho, M. A1 - Choi, S. H. A1 - Chuang, L. M. A1 - Chung, M. A1 - Chung, R. H. A1 - Clish, C. A1 - Comhair, S. A1 - Conomos, M. P. A1 - Cornell, E. A1 - Correa, A. A1 - Crandall, C. A1 - Crapo, J. A1 - Cupples, L. A. A1 - Curran, J. E. A1 - Curtis, J. A1 - Custer, B. A1 - Damcott, C. A1 - Darbar, D. A1 - Das, S. A1 - David, S. A1 - Davis, C. A1 - Daya, M. A1 - de Andrade, M. A1 - Fuentes, L. L. A1 - DeBaun, M. A1 - Deka, R. A1 - DeMeo, D. A1 - Devine, S. A1 - Duan, Q. A1 - Duggirala, R. A1 - Durda, J. P. A1 - Dutcher, S. A1 - Eaton, C. A1 - Ekunwe, L. A1 - El Boueiz, A. A1 - Ellinor, P. A1 - Emery, L. A1 - Erzurum, S. A1 - Farber, C. A1 - Fingerlin, T. A1 - Flickinger, M. A1 - Fornage, M. A1 - Franceschini, N. A1 - Frazar, C. A1 - Fu, M. A1 - Fullerton, S. M. A1 - Fulton, L. A1 - Gabriel, S. A1 - Gan, W. A1 - Gao, S. A1 - Gao, Y. A1 - Gass, M. A1 - Gelb, B. A1 - Geng, X. P. A1 - Geraci, M. A1 - Germer, S. A1 - Gerszten, R. A1 - Ghosh, A. A1 - Gibbs, R. A1 - Gignoux, C. A1 - Gladwin, M. A1 - Glahn, D. A1 - Gogarten, S. A1 - Gong, D. W. A1 - Goring, H. A1 - Graw, S. A1 - Grine, D. A1 - Gu, C. C. A1 - Guan, Y. A1 - Guo, X. A1 - Gupta, N. A1 - Haessler, J. A1 - Hall, M. A1 - Harris, D. A1 - Hawley, N. L. A1 - He, J. A1 - Heckbert, S. A1 - Hernandez, R. A1 - Herrington, D. A1 - Hersh, C. A1 - Hidalgo, B. A1 - Hixson, J. A1 - Hobbs, B. A1 - Hokanson, J. A1 - Hong, E. A1 - Hoth, K. A1 - Hsiung, C. A. A1 - Hung, Y. J. A1 - Huston, H. A1 - Hwu, C. M. A1 - Irvin, M. R. A1 - Jackson, R. A1 - Jain, D. 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A1 - O'Donnell, C. A1 - Palmer, N. D. A1 - Pampana, A. A1 - Patel, A. A1 - Peloso, G. M. A1 - Perry, J. A1 - Peters, U. A1 - Peyser, P. A. A1 - Pirruccello, J. A1 - Pollin, T. A1 - Preuss, M. A1 - Psaty, B. M. A1 - Rao, D. C. A1 - Redline, S. A1 - Reed, R. A1 - Reiner, A. A1 - Rich, S. S. A1 - Rosenthal, S. A1 - Rotter, J. I. A1 - Schoenberg, J. A1 - Selvaraj, M. S. A1 - Sheu, W. H. A1 - Smith, J. A. A1 - Sofer, T. A1 - Stilp, A. M. A1 - Sunyaev, S. R. A1 - Surakka, I. A1 - Sztalryd, C. A1 - Tang, H. A1 - Taylor, K. D. A1 - Tsai, M. Y. A1 - Uddin, M. M. A1 - Urbut, S. A1 - Verbanck, M. A1 - Von Holle, A. A1 - Wang, H. A1 - Wang, F. F. A1 - Wiggins, K. A1 - Willer, C. J. A1 - Wilson, J. G. A1 - Wolford, B. A1 - Xu, H. A1 - Yanek, L. R. A1 - Zaghloul, N. A1 - Zekavat, M. A1 - Zhang, J. AB - Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol. VL - 52 ER - TY - JOUR T1 - {Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies JF - PLoS Med Y1 - 2020 A1 - Imamura, F. A1 - Fretts, A. M. A1 - Marklund, M. A1 - Ardisson Korat, A. V. A1 - Yang, W. S. A1 - Lankinen, M. A1 - Qureshi, W. A1 - Helmer, C. A1 - Chen, T. A. A1 - Virtanen, J. K. A1 - Wong, K. A1 - Bassett, J. K. A1 - Murphy, R. A1 - Tintle, N. A1 - Yu, C. I. A1 - Brouwer, I. A. A1 - Chien, K. L. A1 - Chen, Y. Y. A1 - Wood, A. C. A1 - Del Gobbo, L. C. A1 - Djousse, L. A1 - Geleijnse, J. M. A1 - Giles, G. G. A1 - de Goede, J. A1 - Gudnason, V. A1 - Harris, W. S. A1 - Hodge, A. A1 - Hu, F. A1 - Koulman, A. A1 - Laakso, M. A1 - Lind, L. A1 - Lin, H. J. A1 - McKnight, B. A1 - Rajaobelina, K. A1 - Riserus, U. A1 - Robinson, J. G. A1 - Samieri, C. A1 - Senn, M. A1 - Siscovick, D. S. A1 - Soedamah-Muthu, S. S. A1 - Sotoodehnia, N. A1 - Sun, Q. A1 - Tsai, M. Y. A1 - Tuomainen, T. P. A1 - Uusitupa, M. A1 - Wagenknecht, L. E. A1 - Wareham, N. J. A1 - Wu, J. H. Y. A1 - Micha, R. A1 - Lemaitre, R. N. A1 - Mozaffarian, D. A1 - Forouhi, N. G. AB - De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).\ Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.\ Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D. VL - 17 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. JF - Mol Psychiatry Y1 - 2020 A1 - de Las Fuentes, Lisa A1 - Sung, Yun Ju A1 - Noordam, Raymond A1 - Winkler, Thomas A1 - Feitosa, Mary F A1 - Schwander, Karen A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Manning, Alisa A1 - Chasman, Daniel I A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Hartwig, Fernando P A1 - Horimoto, A R V R A1 - Li, Changwei A1 - Li-Gao, Ruifang A1 - Liu, Yongmei A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Ntalla, Ioanna A1 - Rankinen, Tuomo A1 - Richard, Melissa A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vojinovic, Dina A1 - Warren, Helen R A1 - Xuan, Deng A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin-Fang A1 - Chen, Xu A1 - Christensen, Kaare A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Girotto, Giorgia A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Brumat, Marco A1 - Burke, Gregory A1 - Cabrera, Claudia P A1 - Canouil, Mickaël A1 - Chee, Miao Li A1 - Chen, Yii-Der Ida A1 - Cocca, Massimiliano A1 - Connell, John A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Eiriksdottir, Gudny A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Fox, Ervin F A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Kraja, Aldi T A1 - Krieger, J E A1 - Langefeld, Carl D A1 - Li, Yize A1 - Liang, Jingjing A1 - Liewald, David C M A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Lohman, Kurt K A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mook-Kanamori, Dennis O A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Norris, Jill M A1 - O'Connell, Jeff A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Pedersen, Nancy L A1 - Perls, Thomas A1 - Peters, Annette A1 - Petersmann, Astrid A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Raffel, Leslie J A1 - Rice, Treva K A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rueda-Ochoa, Oscar-Leonel A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Schreiner, Pamela J A1 - Shikany, James M A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Teumer, Alexander A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Ende, M Yldau A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Weir, David R A1 - Wen, Wanqing A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Marques-Vidal, Pedro A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Correa, Adolfo A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - Palmas, Walter R A1 - Pereira, A C A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotimi, Charles N A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Rice, Kenneth A1 - Gauderman, W James A1 - Morrison, Alanna C A1 - North, Kari E A1 - Kardia, Sharon L R A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Munroe, Patricia B A1 - Franks, Paul W A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

ER - TY - JOUR T1 - Genetic and regulatory architecture of Alzheimer's disease in the region. JF - Alzheimers Dement (Amst) Y1 - 2020 A1 - Kulminski, Alexander M A1 - Shu, Leonardo A1 - Loika, Yury A1 - He, Liang A1 - Nazarian, Alireza A1 - Arbeev, Konstantin A1 - Ukraintseva, Svetlana A1 - Yashin, Anatoliy A1 - Culminskaya, Irina AB -

Introduction: Apolipoprotein E () ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro "risk" factors for Alzheimer's disease (AD).

Methods: We examined differences in linkage disequilibrium (LD) structures between (1) AD-affected and unaffected subjects and (2) older AD-unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358.

Results: AD is associated with sex-nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD-affected subjects. The LD patterns in older AD-unaffected subjects resembled those in younger individuals. Polarization of the ε4- and ε2 allele-related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis.

Discussion: Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue-specific manner, which is not driven by common evolutionary forces.

VL - 12 IS - 1 ER - TY - JOUR T1 - The genetic architecture of the human cerebral cortex JF - Science Y1 - 2020 A1 - Grasby, Katrina L. A1 - Jahanshad, Neda A1 - Painter, Jodie N. A1 - Colodro-Conde, Lucía A1 - Bralten, Janita A1 - Hibar, Derrek P. A1 - Lind, Penelope A. A1 - Pizzagalli, Fabrizio A1 - Ching, Christopher R. K. A1 - McMahon, Mary Agnes B. A1 - Shatokhina, Natalia A1 - Zsembik, Leo C. P. A1 - Thomopoulos, Sophia I. A1 - Zhu, Alyssa H. A1 - Strike, Lachlan T. A1 - Agartz, Ingrid A1 - Alhusaini, Saud A1 - Almeida, Marcio A. A. A1 - Alnæs, Dag A1 - Amlien, Inge K. A1 - Andersson, Micael A1 - Ard, Tyler A1 - Armstrong, Nicola J. A1 - Ashley-Koch, Allison A1 - Atkins, Joshua R. A1 - Bernard, Manon A1 - Brouwer, Rachel M. A1 - Buimer, Elizabeth E. L. A1 - Bülow, Robin A1 - Bürger, Christian A1 - Cannon, Dara M. A1 - Chakravarty, Mallar A1 - Chen, Qiang A1 - Cheung, Joshua W. A1 - Couvy-Duchesne, Baptiste A1 - Dale, Anders M. A1 - Dalvie, Shareefa A1 - de Araujo, Tânia K. A1 - de Zubicaray, Greig I. A1 - de Zwarte, Sonja M. C. A1 - den Braber, Anouk A1 - Doan, Nhat Trung A1 - Dohm, Katharina A1 - Ehrlich, Stefan A1 - Engelbrecht, Hannah-Ruth A1 - Erk, Susanne A1 - Fan, Chun Chieh A1 - Fedko, Iryna O. A1 - Foley, Sonya F. A1 - Ford, Judith M. A1 - Fukunaga, Masaki A1 - Garrett, Melanie E. A1 - Ge, Tian A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L. A1 - Green, Melissa J. A1 - Groenewold, Nynke A. A1 - Grotegerd, Dominik A1 - Gurholt, Tiril P. A1 - Gutman, Boris A. A1 - Hansell, Narelle K. A1 - Harris, Mathew A. A1 - Harrison, Marc B. A1 - Haswell, Courtney C. A1 - Hauser, Michael A1 - Herms, Stefan A1 - Heslenfeld, Dirk J. A1 - Ho, New Fei A1 - Hoehn, David A1 - Hoffmann, Per A1 - Holleran, Laurena A1 - Hoogman, Martine A1 - Hottenga, Jouke-Jan A1 - Ikeda, Masashi A1 - Janowitz, Deborah A1 - Jansen, Iris E. A1 - Jia, Tianye A1 - Jockwitz, Christiane A1 - Kanai, Ryota A1 - Karama, Sherif A1 - Kasperaviciute, Dalia A1 - Kaufmann, Tobias A1 - Kelly, Sinead A1 - Kikuchi, Masataka A1 - Klein, Marieke A1 - Knapp, Michael A1 - Knodt, Annchen R. A1 - Krämer, Bernd A1 - Lam, Max A1 - Lancaster, Thomas M. A1 - Lee, Phil H. A1 - Lett, Tristram A. A1 - Lewis, Lindsay B. A1 - Lopes-Cendes, Iscia A1 - Luciano, Michelle A1 - Macciardi, Fabio A1 - Marquand, Andre F. A1 - Mathias, Samuel R. A1 - Melzer, Tracy R. A1 - Milaneschi, Yuri A1 - Mirza-Schreiber, Nazanin A1 - Moreira, Jose C. V. A1 - Mühleisen, Thomas W. A1 - Müller-Myhsok, Bertram A1 - Najt, Pablo A1 - Nakahara, Soichiro A1 - Nho, Kwangsik A1 - Olde Loohuis, Loes M. A1 - Orfanos, Dimitri Papadopoulos A1 - Pearson, John F. A1 - Pitcher, Toni L. A1 - Pütz, Benno A1 - Quidé, Yann A1 - Ragothaman, Anjanibhargavi A1 - Rashid, Faisal M. A1 - Reay, William R. A1 - Redlich, Ronny A1 - Reinbold, Céline S. A1 - Repple, Jonathan A1 - Richard, Geneviève A1 - Riedel, Brandalyn C. A1 - Risacher, Shannon L. A1 - Rocha, Cristiane S. A1 - Mota, Nina Roth A1 - Salminen, Lauren A1 - Saremi, Arvin A1 - Saykin, Andrew J. A1 - Schlag, Fenja A1 - Schmaal, Lianne A1 - Schofield, Peter R. A1 - Secolin, Rodrigo A1 - Shapland, Chin Yang A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Sønderby, Ida E. A1 - Sprooten, Emma A1 - Tansey, Katherine E. A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Tordesillas-Gutierrez, Diana A1 - Turner, Jessica A. A1 - Uhlmann, Anne A1 - Vallerga, Costanza Ludovica A1 - van der Meer, Dennis A1 - van Donkelaar, Marjolein M. J. A1 - van Eijk, Liza A1 - van Erp, Theo G. M. A1 - van Haren, Neeltje E. M. A1 - van Rooij, Daan A1 - van Tol, Marie-Jose A1 - Veldink, Jan H. A1 - Verhoef, Ellen A1 - Walton, Esther A1 - Wang, Mingyuan A1 - Wang, Yunpeng A1 - Wardlaw, Joanna M. A1 - Wen, Wei A1 - Westlye, Lars T. A1 - Whelan, Christopher D. A1 - Witt, Stephanie H. A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Wu, Jing Qin A1 - Yasuda, Clarissa L. A1 - Zaremba, Dario A1 - Zhang, Zuo A1 - Zwiers, Marcel P. A1 - Artiges, Eric A1 - Assareh, Amelia A. A1 - Ayesa-Arriola, Rosa A1 - Belger, Aysenil A1 - Brandt, Christine L. A1 - Brown, Gregory G. A1 - Cichon, Sven A1 - Curran, Joanne E. A1 - Davies, Gareth E. A1 - Degenhardt, Franziska A1 - Dennis, Michelle F. A1 - Dietsche, Bruno A1 - Djurovic, Srdjan A1 - Doherty, Colin P. A1 - Espiritu, Ryan A1 - Garijo, Daniel A1 - Gil, Yolanda A1 - Gowland, Penny A. A1 - Green, Robert C. A1 - Häusler, Alexander N. A1 - Heindel, Walter A1 - Ho, Beng-Choon A1 - Hoffmann, Wolfgang U. A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Jack, Clifford R. A1 - Jang, MiHyun A1 - Jansen, Andreas A1 - Kimbrel, Nathan A. A1 - Kolskår, Knut A1 - Koops, Sanne A1 - Krug, Axel A1 - Lim, Kelvin O. A1 - Luykx, Jurjen J. A1 - Mathalon, Daniel H. A1 - Mather, Karen A. A1 - Mattay, Venkata S. A1 - Matthews, Sarah A1 - Mayoral Van Son, Jaqueline A1 - McEwen, Sarah C. A1 - Melle, Ingrid A1 - Morris, Derek W. A1 - Mueller, Bryon A. A1 - Nauck, Matthias A1 - Nordvik, Jan E. A1 - Nöthen, Markus M. A1 - O’Leary, Daniel S. A1 - Opel, Nils A1 - Martinot, Marie-Laure Paillère A1 - Pike, G. Bruce A1 - Preda, Adrian A1 - Quinlan, Erin B. A1 - Rasser, Paul E. A1 - Ratnakar, Varun A1 - Reppermund, Simone A1 - Steen, Vidar M. A1 - Tooney, Paul A. A1 - Torres, Fábio R. A1 - Veltman, Dick J. A1 - Voyvodic, James T. A1 - Whelan, Robert A1 - White, Tonya A1 - Yamamori, Hidenaga A1 - Adams, Hieab H. H. A1 - Bis, Joshua C. A1 - Debette, Stephanie A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofer, Edith A1 - Ikram, M. Arfan A1 - Launer, Lenore A1 - Longstreth, W. T. A1 - Lopez, Oscar L. A1 - Mazoyer, Bernard A1 - Mosley, Thomas H. A1 - Roshchupkin, Gennady V. A1 - Satizabal, Claudia L. A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Yang, Qiong A1 - Alvim, Marina K. M. A1 - Ames, David A1 - Anderson, Tim J. A1 - Andreassen, Ole A. A1 - Arias-Vasquez, Alejandro A1 - Bastin, Mark E. A1 - Baune, Bernhard T. A1 - Beckham, Jean C. A1 - Blangero, John A1 - Boomsma, Dorret I. A1 - Brodaty, Henry A1 - Brunner, Han G. A1 - Buckner, Randy L. A1 - Buitelaar, Jan K. A1 - Bustillo, Juan R. A1 - Cahn, Wiepke A1 - Cairns, Murray J. A1 - Calhoun, Vince A1 - Carr, Vaughan J. A1 - Caseras, Xavier A1 - Caspers, Svenja A1 - Cavalleri, Gianpiero L. A1 - Cendes, Fernando A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Dalrymple-Alford, John C. A1 - Dannlowski, Udo A1 - de Geus, Eco J. C. A1 - Deary, Ian J. A1 - Delanty, Norman A1 - Depondt, Chantal A1 - Desrivières, Sylvane A1 - Donohoe, Gary A1 - Espeseth, Thomas A1 - Fernández, Guillén A1 - Fisher, Simon E. A1 - Flor, Herta A1 - Forstner, Andreas J. A1 - Francks, Clyde A1 - Franke, Barbara A1 - Glahn, David C. A1 - Gollub, Randy L. A1 - Grabe, Hans J. A1 - Gruber, Oliver A1 - Håberg, Asta K. A1 - Hariri, Ahmad R. A1 - Hartman, Catharina A. A1 - Hashimoto, Ryota A1 - Heinz, Andreas A1 - Henskens, Frans A. A1 - Hillegers, Manon H. J. A1 - Hoekstra, Pieter J. A1 - Holmes, Avram J. A1 - Hong, L. Elliot A1 - Hopkins, William D. A1 - Hulshoff Pol, Hilleke E. A1 - Jernigan, Terry L. A1 - Jönsson, Erik G. A1 - Kahn, René S. A1 - Kennedy, Martin A. A1 - Kircher, Tilo T. J. A1 - Kochunov, Peter A1 - Kwok, John B. J. A1 - Le Hellard, Stephanie A1 - Loughland, Carmel M. A1 - Martin, Nicholas G. A1 - Martinot, Jean-Luc A1 - McDonald, Colm A1 - McMahon, Katie L. A1 - Meyer-Lindenberg, Andreas A1 - Michie, Patricia T. A1 - Morey, Rajendra A. A1 - Mowry, Bryan A1 - Nyberg, Lars A1 - Oosterlaan, Jaap A1 - Ophoff, Roel A. A1 - Pantelis, Christos A1 - Paus, Tomáš A1 - Pausova, Zdenka A1 - Penninx, Brenda W. J. H. A1 - Polderman, Tinca J. C. A1 - Posthuma, Danielle A1 - Rietschel, Marcella A1 - Roffman, Joshua L. A1 - Rowland, Laura M. A1 - Sachdev, Perminder S. A1 - Sämann, Philipp G. A1 - Schall, Ulrich A1 - Schumann, Gunter A1 - Scott, Rodney J. A1 - Sim, Kang A1 - Sisodiya, Sanjay M. A1 - Smoller, Jordan W. A1 - Sommer, Iris E. A1 - St Pourcain, Beate A1 - Stein, Dan J. A1 - Toga, Arthur W. A1 - Trollor, Julian N. A1 - Van der Wee, Nic J. A. A1 - van ’t Ent, Dennis A1 - Völzke, Henry A1 - Walter, Henrik A1 - Weber, Bernd A1 - Weinberger, Daniel R. A1 - Wright, Margaret J. A1 - Zhou, Juan A1 - Stein, Jason L. A1 - Thompson, Paul M. A1 - Medland, Sarah E. VL - 367 UR - https://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690 IS - 6484 JO - Science ER - TY - JOUR T1 - {Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults JF - Nat Commun Y1 - 2020 A1 - Hofer, E. A1 - Roshchupkin, G. V. A1 - Adams, H. H. H. A1 - Knol, M. J. A1 - Lin, H. A1 - Li, S. A1 - Zare, H. A1 - Ahmad, S. A1 - Armstrong, N. J. A1 - Satizabal, C. L. A1 - Bernard, M. A1 - Bis, J. C. A1 - Gillespie, N. A. A1 - Luciano, M. A1 - Mishra, A. A1 - Scholz, M. A1 - Teumer, A. A1 - Xia, R. A1 - Jian, X. A1 - Mosley, T. H. A1 - Saba, Y. A1 - Pirpamer, L. A1 - Seiler, S. A1 - Becker, J. T. A1 - Carmichael, O. A1 - Rotter, J. I. A1 - Psaty, B. M. A1 - Lopez, O. L. A1 - Amin, N. A1 - van der Lee, S. J. A1 - Yang, Q. A1 - Himali, J. J. A1 - Maillard, P. A1 - Beiser, A. S. A1 - DeCarli, C. A1 - Karama, S. A1 - Lewis, L. A1 - Harris, M. A1 - Bastin, M. E. A1 - Deary, I. J. A1 - Veronica Witte, A. A1 - Beyer, F. A1 - Loeffler, M. A1 - Mather, K. A. A1 - Schofield, P. R. A1 - Thalamuthu, A. A1 - Kwok, J. B. A1 - Wright, M. J. A1 - Ames, D. A1 - Trollor, J. A1 - Jiang, J. A1 - Brodaty, H. A1 - Wen, W. A1 - Vernooij, M. W. A1 - Hofman, A. A1 - Uitterlinden, A. G. A1 - Niessen, W. J. A1 - Wittfeld, K. A1 - B?low, R. A1 - V?lker, U. A1 - Pausova, Z. A1 - Bruce Pike, G. A1 - Maingault, S. A1 - Crivello, F. A1 - Tzourio, C. A1 - Amouyel, P. A1 - Mazoyer, B. A1 - Neale, M. C. A1 - Franz, C. E. A1 - Lyons, M. J. A1 - Panizzon, M. S. A1 - Andreassen, O. A. A1 - Dale, A. M. A1 - Logue, M. A1 - Grasby, K. L. A1 - Jahanshad, N. A1 - Painter, J. N. A1 - Colodro-Conde, L. A1 - Bralten, J. A1 - Hibar, D. P. A1 - Lind, P. A. A1 - Pizzagalli, F. A1 - Stein, J. L. A1 - Thompson, P. M. A1 - Medland, S. E. A1 - Sachdev, P. S. A1 - Kremen, W. S. A1 - Wardlaw, J. M. 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A1 - Fisher, S. E. A1 - Flor, H. A1 - Forstner, A. J. A1 - Francks, C. A1 - Franke, B. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - Grabe, H. J. A1 - Gruber, O. A1 - H?berg, A. K. A1 - Hariri, A. R. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Heinz, A. A1 - Hillegers, M. H. J. A1 - Hoekstra, P. J. A1 - Holmes, A. J. A1 - Hong, L. E. A1 - Hopkins, W. D. A1 - Hulshoff Pol, H. E. A1 - Jernigan, T. L. A1 - J?nsson, E. G. A1 - Kahn, R. S. A1 - Kennedy, M. A. A1 - Kircher, T. T. J. A1 - Kochunov, P. A1 - Kwok, J. B. J. A1 - Hellard, S. L. A1 - Martin, N. G. A1 - Martinot, J. - A1 - McDonald, C. A1 - McMahon, K. L. A1 - Meyer-Lindenberg, A. A1 - Morey, R. A. A1 - Nyberg, L. A1 - Oosterlaan, J. A1 - Ophoff, R. A. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. J. H. A1 - Polderman, T. J. C. A1 - Posthuma, D. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Rowland, L. M. A1 - Sachdev, P. S. A1 - S?mann, P. G. A1 - Schumann, G. A1 - Sim, K. A1 - Sisodiya, S. M. A1 - Smoller, J. W. A1 - Sommer, I. E. A1 - Pourcain, B. S. A1 - Stein, D. J. A1 - Toga, A. W. A1 - Trollor, J. N. A1 - Van der Wee, N. J. A. A1 - van 't Ent, D. A1 - V?lzke, H. A1 - Walter, H. A1 - Weber, B. A1 - Weinberger, D. R. A1 - Wright, M. J. A1 - Zhou, J. A1 - Stein, J. L. A1 - Thompson, P. M. A1 - Medland, S. E. AB - Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging. VL - 11 ER - TY - JOUR T1 - {Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation JF - Circ Genom Precis Med Y1 - 2020 A1 - Weng, L. C. A1 - Hall, A. W. A1 - Choi, S. H. A1 - Jurgens, S. J. A1 - Haessler, J. A1 - Bihlmeyer, N. A. A1 - Grarup, N. A1 - Lin, H. A1 - Teumer, A. A1 - Li-Gao, R. A1 - Yao, J. A1 - Guo, X. A1 - Brody, J. A. A1 - M?ller-Nurasyid, M. A1 - Schramm, K. A1 - Verweij, N. A1 - van den Berg, M. E. A1 - van Setten, J. A1 - Isaacs, A. A1 - Ram?rez, J. A1 - Warren, H. R. A1 - Padmanabhan, S. A1 - Kors, J. A. A1 - de Boer, R. A. A1 - van der Meer, P. A1 - Sinner, M. F. A1 - Waldenberger, M. A1 - Psaty, B. M. A1 - Taylor, K. D. A1 - V?lker, U. A1 - Kanters, J. K. A1 - Li, M. A1 - Alonso, A. A1 - Perez, M. V. A1 - Vaartjes, I. A1 - Bots, M. L. A1 - Huang, P. L. A1 - Heckbert, S. R. A1 - Lin, H. J. A1 - Kornej, J. A1 - Munroe, P. B. A1 - van Duijn, C. M. A1 - Asselbergs, F. W. A1 - Stricker, B. H. A1 - van der Harst, P. A1 - K??b, S. A1 - Peters, A. A1 - Sotoodehnia, N. A1 - Rotter, J. I. A1 - Mook-Kanamori, D. O. A1 - D?rr, M. A1 - Felix, S. B. A1 - Linneberg, A. A1 - Hansen, T. A1 - Arking, D. E. A1 - Kooperberg, C. A1 - Benjamin, E. J. A1 - Lunetta, K. L. A1 - Ellinor, P. T. A1 - Lubitz, S. A. AB - Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and 230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF. ER - TY - JOUR T1 - Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. JF - PLoS One Y1 - 2020 A1 - Hahn, Julie A1 - Fu, Yi-Ping A1 - Brown, Michael R A1 - Bis, Joshua C A1 - de Vries, Paul S A1 - Feitosa, Mary F A1 - Yanek, Lisa R A1 - Weiss, Stefan A1 - Giulianini, Franco A1 - Smith, Albert Vernon A1 - Guo, Xiuqing A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Chen, Yii-Der Ida A1 - Franco, Oscar H A1 - Grove, Megan A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Hwang, Shih-Jen A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Markus, Marcello R P A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Yao, Jie A1 - Chasman, Daniel I A1 - Dörr, Marcus A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Morrison, Alanna C KW - Aging KW - Coronary Artery Disease KW - Cross-Sectional Studies KW - Europe KW - European Continental Ancestry Group KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

VL - 15 IS - 11 ER - TY - JOUR T1 - Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. JF - Diabetes Y1 - 2020 A1 - Yaghootkar, Hanieh A1 - Zhang, Yiying A1 - Spracklen, Cassandra N A1 - Karaderi, Tugce A1 - Huang, Lam Opal A1 - Bradfield, Jonathan A1 - Schurmann, Claudia A1 - Fine, Rebecca S A1 - Preuss, Michael H A1 - Kutalik, Zoltán A1 - Wittemans, Laura Bl A1 - Lu, Yingchang A1 - Metz, Sophia A1 - Willems, Sara M A1 - Li-Gao, Ruifang A1 - Grarup, Niels A1 - Wang, Shuai A1 - Molnos, Sophie A1 - Sandoval-Zárate, América A A1 - Nalls, Mike A A1 - Lange, Leslie A A1 - Haesser, Jeffrey A1 - Guo, Xiuqing A1 - Lyytikäinen, Leo-Pekka A1 - Feitosa, Mary F A1 - Sitlani, Colleen M A1 - Venturini, Cristina A1 - Mahajan, Anubha A1 - Kacprowski, Tim A1 - Wang, Carol A A1 - Chasman, Daniel I A1 - Amin, Najaf A1 - Broer, Linda A1 - Robertson, Neil A1 - Young, Kristin L A1 - Allison, Matthew A1 - Auer, Paul L A1 - Blüher, Matthias A1 - Borja, Judith B A1 - Bork-Jensen, Jette A1 - Carrasquilla, Germán D A1 - Christofidou, Paraskevi A1 - Demirkan, Ayse A1 - Doege, Claudia A A1 - Garcia, Melissa E A1 - Graff, Mariaelisa A1 - Guo, Kaiying A1 - Hakonarson, Hakon A1 - Hong, Jaeyoung A1 - Ida Chen, Yii-Der A1 - Jackson, Rebecca A1 - Jakupović, Hermina A1 - Jousilahti, Pekka A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Kizer, Jorge R A1 - Kriebel, Jennifer A1 - LeDuc, Charles A A1 - Li, Jin A1 - Lind, Lars A1 - Luan, Jian'an A1 - Mackey, David A1 - Mangino, Massimo A1 - Männistö, Satu A1 - Martin Carli, Jayne F A1 - Medina-Gómez, Carolina A1 - Mook-Kanamori, Dennis O A1 - Morris, Andrew P A1 - de Mutsert, Renée A1 - Nauck, Matthias A1 - Nedeljkovic, Ivana A1 - Pennell, Craig E A1 - Pradhan, Arund D A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Scott, Robert A A1 - Skaaby, Tea A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Wu, Ying A1 - Yao, Jie A1 - Walker, Mark A1 - North, Kari E A1 - Kovacs, Peter A1 - Ikram, M Arfan A1 - van Duijn, Cornelia M A1 - Ridker, Paul M A1 - Lye, Stephen A1 - Homuth, Georg A1 - Ingelsson, Erik A1 - Spector, Tim D A1 - McKnight, Barbara A1 - Province, Michael A A1 - Lehtimäki, Terho A1 - Adair, Linda S A1 - Rotter, Jerome I A1 - Reiner, Alexander P A1 - Wilson, James G A1 - Harris, Tamara B A1 - Ripatti, Samuli A1 - Grallert, Harald A1 - Meigs, James B A1 - Salomaa, Veikko A1 - Hansen, Torben A1 - Willems van Dijk, Ko A1 - Wareham, Nicholas J A1 - Grant, Struan Fa A1 - Langenberg, Claudia A1 - Frayling, Timothy M A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L A1 - Leibel, Rudolph L A1 - Loos, Ruth Jf A1 - Kilpeläinen, Tuomas O AB -

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

ER - TY - JOUR T1 - {Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure JF - Nat Commun Y1 - 2020 A1 - Shah, S. A1 - Henry, A. A1 - Roselli, C. A1 - Lin, H. A1 - Sveinbj?rnsson, G. A1 - Fatemifar, G. A1 - Hedman, ?. K. A1 - Wilk, J. B. A1 - Morley, M. P. A1 - Chaffin, M. D. A1 - Helgadottir, A. A1 - Verweij, N. A1 - Dehghan, A. A1 - Almgren, P. A1 - Andersson, C. A1 - Aragam, K. G. A1 - ?rnl?v, J. A1 - Backman, J. D. A1 - Biggs, M. L. A1 - Bloom, H. L. A1 - Brandimarto, J. A1 - Brown, M. R. A1 - Buckbinder, L. A1 - Carey, D. J. A1 - Chasman, D. I. A1 - Chen, X. A1 - Chen, X. A1 - Chung, J. A1 - Chutkow, W. A1 - Cook, J. P. A1 - Delgado, G. E. A1 - Denaxas, S. A1 - Doney, A. S. A1 - D?rr, M. A1 - Dudley, S. C. A1 - Dunn, M. E. A1 - Engstr?m, G. A1 - Esko, T. A1 - Felix, S. B. A1 - Finan, C. A1 - Ford, I. A1 - Ghanbari, M. A1 - Ghasemi, S. A1 - Giedraitis, V. A1 - Giulianini, F. A1 - Gottdiener, J. S. A1 - Gross, S. A1 - Gu?bjartsson, D. F. A1 - Gutmann, R. A1 - Haggerty, C. M. A1 - van der Harst, P. A1 - Hyde, C. L. A1 - Ingelsson, E. A1 - Jukema, J. W. A1 - Kavousi, M. A1 - Khaw, K. T. A1 - Kleber, M. E. A1 - K?ber, L. A1 - Koekemoer, A. A1 - Langenberg, C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - London, B. A1 - Lotta, L. A. A1 - Lovering, R. C. A1 - Luan, J. A1 - Magnusson, P. A1 - Mahajan, A. A1 - Margulies, K. B. A1 - M?rz, W. A1 - Melander, O. A1 - Mordi, I. R. A1 - Morgan, T. A1 - Morris, A. D. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - Nagle, M. W. A1 - Nelson, C. P. A1 - Niessner, A. A1 - Niiranen, T. A1 - O'Donoghue, M. L. A1 - Owens, A. T. A1 - Palmer, C. N. A. A1 - Parry, H. M. A1 - Perola, M. A1 - Portilla-Fernandez, E. A1 - Psaty, B. M. A1 - Rice, K. M. A1 - Ridker, P. M. A1 - Romaine, S. P. R. A1 - Rotter, J. I. A1 - Salo, P. A1 - Salomaa, V. A1 - van Setten, J. A1 - Shalaby, A. A. A1 - Smelser, D. T. A1 - Smith, N. L. A1 - Stender, S. A1 - Stott, D. J. A1 - Svensson, P. A1 - Tammesoo, M. L. A1 - Taylor, K. D. A1 - Teder-Laving, M. A1 - Teumer, A. A1 - Thorgeirsson, G. A1 - Thorsteinsdottir, U. A1 - Torp-Pedersen, C. A1 - Trompet, S. A1 - Tyl, B. A1 - Uitterlinden, A. G. A1 - Veluchamy, A. A1 - V?lker, U. A1 - Voors, A. A. A1 - Wang, X. A1 - Wareham, N. J. A1 - Waterworth, D. A1 - Weeke, P. E. A1 - Weiss, R. A1 - Wiggins, K. L. A1 - Xing, H. A1 - Yerges-Armstrong, L. M. A1 - Yu, B. A1 - Zannad, F. A1 - Zhao, J. H. A1 - Hemingway, H. A1 - Samani, N. J. A1 - McMurray, J. J. V. A1 - Yang, J. A1 - Visscher, P. M. A1 - Newton-Cheh, C. A1 - Malarstig, A. A1 - Holm, H. A1 - Lubitz, S. A. A1 - Sattar, N. A1 - Holmes, M. V. A1 - Cappola, T. P. A1 - Asselbergs, F. W. A1 - Hingorani, A. D. A1 - Kuchenbaecker, K. A1 - Ellinor, P. T. A1 - Lang, C. C. A1 - Stefansson, K. A1 - Smith, J. G. A1 - Vasan, R. S. A1 - Swerdlow, D. I. A1 - Lumbers, R. T. A1 - Abecasis, G. A1 - Backman, J. A1 - Bai, X. A1 - Balasubramanian, S. A1 - Banerjee, N. A1 - Baras, A. A1 - Barnard, L. A1 - Beechert, C. A1 - Blumenfeld, A. A1 - Cantor, M. A1 - Chai, Y. A1 - Chung, J. A1 - Coppola, G. A1 - Damask, A. A1 - Dewey, F. A1 - Economides, A. A1 - Eom, G. A1 - Forsythe, C. A1 - Fuller, E. D. A1 - Gu, Z. A1 - Gurski, L. A1 - Guzzardo, P. M. A1 - Habegger, L. A1 - Hahn, Y. A1 - Hawes, A. A1 - van Hout, C. A1 - Jones, M. B. A1 - Khalid, S. A1 - Lattari, M. A1 - Li, A. A1 - Lin, N. A1 - Liu, D. A1 - Lopez, A. A1 - Manoochehri, K. A1 - Marchini, J. A1 - Marcketta, A. A1 - Maxwell, E. K. A1 - McCarthy, S. A1 - Mitnaul, L. J. A1 - O'Dushlaine, C. A1 - Overton, J. D. A1 - Padilla, M. S. A1 - Paulding, C. A1 - Penn, J. A1 - Pradhan, M. A1 - Reid, J. G. A1 - Schleicher, T. D. A1 - Schurmann, C. A1 - Shuldiner, A. A1 - Staples, J. C. A1 - Sun, D. A1 - Toledo, K. A1 - Ulloa, R. H. A1 - Widom, L. A1 - Wolf, S. E. A1 - Yadav, A. A1 - Ye, B. AB - Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. VL - 11 ER - TY - JOUR T1 - {Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke JF - Stroke Y1 - 2020 A1 - Keene, K. L. A1 - Hyacinth, H. I. A1 - Bis, J. C. A1 - Kittner, S. J. A1 - Mitchell, B. D. A1 - Cheng, Y. C. A1 - Pare, G. A1 - Chong, M. A1 - O'Donnell, M. A1 - Meschia, J. F. A1 - Chen, W. M. A1 - Sale, M. M. A1 - Rich, S. S. A1 - Nalls, M. A. A1 - Zonderman, A. B. A1 - Evans, M. K. A1 - Wilson, J. G. A1 - Correa, A. A1 - Markus, H. S. A1 - Traylor, M. A1 - Lewis, C. M. A1 - Carty, C. L. A1 - Reiner, A. A1 - Haessler, J. A1 - Langefeld, C. D. A1 - Gottesman, R. A1 - Mosley, T. H. A1 - Woo, D. A1 - Yaffe, K. A1 - Liu, Y. A1 - Longstreth, W. T. A1 - Psaty, B. M. A1 - Kooperberg, C. A1 - Lange, L. A. A1 - Sacco, R. A1 - Rundek, T. A1 - Lee, J. M. A1 - Cruchaga, C. A1 - Furie, K. L. A1 - Arnett, D. K. A1 - Benavente, O. R. A1 - Grewal, R. P. A1 - Peddareddygari, L. R. A1 - Dichgans, M. A1 - Malik, R. A1 - Worrall, B. B. A1 - Fornage, M. AB - Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.\ The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.\ In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci.\ These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date. VL - 51 ER - TY - JOUR T1 - {An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms JF - Sci Rep Y1 - 2020 A1 - Wildisen, L. A1 - Del Giovane, C. A1 - Moutzouri, E. A1 - Beglinger, S. A1 - Syrogiannouli, L. A1 - Collet, T. H. A1 - Cappola, A. R. A1 - ?svold, B. O. A1 - Bakker, S. J. L. A1 - Yeap, B. B. A1 - Almeida, O. P. A1 - Ceresini, G. A1 - Dullaart, R. P. F. A1 - Ferrucci, L. A1 - Grabe, H. A1 - Jukema, J. W. A1 - Nauck, M. A1 - Trompet, S. A1 - V?lzke, H. A1 - Westendorp, R. A1 - Gussekloo, J. A1 - Kl?ppel, S. A1 - Aujesky, D. A1 - Bauer, D. A1 - Peeters, R. A1 - Feller, M. A1 - Rodondi, N. AB - {In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76 VL - 10 ER - TY - JOUR T1 - Inherited causes of clonal haematopoiesis in 97,691 whole genomes. JF - Nature Y1 - 2020 A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Nandakumar, Satish K A1 - Fulco, Charles P A1 - Bao, Erik L A1 - Zekavat, Seyedeh M A1 - Szeto, Mindy D A1 - Liao, Xiaotian A1 - Leventhal, Matthew J A1 - Nasser, Joseph A1 - Chang, Kyle A1 - Laurie, Cecelia A1 - Burugula, Bala Bharathi A1 - Gibson, Christopher J A1 - Lin, Amy E A1 - Taub, Margaret A A1 - Aguet, Francois A1 - Ardlie, Kristin A1 - Mitchell, Braxton D A1 - Barnes, Kathleen C A1 - Moscati, Arden A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Silverman, Edwin K A1 - Weiss, Scott T A1 - Palmer, Nicholette D A1 - Vasan, Ramachandran S A1 - Burchard, Esteban G A1 - Kardia, Sharon L R A1 - He, Jiang A1 - Kaplan, Robert C A1 - Smith, Nicholas L A1 - Arnett, Donna K A1 - Schwartz, David A A1 - Correa, Adolfo A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Konkle, Barbara A A1 - Custer, Brian A1 - Peralta, Juan M A1 - Gui, Hongsheng A1 - Meyers, Deborah A A1 - McGarvey, Stephen T A1 - Chen, Ida Yii-Der A1 - Shoemaker, M Benjamin A1 - Peyser, Patricia A A1 - Broome, Jai G A1 - Gogarten, Stephanie M A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Montasser, May E A1 - Daya, Michelle A1 - Kenny, Eimear E A1 - North, Kari E A1 - Launer, Lenore J A1 - Cade, Brian E A1 - Bis, Joshua C A1 - Cho, Michael H A1 - Lasky-Su, Jessica A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Mak, Angel C Y A1 - Becker, Lewis C A1 - Smith, Jennifer A A1 - Kelly, Tanika N A1 - Aslibekyan, Stella A1 - Heckbert, Susan R A1 - Tiwari, Hemant K A1 - Yang, Ivana V A1 - Heit, John A A1 - Lubitz, Steven A A1 - Johnsen, Jill M A1 - Curran, Joanne E A1 - Wenzel, Sally E A1 - Weeks, Daniel E A1 - Rao, Dabeeru C A1 - Darbar, Dawood A1 - Moon, Jee-Young A1 - Tracy, Russell P A1 - Buth, Erin J A1 - Rafaels, Nicholas A1 - Loos, Ruth J F A1 - Durda, Peter A1 - Liu, Yongmei A1 - Hou, Lifang A1 - Lee, Jiwon A1 - Kachroo, Priyadarshini A1 - Freedman, Barry I A1 - Levy, Daniel A1 - Bielak, Lawrence F A1 - Hixson, James E A1 - Floyd, James S A1 - Whitsel, Eric A A1 - Ellinor, Patrick T A1 - Irvin, Marguerite R A1 - Fingerlin, Tasha E A1 - Raffield, Laura M A1 - Armasu, Sebastian M A1 - Wheeler, Marsha M A1 - Sabino, Ester C A1 - Blangero, John A1 - Williams, L Keoki A1 - Levy, Bruce D A1 - Sheu, Wayne Huey-Herng A1 - Roden, Dan M A1 - Boerwinkle, Eric A1 - Manson, JoAnn E A1 - Mathias, Rasika A A1 - Desai, Pinkal A1 - Taylor, Kent D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Zhao, Hongyu A1 - Lange, Ethan A1 - Lange, Leslie A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Scheet, Paul A1 - Kitzman, Jacob O A1 - Lander, Eric S A1 - Engreitz, Jesse M A1 - Ebert, Benjamin L A1 - Reiner, Alexander P A1 - Jaiswal, Siddhartha A1 - Abecasis, Goncalo A1 - Sankaran, Vijay G A1 - Kathiresan, Sekar A1 - Natarajan, Pradeep AB -

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

VL - 586 IS - 7831 ER - TY - JOUR T1 - Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study. JF - Lancet Respir Med Y1 - 2020 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Couper, David A1 - Folsom, Aaron R A1 - Freedman, Neal D A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Mathew, Amanda R A1 - Kronmal, Richard A A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Lewis J A1 - White, Wendy B A1 - Yende, Sachin KW - Adult KW - Aged KW - Case-Control Studies KW - Ex-Smokers KW - Female KW - Follow-Up Studies KW - Humans KW - Lung KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Non-Smokers KW - Respiratory Physiological Phenomena KW - Smokers KW - Smoking KW - Spirometry KW - United States KW - Young Adult AB -

BACKGROUND: Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease.

METHODS: We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption.

FINDINGS: 25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66-31·37) in sustained never-smokers, 34·97 mL per year (34·36-35·57) in former smokers, and 39·92 mL per year (38·92-40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV decline of 1·82 mL per year (95% CI 1·24-2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35-10·08). Compared to never-smokers, accelerated FEV decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV decline in current smokers consuming less than five cigarettes per day (7·65 mL per year; 95% CI 6·21-9·09) was 68% of that in current smokers consuming 30 or more cigarettes per day (11·24 mL per year; 9·86-12·62), and around five times greater than in former smokers (1·57 mL per year; 1·00-2·14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results.

INTERPRETATION: Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage.

FUNDING: National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

VL - 8 IS - 1 ER - TY - JOUR T1 - Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. JF - Eur J Epidemiol Y1 - 2020 A1 - Zheng, Yan A1 - Huang, Tao A1 - Wang, Tiange A1 - Mei, Zhendong A1 - Sun, Zhonghan A1 - Zhang, Tao A1 - Ellervik, Christina A1 - Chai, Jin-Fang A1 - Sim, Xueling A1 - van Dam, Rob M A1 - Tai, E-Shyong A1 - Koh, Woon-Puay A1 - Dorajoo, Rajkumar A1 - Saw, Seang-Mei A1 - Sabanayagam, Charumathi A1 - Wong, Tien Yin A1 - Gupta, Preeti A1 - Rossing, Peter A1 - Ahluwalia, Tarunveer S A1 - Vinding, Rebecca K A1 - Bisgaard, Hans A1 - Bønnelykke, Klaus A1 - Wang, Yujie A1 - Graff, Mariaelisa A1 - Voortman, Trudy A1 - van Rooij, Frank J A A1 - Hofman, Albert A1 - van Heemst, Diana A1 - Noordam, Raymond A1 - Estampador, Angela C A1 - Varga, Tibor V A1 - Enzenbach, Cornelia A1 - Scholz, Markus A1 - Thiery, Joachim A1 - Burkhardt, Ralph A1 - Orho-Melander, Marju A1 - Schulz, Christina-Alexandra A1 - Ericson, Ulrika A1 - Sonestedt, Emily A1 - Kubo, Michiaki A1 - Akiyama, Masato A1 - Zhou, Ang A1 - Kilpeläinen, Tuomas O A1 - Hansen, Torben A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - McCarthy, Mark A1 - Lemaitre, Rozenn N A1 - Felix, Janine F A1 - Jaddoe, Vincent W V A1 - Wu, Ying A1 - Mohlke, Karen L A1 - Lehtimäki, Terho A1 - Wang, Carol A A1 - Pennell, Craig E A1 - Schunkert, Heribert A1 - Kessler, Thorsten A1 - Zeng, Lingyao A1 - Willenborg, Christina A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Grote, Veit A1 - Rzehak, Peter A1 - Koletzko, Berthold A1 - Erdmann, Jeanette A1 - Munz, Matthias A1 - Wu, Tangchun A1 - He, Meian A1 - Yu, Caizheng A1 - Lecoeur, Cécile A1 - Froguel, Philippe A1 - Corella, Dolores A1 - Moreno, Luis A A1 - Lai, Chao-Qiang A1 - Pitkänen, Niina A1 - Boreham, Colin A A1 - Ridker, Paul M A1 - Rosendaal, Frits R A1 - de Mutsert, Renée A1 - Power, Chris A1 - Paternoster, Lavinia A1 - Sørensen, Thorkild I A A1 - Tjønneland, Anne A1 - Overvad, Kim A1 - Djoussé, Luc A1 - Rivadeneira, Fernando A1 - Lee, Nanette R A1 - Raitakari, Olli T A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Langhendries, Jean-Paul A1 - Escribano, Joaquin A1 - Verduci, Elvira A1 - Dedoussis, George A1 - König, Inke A1 - Balkau, Beverley A1 - Coltell, Oscar A1 - Dallongeville, Jean A1 - Meirhaeghe, Aline A1 - Amouyel, Philippe A1 - Gottrand, Frédéric A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Hyppönen, Elina A1 - März, Winfried A1 - Mackey, David A A1 - Gruszfeld, Dariusz A1 - Tucker, Katherine L A1 - Fumeron, Frédéric A1 - Estruch, Ramon A1 - Ordovas, Jose M A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - North, Kari E A1 - Chasman, Daniel I A1 - Qi, Lu AB -

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

VL - 35 IS - 7 ER - TY - JOUR T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. JF - Kidney Int Y1 - 2020 A1 - Gorski, Mathias A1 - Jung, Bettina A1 - Li, Yong A1 - Matias-Garcia, Pamela R A1 - Wuttke, Matthias A1 - Coassin, Stefan A1 - Thio, Chris H L A1 - Kleber, Marcus E A1 - Winkler, Thomas W A1 - Wanner, Veronika A1 - Chai, Jin-Fang A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Feitosa, Mary F A1 - Ghasemi, Sahar A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Li, Man A1 - Nutile, Teresa A1 - Scholz, Markus A1 - Sieber, Karsten B A1 - Teumer, Alexander A1 - Tin, Adrienne A1 - Wang, Judy A1 - Tayo, Bamidele O A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Carroll, Robert J A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Coresh, Josef A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Gieger, Christian A1 - Hamet, Pavel A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Xian Foo, Valencia Hui A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Kähönen, Mika A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - O'Donoghue, Michelle L A1 - Orho-Melander, Marju A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Sabanayagam, Charumathi A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Strauch, Konstantin A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Tremblay, Johanne A1 - Chaker, Layal A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Yan A1 - Snieder, Harold A1 - Wanner, Christoph A1 - Böger, Carsten A A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Pattaro, Cristian A1 - Heid, Iris M AB -

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

ER - TY - JOUR T1 - {Mitochondrial DNA copy number and incident atrial fibrillation JF - BMC Med Y1 - 2020 A1 - Zhao, D. A1 - Bartz, T. M. A1 - Sotoodehnia, N. A1 - Post, W. S. A1 - Heckbert, S. R. A1 - Alonso, A. A1 - Longchamps, R. J. A1 - Castellani, C. A. A1 - Hong, Y. S. A1 - Rotter, J. I. A1 - Lin, H. J. A1 - O'Rourke, B. A1 - Pankratz, N. A1 - Lane, J. A. A1 - Yang, S. Y. A1 - Guallar, E. A1 - Arking, D. E. AB - Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.\ We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.\ The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.\ Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk. VL - 18 ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

VL - 11 IS - 1 ER - TY - JOUR T1 - Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. JF - Circ Genom Precis Med Y1 - 2020 A1 - Wang, Zhe A1 - Chen, Han A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chasman, Daniel I A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Lim, Elise A1 - Noordam, Raymond A1 - Richard, Melissa A A1 - Wang, Heming A1 - Cade, Brian A1 - Cupples, L Adrienne A1 - de Vries, Paul S A1 - Giulanini, Franco A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Willems van Dijk, Ko A1 - Yao, Jie A1 - Zhao, Wei A1 - Fornage, Myriam A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Morrison, Alanna C AB -

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

VL - 13 IS - 4 ER - TY - JOUR T1 - A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function. JF - Kidney Int Y1 - 2020 A1 - Lye, Weng Kit A1 - Paterson, Euan A1 - Patterson, Christopher C A1 - Maxwell, Alexander P A1 - Binte Mohammed Abdul, Riswana Banu A1 - Tai, E Shyong A1 - Cheng, Ching Yu A1 - Kayama, Takamasa A1 - Yamashita, Hidetoshi A1 - Sarnak, Mark A1 - Shlipak, Michael A1 - Matsushita, Kunihiro A1 - Mutlu, Unal A1 - Ikram, Mohammad A A1 - Klaver, Caroline A1 - Kifley, Annette A1 - Mitchell, Paul A1 - Myers, Chelsea A1 - Klein, Barbara E A1 - Klein, Ronald A1 - Wong, Tien Y A1 - Sabanayagam, Charumathi A1 - McKay, Gareth J AB -

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2 % of 33,222 and 11.3 % of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95- 1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

ER - TY - JOUR T1 - Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. JF - Circ Genom Precis Med Y1 - 2020 A1 - Ma, Jiantao A1 - Rebholz, Casey M A1 - Braun, Kim V E A1 - Reynolds, Lindsay M A1 - Aslibekyan, Stella A1 - Xia, Rui A1 - Biligowda, Niranjan G A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Joehanes, Roby A1 - Hu, Emily A A1 - Vitolins, Mara Z A1 - Wood, Alexis C A1 - Lohman, Kurt A1 - Ochoa-Rosales, Carolina A1 - van Meurs, Joyce A1 - Uitterlinden, Andre A1 - Liu, Yongmei A1 - Elhadad, Mohamed A A1 - Heier, Margit A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Colicino, Elena A1 - Whitsel, Eric A A1 - Baldassari, Antoine A1 - Gharib, Sina A A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Sitlani, Colleen M A1 - Tanaka, Toshiko A1 - Hill, W David A1 - Corley, Janie A1 - Deary, Ian J A1 - Zhang, Yan A1 - Schöttker, Ben A1 - Brenner, Hermann A1 - Walker, Maura E A1 - Ye, Shumao A1 - Nguyen, Steve A1 - Pankow, Jim A1 - Demerath, Ellen W A1 - Zheng, Yinan A1 - Hou, Lifang A1 - Liang, Liming A1 - Lichtenstein, Alice H A1 - Hu, Frank B A1 - Fornage, Myriam A1 - Voortman, Trudy A1 - Levy, Daniel AB -

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

VL - 13 IS - 4 ER - TY - JOUR T1 - Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. JF - Nat Commun Y1 - 2020 A1 - Zhao, Xutong A1 - Qiao, Dandi A1 - Yang, Chaojie A1 - Kasela, Silva A1 - Kim, Wonji A1 - Ma, Yanlin A1 - Shrine, Nick A1 - Batini, Chiara A1 - Sofer, Tamar A1 - Taliun, Sarah A Gagliano A1 - Sakornsakolpat, Phuwanat A1 - Balte, Pallavi P A1 - Prokopenko, Dmitry A1 - Yu, Bing A1 - Lange, Leslie A A1 - Dupuis, Josée A1 - Cade, Brian E A1 - Lee, Jiwon A1 - Gharib, Sina A A1 - Daya, Michelle A1 - Laurie, Cecelia A A1 - Ruczinski, Ingo A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Bartz, Traci M A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Taylor, Kent D A1 - Durda, Peter A1 - Johnson, W Craig A1 - Cornell, Elaine A1 - Guo, Xiuqing A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Ardlie, Kristin G A1 - Aguet, Francois A1 - VanDenBerg, David J A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Barnes, Kathleen C A1 - Jain, Deepti A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Dugan-Perez, Shannon A1 - Gupta, Namrata A1 - Gabriel, Stacey A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Redline, Susan A1 - Reed, Robert M A1 - Laurie, Cathy C A1 - Daviglus, Martha L A1 - Preudhomme, Liana K A1 - Burkart, Kristin M A1 - Kaplan, Robert C A1 - Wain, Louise V A1 - Tobin, Martin D A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Abecasis, Goncalo R A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Cho, Michael H A1 - Manichaikul, Ani KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Calcium-Binding Proteins KW - Feasibility Studies KW - Female KW - Follow-Up Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Inhibitors of Activated STAT KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Physiological Phenomena KW - Small Ubiquitin-Related Modifier Proteins KW - Whole Genome Sequencing AB -

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

VL - 11 IS - 1 ER - TY - JOUR T1 - Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults. JF - JAMA Y1 - 2021 A1 - Wan, Emily S A1 - Balte, Pallavi A1 - Schwartz, Joseph E A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Couper, David A1 - Daviglus, Martha L A1 - Dransfield, Mark T A1 - Gharib, Sina A A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - London, Stephanie J A1 - Navas-Acien, Ana A1 - O'Connor, George T A1 - Sanders, Jason L A1 - Smith, Benjamin M A1 - White, Wendy A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Forced Expiratory Volume KW - Humans KW - Lung KW - Lung Diseases KW - Male KW - Middle Aged KW - Prevalence KW - Retrospective Studies KW - Spirometry KW - United States KW - Vital Capacity AB -

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood.

Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018).

Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted.

Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities.

Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]).

Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

VL - 326 IS - 22 ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

VL - 11 IS - 1 ER - TY - JOUR T1 - Association of mitochondrial DNA copy number with cardiometabolic diseases. JF - Cell Genom Y1 - 2021 A1 - Liu, Xue A1 - Longchamps, Ryan J A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Kurniansyah, Nuzulul A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Cupples, L Adrienne A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Sofer, Tamar A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Correa, Adolfo A1 - Abecasis, Goncalo A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

VL - 1 IS - 1 ER - TY - JOUR T1 - Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort. JF - Alzheimers Dement Y1 - 2021 A1 - Zeki Al Hazzouri, Adina A1 - Vittinghoff, Eric A1 - Hoang, Tina A1 - Golden, Sherita H A1 - Fitzpatrick, Annette L A1 - Zhang, Adina A1 - Grasset, Leslie A1 - Yaffe, Kristine AB -

INTRODUCTION: To examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women.

METHODS: We studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used.

RESULTS: Compared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.31 to 2.54) and obese (OR = 2.45; 95% CI = 1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men.

CONCLUSIONS: With the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

ER - TY - JOUR T1 - Cardiovascular Risk Factors Across the Life Course and Cognitive Decline: A Pooled Cohort Study. JF - Neurology Y1 - 2021 A1 - Yaffe, Kristine A1 - Vittinghoff, Eric A1 - Hoang, Tina A1 - Matthews, Karen A1 - Golden, Sherita H A1 - Zeki Al Hazzouri, Adina KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cardiovascular Diseases KW - Cognition KW - Cognitive Dysfunction KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Risk Factors KW - Young Adult AB -

OBJECTIVE: Cardiovascular risk factors (CVRFs) are associated with increased risk of cognitive decline, but little is known about how early adult CVRFs and those across the life course might influence late-life cognition. To test the hypothesis that CVRFs across the adult life course are associated with late-life cognitive changes, we pooled data from 4 prospective cohorts (n = 15,001, ages 18-95).

METHODS: We imputed trajectories of body mass index (BMI), fasting glucose (FG), systolic blood pressure (SBP), and total cholesterol (TC) for older adults. We used linear mixed models to determine the association of early adult, midlife, and late-life CVRFs with late-life decline on global cognition (Modified Mini-Mental State Examination [3MS]) and processing speed (Digit Symbol Substitution Test [DSST]), adjusting for demographics, education, and cohort.

RESULTS: Elevated BMI, FG, and SBP (but not TC) at each time period were associated with greater late-life decline. Early life CVRFs were associated with the greatest change, an approximate doubling of mean 10-year decline (an additional 3-4 points for 3MS or DSST). Late-life CVRFs were associated with declines in early late life (<80 years) but with gains in very late life (≥80 years). After adjusting for CVRF exposures at all time periods, the associations for early adult and late-life CVRFs persisted.

CONCLUSIONS: We found that imputed CVRFs across the life course, especially in early adulthood, were associated with greater late-life cognitive decline. Our results suggest that CVRF treatment in early adulthood could benefit late-life cognition, but that treatment in very late life may not be as helpful for these outcomes.

VL - 96 IS - 17 ER - TY - JOUR T1 - Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. JF - Nat Commun Y1 - 2021 A1 - Natarajan, Pradeep A1 - Pampana, Akhil A1 - Graham, Sarah E A1 - Ruotsalainen, Sanni E A1 - Perry, James A A1 - de Vries, Paul S A1 - Broome, Jai G A1 - Pirruccello, James P A1 - Honigberg, Michael C A1 - Aragam, Krishna A1 - Wolford, Brooke A1 - Brody, Jennifer A A1 - Antonacci-Fulton, Lucinda A1 - Arden, Moscati A1 - Aslibekyan, Stella A1 - Assimes, Themistocles L A1 - Ballantyne, Christie M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Do, Ron A1 - Doddapaneni, Harsha A1 - Emery, Leslie S A1 - Hung, Yi-Jen A1 - Irvin, Marguerite R A1 - Khan, Alyna T A1 - Lange, Leslie A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Metcalf, Ginger A1 - Montasser, May E A1 - Moon, Jee-Young A1 - Muzny, Donna A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Stilp, Adrienne M A1 - Tsai, Michael A1 - Wang, Fei Fei A1 - Weeks, Daniel E A1 - Yanek, Lisa R A1 - Wilson, James G A1 - Abecasis, Goncalo A1 - Arnett, Donna K A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Chang, Yi-Cheng A1 - Chen, Yii-der I A1 - Choi, Won Jung A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Daly, Mark J A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - He, Jiang A1 - Hveem, Kristian A1 - Jarvik, Gail P A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kenny, Eimear A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Lee, Seonwook A1 - Lloyd-Jones, Don M A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Mathias, Rasika A A1 - Martinez, Karine A Viaud A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Nickerson, Deborah A A1 - North, Kari E A1 - Palotie, Aarno A1 - Park, Cheol Joo A1 - Psaty, Bruce M A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Seo, Daekwan A1 - Seo, Jeong-Sun A1 - Smith, Albert V A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Rich, Stephen S A1 - Ripatti, Samuli A1 - Willer, Cristen A1 - Peloso, Gina M AB -

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

VL - 12 IS - 1 ER - TY - JOUR T1 - Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline. JF - J Alzheimers Dis Y1 - 2021 A1 - Brenowitz, Willa D A1 - Zeki Al Hazzouri, Adina A1 - Vittinghoff, Eric A1 - Golden, Sherita H A1 - Fitzpatrick, Annette L A1 - Yaffe, Kristine KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cognitive Dysfunction KW - Cohort Studies KW - Dementia KW - Depression KW - Female KW - Humans KW - Male KW - Middle Aged KW - Prodromal Symptoms KW - Risk Factors AB -

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

VL - 83 IS - 3 ER - TY - JOUR T1 - Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. JF - Am J Hum Genet Y1 - 2021 A1 - Graff, Mariaelisa A1 - Justice, Anne E A1 - Young, Kristin L A1 - Marouli, Eirini A1 - Zhang, Xinruo A1 - Fine, Rebecca S A1 - Lim, Elise A1 - Buchanan, Victoria A1 - Rand, Kristin A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Shao, Yaming A1 - Rohde, Rebecca A1 - Adeyemo, Adebowale A A1 - Aldrich, Melinda C A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Amos, Christopher A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Bandera, Elisa V A1 - Bartz, Traci A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Bielak, Lawrence F A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Burke, Gregory A1 - Cade, Brian E A1 - Cai, Qiuyin A1 - Caporaso, Neil A1 - Carlson, Chris A1 - Carpten, John A1 - Casey, Graham A1 - Chanock, Stephen J A1 - Chen, Guanjie A1 - Chen, Minhui A1 - Chen, Yii-der I A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Chiang, Charleston W K A1 - Chu, Lisa A1 - Coetzee, Gerry A A1 - Conti, David V A1 - Cooper, Richard S A1 - Cushman, Mary A1 - Demerath, Ellen A1 - Deming, Sandra L A1 - Dimitrov, Latchezar A1 - Ding, Jingzhong A1 - Diver, W Ryan A1 - Duan, Qing A1 - Evans, Michele K A1 - Falusi, Adeyinka G A1 - Faul, Jessica D A1 - Fornage, Myriam A1 - Fox, Caroline A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Gillanders, Elizabeth M A1 - Goodman, Phyllis A1 - Gottesman, Omri A1 - Grant, Struan F A A1 - Guo, Xiuqing A1 - Hakonarson, Hakon A1 - Haritunians, Talin A1 - Harris, Tamara B A1 - Harris, Curtis C A1 - Henderson, Brian E A1 - Hennis, Anselm A1 - Hernandez, Dena G A1 - Hirschhorn, Joel N A1 - McNeill, Lorna Haughton A1 - Howard, Timothy D A1 - Howard, Barbara A1 - Hsing, Ann W A1 - Hsu, Yu-Han H A1 - Hu, Jennifer J A1 - Huff, Chad D A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - Irvin, Marguerite R A1 - John, Esther M A1 - Johnson, Karen C A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kang, Sun J A1 - Kardia, Sharon L A1 - Keating, Brendan J A1 - Kittles, Rick A A1 - Klein, Eric A A1 - Kolb, Suzanne A1 - Kolonel, Laurence N A1 - Kooperberg, Charles A1 - Kuller, Lewis A1 - Kutlar, Abdullah A1 - Lange, Leslie A1 - Langefeld, Carl D A1 - Le Marchand, Loïc A1 - Leonard, Hampton A1 - Lettre, Guillaume A1 - Levin, Albert M A1 - Li, Yun A1 - Li, Jin A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Liu, Simin A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lu, Yingchang A1 - Maixner, William A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Meng, Yan A1 - Monda, Keri L A1 - Monroe, Kris A1 - Moore, Jason H A1 - Mosley, Thomas H A1 - Mudgal, Poorva A1 - Murphy, Adam B A1 - Nadukuru, Rajiv A1 - Nalls, Mike A A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian L A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogundiran, Temidayo O A1 - Ogunniyi, Adesola A1 - Ojengbede, Oladosu A1 - Okut, Hayrettin A1 - Olopade, Olufunmilayo I A1 - Olshan, Andrew A1 - Padhukasahasram, Badri A1 - Palmer, Julie A1 - Palmer, Cameron D A1 - Palmer, Nicholette D A1 - Papanicolaou, George A1 - Patel, Sanjay R A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Press, Michael F A1 - Rao, D C A1 - Rasmussen-Torvik, Laura J A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rhie, Suhn K A1 - Rodriguez-Gil, Jorge L A1 - Rotimi, Charles N A1 - Rotter, Jerome I A1 - Ruiz-Narvaez, Edward A A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sale, Michèle M A1 - Sanderson, Maureen A1 - Schadt, Eric A1 - Schreiner, Pamela J A1 - Schurmann, Claudia A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Siscovick, David S A1 - Smith, Jennifer A A1 - Smith, Shad A1 - Speliotes, Elizabeth A1 - Spitz, Margaret A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Sucheston, Lara A1 - Sun, Yan V A1 - Tajuddin, Salman M A1 - Taylor, Herman A1 - Taylor, Kira A1 - Tayo, Bamidele O A1 - Thun, Michael J A1 - Tucker, Margaret A A1 - Vaidya, Dhananjay A1 - Van Den Berg, David J A1 - Vedantam, Sailaja A1 - Vitolins, Mara A1 - Wang, Zhaoming A1 - Ware, Erin B A1 - Wassertheil-Smoller, Sylvia A1 - Weir, David R A1 - Wiencke, John K A1 - Williams, Scott M A1 - Williams, L Keoki A1 - Wilson, James G A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yao, Jie A1 - Zakai, Neil A1 - Zanetti, Krista A1 - Zemel, Babette S A1 - Zhao, Wei A1 - Zhao, Jing Hua A1 - Zheng, Wei A1 - Zhi, Degui A1 - Zhou, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zmuda, Joe A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Liu, Ching-Ti A1 - Haiman, Christopher A A1 - Loos, Ruth A1 - Ng, Maggie C Y A1 - North, Kari E AB -

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

VL - 108 IS - 4 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

VL - 12 IS - 1 ER - TY - JOUR T1 - FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer. JF - J Thromb Haemost Y1 - 2021 A1 - Thibord, Florian A1 - Song, Ci A1 - Pattee, Jack A1 - Rodriguez, Benjamin A T A1 - Chen, Ming-Huei A1 - O'Donnell, Christopher J A1 - Kleber, Marcus E A1 - Delgado, Graciela E A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Taylor, Kent D A1 - Ozel, Ayse Bilge A1 - Brody, Jennifer A A1 - McKnight, Barbara A1 - Gyorgy, Beata A1 - Simonsick, Eleanor A1 - Leonard, Hampton L A1 - Carrasquilla, Germán D A1 - Guindo-Martinez, Marta A1 - Silveira, Angela A1 - Temprano-Sagrera, Gerard A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Mathias, Rasika A A1 - Becker, Lewis C A1 - Raffield, Laura M A1 - Kilpeläinen, Tuomas O A1 - Grarup, Niels A1 - Pedersen, Oluf A1 - Hansen, Torben A1 - Linneberg, Allan A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Sabater-Lleal, Maria A1 - Nalls, Mike A A1 - Trégouët, David-Alexandre A1 - Morange, Pierre-Emmanuel A1 - Psaty, Bruce M A1 - Tracy, Russel P A1 - Smith, Nicholas L A1 - Desch, Karl C A1 - Cushman, Mary A1 - Rotter, Jerome I A1 - de Vries, Paul S A1 - Pankratz, Nathan D A1 - Folsom, Aaron R A1 - Morrison, Alanna C A1 - März, Winfried A1 - Tang, Weihong A1 - Johnson, Andrew D AB -

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

ER - TY - JOUR T1 - {Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women JF - Nat Commun Y1 - 2021 A1 - Jones, G. A1 - Trajanoska, K. A1 - Santanasto, A. J. A1 - Stringa, N. A1 - Kuo, C. L. A1 - Atkins, J. L. A1 - Lewis, J. R. A1 - Duong, T. A1 - Hong, S. A1 - Biggs, M. L. A1 - Luan, J. A1 - Sarnowski, C. A1 - Lunetta, K. L. A1 - Tanaka, T. A1 - Wojczynski, M. K. A1 - Cvejkus, R. A1 - Nethander, M. A1 - Ghasemi, S. A1 - Yang, J. A1 - Zillikens, M. C. A1 - Walter, S. A1 - Sicinski, K. A1 - Kague, E. A1 - Ackert-Bicknell, C. L. A1 - Arking, D. E. A1 - Windham, B. G. A1 - Boerwinkle, E. A1 - Grove, M. L. A1 - Graff, M. A1 - Spira, D. A1 - Demuth, I. A1 - Van der Velde, N. A1 - de Groot, L. C. P. G. M. A1 - Psaty, B. M. A1 - Odden, M. C. A1 - Fohner, A. E. A1 - Langenberg, C. A1 - Wareham, N. J. A1 - Bandinelli, S. A1 - van Schoor, N. M. A1 - Huisman, M. A1 - Tan, Q. A1 - Zmuda, J. A1 - Mellström, D. A1 - Karlsson, M. A1 - Bennett, D. A. A1 - Buchman, A. S. A1 - De Jager, P. L. A1 - Uitterlinden, A. G. A1 - Völker, U. A1 - Kocher, T. A1 - Teumer, A. A1 - Rodriguéz-Mañas, L. A1 - García, F. J. A1 - Carnicero, J. A. A1 - Herd, P. A1 - Bertram, L. A1 - Ohlsson, C. A1 - Murabito, J. M. A1 - Melzer, D. A1 - Kuchel, G. A. A1 - Ferrucci, L. A1 - Karasik, D. A1 - Rivadeneira, F. A1 - Kiel, D. P. A1 - Pilling, L. C. AB - Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. VL - 12 ER - TY - JOUR T1 - {The genomics of heart failure: design and rationale of the HERMES consortium JF - ESC Heart Fail Y1 - 2021 A1 - Lumbers, R. T. A1 - Shah, S. A1 - Lin, H. A1 - Czuba, T. A1 - Henry, A. A1 - Swerdlow, D. I. A1 - Malarstig, A. A1 - Andersson, C. A1 - Verweij, N. A1 - Holmes, M. V. A1 - Ärnlöv, J. A1 - Svensson, P. A1 - Hemingway, H. A1 - Sallah, N. A1 - Almgren, P. A1 - Aragam, K. G. A1 - Asselin, G. A1 - Backman, J. D. A1 - Biggs, M. L. A1 - Bloom, H. L. A1 - Boersma, E. A1 - Brandimarto, J. A1 - Brown, M. R. A1 - Brunner-La Rocca, H. P. A1 - Carey, D. J. A1 - Chaffin, M. D. A1 - Chasman, D. I. A1 - Chazara, O. A1 - Chen, X. A1 - Chen, X. A1 - Chung, J. H. A1 - Chutkow, W. A1 - Cleland, J. G. F. A1 - Cook, J. P. A1 - de Denus, S. A1 - Dehghan, A. A1 - Delgado, G. E. A1 - Denaxas, S. A1 - Doney, A. S. A1 - Dörr, M. A1 - Dudley, S. C. A1 - Engström, G. A1 - Esko, T. A1 - Fatemifar, G. A1 - Felix, S. B. A1 - Finan, C. A1 - Ford, I. A1 - Fougerousse, F. A1 - Fouodjio, R. A1 - Ghanbari, M. A1 - Ghasemi, S. A1 - Giedraitis, V. A1 - Giulianini, F. A1 - Gottdiener, J. S. A1 - Gross, S. A1 - Guðbjartsson, D. F. A1 - Gui, H. A1 - Gutmann, R. A1 - Haggerty, C. M. A1 - van der Harst, P. A1 - Hedman, Å. K. A1 - Helgadottir, A. A1 - Hillege, H. A1 - Hyde, C. L. A1 - Jacob, J. A1 - Jukema, J. W. A1 - Kamanu, F. A1 - Kardys, I. A1 - Kavousi, M. A1 - Khaw, K. T. A1 - Kleber, M. E. A1 - Køber, L. A1 - Koekemoer, A. A1 - Kraus, B. A1 - Kuchenbaecker, K. A1 - Langenberg, C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - London, B. A1 - Lotta, L. A. A1 - Lovering, R. C. A1 - Luan, J. A1 - Magnusson, P. A1 - Mahajan, A. A1 - Mann, D. A1 - Margulies, K. B. A1 - Marston, N. A. A1 - März, W. A1 - McMurray, J. J. V. A1 - Melander, O. A1 - Melloni, G. A1 - Mordi, I. R. A1 - Morley, M. P. A1 - Morris, A. D. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - Nagle, M. W. A1 - Nelson, C. P. A1 - Newton-Cheh, C. A1 - Niessner, A. A1 - Niiranen, T. A1 - Nowak, C. A1 - O'Donoghue, M. L. A1 - Owens, A. T. A1 - Palmer, C. N. A. A1 - Pare, G. A1 - Perola, M. A1 - Perreault, L. L. A1 - Portilla-Fernandez, E. A1 - Psaty, B. M. A1 - Rice, K. M. A1 - Ridker, P. M. A1 - Romaine, S. P. R. A1 - Roselli, C. A1 - Rotter, J. I. A1 - Ruff, C. T. A1 - Sabatine, M. S. A1 - Salo, P. A1 - Salomaa, V. A1 - van Setten, J. A1 - Shalaby, A. A. A1 - Smelser, D. T. A1 - Smith, N. L. A1 - Stefansson, K. A1 - Stender, S. A1 - Stott, D. J. A1 - Sveinbjornsson, G. A1 - Tammesoo, M. L. A1 - Tardif, J. C. A1 - Taylor, K. D. A1 - Teder-Laving, M. A1 - Teumer, A. A1 - Thorgeirsson, G. A1 - Thorsteinsdottir, U. A1 - Torp-Pedersen, C. A1 - Trompet, S. A1 - Tuckwell, D. A1 - Tyl, B. A1 - Uitterlinden, A. G. A1 - Vaura, F. A1 - Veluchamy, A. A1 - Visscher, P. M. A1 - Völker, U. A1 - Voors, A. A. A1 - Wang, X. A1 - Wareham, N. J. A1 - Weeke, P. E. A1 - Weiss, R. A1 - White, H. D. A1 - Wiggins, K. L. A1 - Xing, H. A1 - Yang, J. A1 - Yang, Y. A1 - Yerges-Armstrong, L. M. A1 - Yu, B. A1 - Zannad, F. A1 - Zhao, F. A1 - Wilk, J. B. A1 - Holm, H. A1 - Sattar, N. A1 - Lubitz, S. A. A1 - Lanfear, D. E. A1 - Shah, S. A1 - Dunn, M. E. A1 - Wells, Q. S. A1 - Asselbergs, F. W. A1 - Hingorani, A. D. A1 - Dubé, M. P. A1 - Samani, N. J. A1 - Lang, C. C. A1 - Cappola, T. P. A1 - Ellinor, P. T. A1 - Vasan, R. S. A1 - Smith, J. G. AB - The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.\ under an additive genetic model.\ HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. ER - TY - JOUR T1 - Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation. JF - Circ Genom Precis Med Y1 - 2021 A1 - Yang, Yunju A1 - Bartz, Traci M A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Zilhão, Nuno R A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Yao, Jie A1 - Brody, Jennifer A A1 - deFilippi, Christopher R A1 - Hoogeveen, Ron C A1 - Lin, Henry J A1 - Gudnason, Vilmundur A1 - Ballantyne, Christie M A1 - Dörr, Marcus A1 - Jukema, J Wouter A1 - Petersmann, Astrid A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Jun, Goo A1 - Yu, Bing AB -

BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.

METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.

RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in and 3 previously reported loci at , , and . One known locus at was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; =2.80×10). We observed pleiotropic loci located at and . The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with expression in heart tissues and hs-cTnT and with expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI).

CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

VL - 14 IS - 6 ER - TY - JOUR T1 - Meta-analyses identify DNA methylation associated with kidney function and damage. JF - Nat Commun Y1 - 2021 A1 - Schlosser, Pascal A1 - Tin, Adrienne A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Weihs, Antoine A1 - Yu, Zhi A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Chambers, John C A1 - Cole, Shelley A A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - de Klein, Niek A1 - Delgado, Graciela E A1 - Domingo-Relloso, Arce A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Evans, Kathryn L A1 - Floyd, James S A1 - Fornage, Myriam A1 - Franke, Lude A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kramer, Holly A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Liu, Yongmei A1 - Lloyd-Jones, Donald M A1 - Lohman, Kurt A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Navas-Acien, Ana A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Rosas, Sylvia E A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - Tellez-Plaza, Maria A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Verweij, Niek A1 - Walker, Rosie M A1 - Wielscher, Matthias A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Susztak, Katalin A1 - Köttgen, Anna A1 - Teumer, Alexander KW - Adult KW - Aged KW - CpG Islands KW - DNA Methylation KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Interferon Regulatory Factors KW - Kidney KW - Kidney Function Tests KW - LIM Domain Proteins KW - Male KW - Membrane Proteins KW - Middle Aged KW - Renal Insufficiency, Chronic KW - Transcription Factors AB -

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

VL - 12 IS - 1 ER - TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - HGG Adv Y1 - 2021 A1 - Sun, Daokun A1 - Richard, Melissa A1 - Musani, Solomon K A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Chai, Jin Fang A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Harris, Sarah E A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Roux, Ana V Diez A1 - Dörr, Marcus A1 - Faul, Jessica D A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Grabe, Hans Jörgen A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jonas, Jost Bruno A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - O'Connell, Jeff R A1 - Palmas, Walter R A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Råback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Rice, Kenneth A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Deary, Ian J A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - Weir, David R A1 - Zheng, Wei A1 - Evans, Michele K A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Sim, Xueling A1 - Bierut, Laura A1 - Rotter, Jerome I A1 - Kardia, Sharon L R A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

VL - 2 IS - 1 ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. JF - Mol Psychiatry Y1 - 2021 A1 - Wang, Heming A1 - Noordam, Raymond A1 - Cade, Brian E A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Lee, Jiwon A1 - Sung, Yun Ju A1 - Bentley, Amy R A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Kilpeläinen, Tuomas O A1 - Ilkov, Marjan A1 - Brown, Michael R A1 - Horimoto, Andrea R A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Vojinovic, Dina A1 - Lim, Elise A1 - Nierenberg, Jovia L A1 - Liu, Yongmei A1 - Chitrala, Kumaraswamynaidu A1 - Rankinen, Tuomo A1 - Musani, Solomon K A1 - Franceschini, Nora A1 - Rauramaa, Rainer A1 - Alver, Maris A1 - Zee, Phyllis C A1 - Harris, Sarah E A1 - van der Most, Peter J A1 - Nolte, Ilja M A1 - Munroe, Patricia B A1 - Palmer, Nicholette D A1 - Kuhnel, Brigitte A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Hall, Kelly A A1 - Lyytikäinen, Leo-Pekka A1 - O'Connell, Jeff A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - de Vries, Paul S A1 - Arking, Dan E A1 - Chen, Han A1 - Boerwinkle, Eric A1 - Krieger, Jose E A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Shikany, James M A1 - Rice, Kenneth A1 - Chen, Yii-Der Ida A1 - Gharib, Sina A A1 - Bis, Joshua C A1 - Luik, Annemarie I A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Amin, Najaf A1 - Xu, Hanfei A1 - Levy, Daniel A1 - He, Jiang A1 - Lohman, Kurt K A1 - Zonderman, Alan B A1 - Rice, Treva K A1 - Sims, Mario A1 - Wilson, Gregory A1 - Sofer, Tamar A1 - Rich, Stephen S A1 - Palmas, Walter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Biermasz, Nienke R A1 - Mook-Kanamori, Dennis O A1 - Martin, Lisa W A1 - Barac, Ana A1 - Wallace, Robert B A1 - Gottlieb, Daniel J A1 - Komulainen, Pirjo A1 - Heikkinen, Sami A1 - Mägi, Reedik A1 - Milani, Lili A1 - Metspalu, Andres A1 - Starr, John M A1 - Milaneschi, Yuri A1 - Waken, R J A1 - Gao, Chuan A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Roenneberg, Till A1 - Völker, Uwe A1 - Dörr, Marcus A1 - Shu, Xiao-Ou A1 - Mukherjee, Sutapa A1 - Hillman, David R A1 - Kähönen, Mika A1 - Wagenknecht, Lynne E A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Zheng, Wei A1 - Palmer, Lyle J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Liu, Ching-Ti A1 - Kelly, Tanika N A1 - Evans, Michele K A1 - Bouchard, Claude A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Zhu, Xiaofeng A1 - Lakka, Timo A A1 - Esko, Tõnu A1 - North, Kari E A1 - Deary, Ian J A1 - Snieder, Harold A1 - Penninx, Brenda W J H A1 - Gauderman, W James A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - van Heemst, Diana AB -

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

ER - TY - JOUR T1 - {A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids JF - Nat Commun Y1 - 2021 A1 - Jhun, M. A. A1 - Mendelson, M. A1 - Wilson, R. A1 - Gondalia, R. A1 - Joehanes, R. A1 - Salfati, E. A1 - Zhao, X. A1 - Braun, K. V. E. A1 - Do, A. N. A1 - Hedman, Å. K. A1 - Zhang, T. A1 - Carnero-Montoro, E. A1 - Shen, J. A1 - Bartz, T. M. A1 - Brody, J. A. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Yao, C. A1 - Xia, R. A1 - Boerwinkle, E. A1 - Grove, M. A1 - Guan, W. A1 - Liliane, P. A1 - Singmann, P. A1 - Müller-Nurasyid, M. A1 - Meitinger, T. A1 - Gieger, C. A1 - Peters, A. A1 - Zhao, W. A1 - Ware, E. B. A1 - Smith, J. A. A1 - Dhana, K. A1 - van Meurs, J. A1 - Uitterlinden, A. A1 - Ikram, M. A. A1 - Ghanbari, M. A1 - Zhi, D. A1 - Gustafsson, S. A1 - Lind, L. A1 - Li, S. A1 - Sun, D. A1 - Spector, T. D. A1 - Chen, Y. I. A1 - Damcott, C. A1 - Shuldiner, A. R. A1 - Absher, D. M. A1 - Horvath, S. A1 - Tsao, P. S. A1 - Kardia, S. A1 - Psaty, B. M. A1 - Sotoodehnia, N. A1 - Bell, J. T. A1 - Ingelsson, E. A1 - Chen, W. A1 - Dehghan, A. A1 - Arnett, D. K. A1 - Waldenberger, M. A1 - Hou, L. A1 - Whitsel, E. A. A1 - Baccarelli, A. A1 - Levy, D. A1 - Fornage, M. A1 - Irvin, M. R. A1 - Assimes, T. L. AB - 10.1038/s41467-021-23899-yHere we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups. VL - 12 ER - TY - JOUR T1 - Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes. JF - Circ Genom Precis Med Y1 - 2021 A1 - Lu, Yingchang A1 - Dimitrov, Latchezar A1 - Chen, Shyh-Huei A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Lu, Lingyi A1 - Kavousi, Maryam A1 - Raffield, Laura M A1 - Smith, Albert V A1 - Wang, Lihua A1 - Weiss, Stefan A1 - Yao, Jie A1 - Zhu, Jiaxi A1 - Gudmundsson, Elias F A1 - Gudmundsdottir, Valborg A1 - Bos, Daniel A1 - Ghanbari, Mohsen A1 - Ikram, M Arfan A1 - Hwang, Shih-Jen A1 - Taylor, Kent D A1 - Budoff, Matthew J A1 - Gislason, Gauti K A1 - O'Donnell, Christopher J A1 - An, Ping A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Fu, Yi-Ping A1 - Guo, Xiuqing A1 - Heiss, Gerardo A1 - Kardia, Sharon L R A1 - Wilson, James G A1 - Langefeld, Carl D A1 - Schminke, Ulf A1 - Uitterlinden, André G A1 - Lange, Leslie A A1 - Peyser, Patricia A A1 - Gudnason, Vilmundur G A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Bowden, Donald W A1 - Ng, Maggie C Y AB -

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

VL - 14 IS - 4 ER - TY - JOUR T1 - {The power of genetic diversity in genome-wide association studies of lipids JF - Nature Y1 - 2021 A1 - Graham, S. E. A1 - Clarke, S. L. A1 - Wu, K. H. A1 - Kanoni, S. A1 - Zajac, G. J. M. A1 - Ramdas, S. A1 - Surakka, I. A1 - Ntalla, I. A1 - Vedantam, S. A1 - Winkler, T. W. A1 - Locke, A. E. A1 - Marouli, E. A1 - Hwang, M. Y. A1 - Han, S. A1 - Narita, A. A1 - Choudhury, A. A1 - Bentley, A. R. A1 - Ekoru, K. A1 - Verma, A. A1 - Trivedi, B. A1 - Martin, H. C. A1 - Hunt, K. A. A1 - Hui, Q. A1 - Klarin, D. A1 - Zhu, X. A1 - Thorleifsson, G. A1 - Helgadottir, A. A1 - Gudbjartsson, D. F. A1 - Holm, H. A1 - Olafsson, I. A1 - Akiyama, M. A1 - Sakaue, S. A1 - Terao, C. A1 - Kanai, M. A1 - Zhou, W. A1 - Brumpton, B. M. A1 - Rasheed, H. A1 - Ruotsalainen, S. E. A1 - Havulinna, A. S. A1 - Veturi, Y. A1 - Feng, Q. A1 - Rosenthal, E. A. A1 - Lingren, T. A1 - Pacheco, J. A. A1 - Pendergrass, S. A. A1 - Haessler, J. A1 - Giulianini, F. A1 - Bradford, Y. A1 - Miller, J. E. A1 - Campbell, A. A1 - Lin, K. A1 - Millwood, I. Y. A1 - Hindy, G. A1 - Rasheed, A. A1 - Faul, J. D. A1 - Zhao, W. A1 - Weir, D. R. A1 - Turman, C. A1 - Huang, H. A1 - Graff, M. A1 - Mahajan, A. A1 - Brown, M. R. A1 - Zhang, W. A1 - Yu, K. A1 - Schmidt, E. M. A1 - Pandit, A. A1 - Gustafsson, S. A1 - Yin, X. A1 - Luan, J. A1 - Zhao, J. H. A1 - Matsuda, F. A1 - Jang, H. M. A1 - Yoon, K. A1 - Medina-Gomez, C. A1 - Pitsillides, A. A1 - Hottenga, J. J. A1 - Willemsen, G. A1 - Wood, A. R. A1 - Ji, Y. A1 - Gao, Z. A1 - Haworth, S. A1 - Mitchell, R. E. A1 - Chai, J. F. A1 - Aadahl, M. A1 - Yao, J. A1 - Manichaikul, A. A1 - Warren, H. R. A1 - Ramirez, J. A1 - Bork-Jensen, J. A1 - Kårhus, L. L. A1 - Goel, A. A1 - Sabater-Lleal, M. A1 - Noordam, R. A1 - Sidore, C. A1 - Fiorillo, E. A1 - McDaid, A. F. A1 - Marques-Vidal, P. A1 - Wielscher, M. A1 - Trompet, S. A1 - Sattar, N. A1 - Møllehave, L. T. A1 - Thuesen, B. H. A1 - Munz, M. A1 - Zeng, L. A1 - Huang, J. A1 - Yang, B. A1 - Poveda, A. A1 - Kurbasic, A. A1 - Lamina, C. A1 - Forer, L. A1 - Scholz, M. A1 - Galesloot, T. E. A1 - Bradfield, J. P. A1 - Daw, E. W. A1 - Zmuda, J. M. A1 - Mitchell, J. S. A1 - Fuchsberger, C. A1 - Christensen, H. A1 - Brody, J. A. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Preuss, M. A1 - Mangino, M. A1 - Christofidou, P. A1 - Verweij, N. A1 - Benjamins, J. W. A1 - Engmann, J. A1 - Kember, R. L. A1 - Slieker, R. C. A1 - Lo, K. S. A1 - Zilhao, N. R. A1 - Le, P. A1 - Kleber, M. E. A1 - Delgado, G. E. A1 - Huo, S. A1 - Ikeda, D. D. A1 - Iha, H. A1 - Yang, J. A1 - Liu, J. A1 - Leonard, H. L. A1 - Marten, J. A1 - Schmidt, B. A1 - Arendt, M. A1 - Smyth, L. J. A1 - Cañadas-Garre, M. A1 - Wang, C. A1 - Nakatochi, M. A1 - Wong, A. A1 - Hutri-Kähönen, N. A1 - Sim, X. A1 - Xia, R. A1 - Huerta-Chagoya, A. A1 - Fernandez-Lopez, J. C. A1 - Lyssenko, V. A1 - Ahmed, M. A1 - Jackson, A. U. A1 - Irvin, M. R. A1 - Oldmeadow, C. A1 - Kim, H. N. A1 - Ryu, S. A1 - Timmers, P. R. H. J. A1 - Arbeeva, L. A1 - Dorajoo, R. A1 - Lange, L. A. A1 - Chai, X. A1 - Prasad, G. A1 - Lorés-Motta, L. A1 - Pauper, M. A1 - Long, J. A1 - Li, X. A1 - Theusch, E. A1 - Takeuchi, F. A1 - Spracklen, C. N. A1 - Loukola, A. A1 - Bollepalli, S. A1 - Warner, S. C. A1 - Wang, Y. X. A1 - Wei, W. B. A1 - Nutile, T. A1 - Ruggiero, D. A1 - Sung, Y. J. A1 - Hung, Y. J. A1 - Chen, S. A1 - Liu, F. A1 - Yang, J. A1 - Kentistou, K. A. A1 - Gorski, M. A1 - Brumat, M. A1 - Meidtner, K. A1 - Bielak, L. F. A1 - Smith, J. A. A1 - Hebbar, P. A1 - Farmaki, A. E. A1 - Hofer, E. A1 - Lin, M. A1 - Xue, C. A1 - Zhang, J. A1 - Concas, M. P. A1 - Vaccargiu, S. A1 - van der Most, P. J. A1 - Pitkänen, N. A1 - Cade, B. E. A1 - Lee, J. A1 - van der Laan, S. W. A1 - Chitrala, K. N. A1 - Weiss, S. A1 - Zimmermann, M. E. A1 - Lee, J. Y. A1 - Choi, H. S. A1 - Nethander, M. A1 - Freitag-Wolf, S. A1 - Southam, L. A1 - Rayner, N. W. A1 - Wang, C. A. A1 - Lin, S. Y. A1 - Wang, J. S. A1 - Couture, C. A1 - Lyytikäinen, L. P. A1 - Nikus, K. A1 - Cuellar-Partida, G. A1 - Vestergaard, H. A1 - Hildalgo, B. A1 - Giannakopoulou, O. A1 - Cai, Q. A1 - Obura, M. O. A1 - van Setten, J. A1 - Li, X. A1 - Schwander, K. A1 - Terzikhan, N. A1 - Shin, J. H. A1 - Jackson, R. D. A1 - Reiner, A. P. A1 - Martin, L. W. A1 - Chen, Z. A1 - Li, L. A1 - Highland, H. M. A1 - Young, K. L. A1 - Kawaguchi, T. A1 - Thiery, J. A1 - Bis, J. C. A1 - Nadkarni, G. N. A1 - Launer, L. J. A1 - Li, H. A1 - Nalls, M. A. A1 - Raitakari, O. T. A1 - Ichihara, S. A1 - Wild, S. H. A1 - Nelson, C. P. A1 - Campbell, H. A1 - Jäger, S. A1 - Nabika, T. A1 - Al-Mulla, F. A1 - Niinikoski, H. A1 - Braund, P. S. A1 - Kolcic, I. A1 - Kovacs, P. A1 - Giardoglou, T. A1 - Katsuya, T. A1 - Bhatti, K. F. A1 - de Kleijn, D. A1 - de Borst, G. J. A1 - Kim, E. K. A1 - Adams, H. H. H. A1 - Ikram, M. A. A1 - Zhu, X. A1 - Asselbergs, F. W. A1 - Kraaijeveld, A. O. A1 - Beulens, J. W. J. A1 - Shu, X. O. A1 - Rallidis, L. S. A1 - Pedersen, O. A1 - Hansen, T. A1 - Mitchell, P. A1 - Hewitt, A. W. A1 - Kähönen, M. A1 - Pérusse, L. A1 - Bouchard, C. A1 - Tonjes, A. A1 - Chen, Y. I. A1 - Pennell, C. E. A1 - Mori, T. A. A1 - Lieb, W. A1 - Franke, A. A1 - Ohlsson, C. A1 - Mellström, D. A1 - Cho, Y. S. A1 - Lee, H. A1 - Yuan, J. M. A1 - Koh, W. P. A1 - Rhee, S. Y. A1 - Woo, J. T. A1 - Heid, I. M. A1 - Stark, K. J. A1 - Völzke, H. A1 - Homuth, G. A1 - Evans, M. K. A1 - Zonderman, A. B. A1 - Polasek, O. A1 - Pasterkamp, G. A1 - Hoefer, I. E. A1 - Redline, S. A1 - Pahkala, K. A1 - Oldehinkel, A. J. A1 - Snieder, H. A1 - Biino, G. A1 - Schmidt, R. A1 - Schmidt, H. A1 - Chen, Y. E. A1 - Bandinelli, S. A1 - Dedoussis, G. A1 - Thanaraj, T. A. A1 - Kardia, S. L. R. A1 - Kato, N. A1 - Schulze, M. B. A1 - Girotto, G. A1 - Jung, B. A1 - Böger, C. A. A1 - Joshi, P. K. A1 - Bennett, D. A. A1 - De Jager, P. L. A1 - Lu, X. A1 - Mamakou, V. A1 - Brown, M. A1 - Caulfield, M. J. A1 - Munroe, P. B. A1 - Guo, X. A1 - Ciullo, M. A1 - Jonas, J. B. A1 - Samani, N. J. A1 - Kaprio, J. A1 - Pajukanta, P. A1 - Adair, L. S. A1 - Bechayda, S. A. A1 - de Silva, H. J. A1 - Wickremasinghe, A. R. A1 - Krauss, R. M. A1 - Wu, J. Y. A1 - Zheng, W. A1 - den Hollander, A. I. A1 - Bharadwaj, D. A1 - Correa, A. A1 - Wilson, J. G. A1 - Lind, L. A1 - Heng, C. K. A1 - Nelson, A. E. A1 - Golightly, Y. M. A1 - Wilson, J. F. A1 - Penninx, B. A1 - Kim, H. L. A1 - Attia, J. A1 - Scott, R. J. A1 - Rao, D. C. A1 - Arnett, D. K. A1 - Walker, M. A1 - Koistinen, H. A. A1 - Chandak, G. R. A1 - Yajnik, C. S. A1 - Mercader, J. M. A1 - Tusié-Luna, T. A1 - Aguilar-Salinas, C. A. A1 - Villalpando, C. G. A1 - Orozco, L. A1 - Fornage, M. A1 - Tai, E. S. A1 - van Dam, R. M. A1 - Lehtimäki, T. A1 - Chaturvedi, N. A1 - Yokota, M. A1 - Liu, J. A1 - Reilly, D. F. A1 - McKnight, A. J. A1 - Kee, F. A1 - Jöckel, K. H. A1 - McCarthy, M. I. A1 - Palmer, C. N. A. A1 - Vitart, V. A1 - Hayward, C. A1 - Simonsick, E. A1 - van Duijn, C. M. A1 - Lu, F. A1 - Qu, J. A1 - Hishigaki, H. A1 - Lin, X. A1 - März, W. A1 - Parra, E. J. A1 - Cruz, M. A1 - Gudnason, V. A1 - Tardif, J. C. A1 - Lettre, G. A1 - 't Hart, L. M. A1 - Elders, P. J. M. A1 - Damrauer, S. M. A1 - Kumari, M. A1 - Kivimaki, M. A1 - van der Harst, P. A1 - Spector, T. D. A1 - Loos, R. J. F. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Brandslund, I. A1 - Pramstaller, P. P. A1 - Christensen, K. A1 - Ripatti, S. A1 - Widén, E. A1 - Hakonarson, H. A1 - Grant, S. F. A. A1 - Kiemeney, L. A. L. M. A1 - de Graaf, J. A1 - Loeffler, M. A1 - Kronenberg, F. A1 - Gu, D. A1 - Erdmann, J. A1 - Schunkert, H. A1 - Franks, P. W. A1 - Linneberg, A. A1 - Jukema, J. W. A1 - Khera, A. V. A1 - Männikkö, M. A1 - Jarvelin, M. R. A1 - Kutalik, Z. A1 - Cucca, F. A1 - Mook-Kanamori, D. O. A1 - van Dijk, K. W. A1 - Watkins, H. A1 - Strachan, D. P. A1 - Grarup, N. A1 - Sever, P. A1 - Poulter, N. A1 - Rotter, J. I. A1 - Dantoft, T. M. A1 - Karpe, F. A1 - Neville, M. J. A1 - Timpson, N. J. A1 - Cheng, C. Y. A1 - Wong, T. Y. A1 - Khor, C. C. A1 - Sabanayagam, C. A1 - Peters, A. A1 - Gieger, C. A1 - Hattersley, A. T. A1 - Pedersen, N. L. A1 - Magnusson, P. K. E. A1 - Boomsma, D. I. A1 - de Geus, E. J. C. A1 - Cupples, L. A. A1 - van Meurs, J. B. J. A1 - Ghanbari, M. A1 - Gordon-Larsen, P. A1 - Huang, W. A1 - Kim, Y. J. A1 - Tabara, Y. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Zeggini, E. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Ingelsson, E. A1 - Abecasis, G. A1 - Chambers, J. C. A1 - Kooner, J. S. A1 - de Vries, P. S. A1 - Morrison, A. C. A1 - North, K. E. A1 - Daviglus, M. A1 - Kraft, P. A1 - Martin, N. G. A1 - Whitfield, J. B. A1 - Abbas, S. A1 - Saleheen, D. A1 - Walters, R. G. A1 - Holmes, M. V. A1 - Black, C. A1 - Smith, B. H. A1 - Justice, A. E. A1 - Baras, A. A1 - Buring, J. E. A1 - Ridker, P. M. A1 - Chasman, D. I. A1 - Kooperberg, C. A1 - Wei, W. Q. A1 - Jarvik, G. P. A1 - Namjou, B. A1 - Hayes, M. G. A1 - Ritchie, M. D. A1 - Jousilahti, P. A1 - Salomaa, V. A1 - Hveem, K. A1 - Åsvold, B. O. A1 - Kubo, M. A1 - Kamatani, Y. A1 - Okada, Y. A1 - Murakami, Y. A1 - Thorsteinsdottir, U. A1 - Stefansson, K. A1 - Ho, Y. L. A1 - Lynch, J. A. A1 - Rader, D. J. A1 - Tsao, P. S. A1 - Chang, K. M. A1 - Cho, K. A1 - O'Donnell, C. J. A1 - Gaziano, J. M. A1 - Wilson, P. A1 - Rotimi, C. N. A1 - Hazelhurst, S. A1 - Ramsay, M. A1 - Trembath, R. C. A1 - van Heel, D. A. A1 - Tamiya, G. A1 - Yamamoto, M. A1 - Kim, B. J. A1 - Mohlke, K. L. A1 - Frayling, T. M. A1 - Hirschhorn, J. N. A1 - Kathiresan, S. A1 - Boehnke, M. A1 - Natarajan, P. A1 - Peloso, G. M. A1 - Brown, C. D. A1 - Morris, A. P. A1 - Assimes, T. L. A1 - Deloukas, P. A1 - Sun, Y. V. A1 - Willer, C. J. AB - application of polygenic scores in clinical practice. VL - 600 ER - TY - JOUR T1 - Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS. JF - J Alzheimers Dis Y1 - 2021 A1 - Briceño, Emily M A1 - Gross, Alden L A1 - Giordani, Bruno J A1 - Manly, Jennifer J A1 - Gottesman, Rebecca F A1 - Elkind, Mitchell S V A1 - Sidney, Stephen A1 - Hingtgen, Stephanie A1 - Sacco, Ralph L A1 - Wright, Clinton B A1 - Fitzpatrick, Annette A1 - Fohner, Alison E A1 - Mosley, Thomas H A1 - Yaffe, Kristine A1 - Levine, Deborah A AB -

BACKGROUND: Meta-analyses of individuals' cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear.

OBJECTIVE: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study.

METHODS: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item's administration and scoring procedures, and score distributions.

RESULTS: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences.

CONCLUSION: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.

VL - 83 IS - 4 ER - TY - JOUR T1 - {Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function JF - Sci Rep Y1 - 2021 A1 - Yang, T. A1 - Jackson, V. E. A1 - Smith, A. V. A1 - Chen, H. A1 - Bartz, T. M. A1 - Sitlani, C. M. A1 - Psaty, B. M. A1 - Gharib, S. A. A1 - O'Connor, G. T. A1 - Dupuis, J. A1 - Xu, J. A1 - Lohman, K. A1 - Liu, Y. A1 - Kritchevsky, S. B. A1 - Cassano, P. A. A1 - Flexeder, C. A1 - Gieger, C. A1 - Karrasch, S. A1 - Peters, A. A1 - Schulz, H. A1 - Harris, S. E. A1 - Starr, J. M. A1 - Deary, I. J. A1 - Manichaikul, A. A1 - Oelsner, E. C. A1 - Barr, R. G. A1 - Taylor, K. D. A1 - Rich, S. S. A1 - Bonten, T. N. A1 - Mook-Kanamori, D. O. A1 - Noordam, R. A1 - Li-Gao, R. A1 - Jarvelin, M. R. A1 - Wielscher, M. A1 - Terzikhan, N. A1 - Lahousse, L. A1 - Brusselle, G. A1 - Weiss, S. A1 - Ewert, R. A1 - Gläser, S. A1 - Homuth, G. A1 - Shrine, N. A1 - Hall, I. P. A1 - Tobin, M. A1 - London, S. J. A1 - Wei, P. A1 - Morrison, A. C. AB - . This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function. VL - 11 ER - TY - JOUR T1 - Sex Differences in Cognitive Decline Among US Adults. JF - JAMA Netw Open Y1 - 2021 A1 - Levine, Deborah A A1 - Gross, Alden L A1 - Briceño, Emily M A1 - Tilton, Nicholas A1 - Giordani, Bruno J A1 - Sussman, Jeremy B A1 - Hayward, Rodney A A1 - Burke, James F A1 - Hingtgen, Stephanie A1 - Elkind, Mitchell S V A1 - Manly, Jennifer J A1 - Gottesman, Rebecca F A1 - Gaskin, Darrell J A1 - Sidney, Stephen A1 - Sacco, Ralph L A1 - Tom, Sarah E A1 - Wright, Clinton B A1 - Yaffe, Kristine A1 - Galecki, Andrzej T KW - Aged KW - Cognitive Dysfunction KW - Cognitive Reserve KW - Cohort Studies KW - Executive Function KW - Humans KW - Memory KW - Middle Aged KW - Risk KW - Sex Factors KW - Time Factors KW - United States AB -

Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women.

Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.

Design, Setting, and Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.

Exposure: Sex.

Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.

Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).

Conclusions and Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

VL - 4 IS - 2 ER - TY - JOUR T1 - {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability JF - Nat Commun Y1 - 2021 A1 - Lagou, V. A1 - M?gi, R. A1 - Hottenga, J. J. A1 - Grallert, H. A1 - Perry, J. R. B. A1 - Bouatia-Naji, N. A1 - Marullo, L. A1 - Rybin, D. A1 - Jansen, R. A1 - Min, J. L. A1 - Dimas, A. S. A1 - Ulrich, A. A1 - Zudina, L. A1 - G?din, J. R. A1 - Jiang, L. A1 - Faggian, A. A1 - Bonnefond, A. A1 - Fadista, J. A1 - Stathopoulou, M. G. A1 - Isaacs, A. A1 - Willems, S. M. A1 - Navarro, P. A1 - Tanaka, T. A1 - Jackson, A. U. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Bielak, L. F. A1 - Webster, R. J. A1 - Saxena, R. A1 - Stafford, J. M. A1 - Pourcain, B. S. A1 - Timpson, N. J. A1 - Salo, P. A1 - Shin, S. Y. A1 - Amin, N. A1 - Smith, A. V. A1 - Li, G. A1 - Verweij, N. A1 - Goel, A. A1 - Ford, I. A1 - Johnson, P. C. D. A1 - Johnson, T. A1 - Kapur, K. A1 - Thorleifsson, G. A1 - Strawbridge, R. J. A1 - Rasmussen-Torvik, L. J. A1 - Esko, T. A1 - Mihailov, E. A1 - Fall, T. A1 - Fraser, R. M. A1 - Mahajan, A. A1 - Kanoni, S. A1 - Giedraitis, V. A1 - Kleber, M. E. A1 - Silbernagel, G. A1 - Meyer, J. A1 - M?ller-Nurasyid, M. A1 - Ganna, A. A1 - Sarin, A. P. A1 - Yengo, L. A1 - Shungin, D. A1 - Luan, J. A1 - Horikoshi, M. A1 - An, P. A1 - Sanna, S. A1 - Boettcher, Y. A1 - Rayner, N. W. A1 - Nolte, I. M. A1 - Zemunik, T. A1 - Iperen, E. V. A1 - Kovacs, P. A1 - Hastie, N. D. A1 - Wild, S. H. A1 - McLachlan, S. A1 - Campbell, S. A1 - Polasek, O. A1 - Carlson, O. A1 - Egan, J. A1 - Kiess, W. A1 - Willemsen, G. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Dimitriou, M. A1 - Hicks, A. A. A1 - Rauramaa, R. A1 - Bandinelli, S. A1 - Thorand, B. A1 - Liu, Y. A1 - Miljkovic, I. A1 - Lind, L. A1 - Doney, A. A1 - Perola, M. A1 - Hingorani, A. A1 - Kivimaki, M. A1 - Kumari, M. A1 - Bennett, A. J. A1 - Groves, C. J. A1 - Herder, C. A1 - Koistinen, H. A. A1 - Kinnunen, L. A1 - Faire, U. A1 - Bakker, S. J. L. A1 - Uusitupa, M. A1 - Palmer, C. N. A. A1 - Jukema, J. W. A1 - Sattar, N. A1 - Pouta, A. A1 - Snieder, H. A1 - Boerwinkle, E. A1 - Pankow, J. S. A1 - Magnusson, P. K. A1 - Krus, U. A1 - Scapoli, C. A1 - de Geus, E. J. C. N. A1 - Bl?her, M. A1 - Wolffenbuttel, B. H. R. A1 - Province, M. A. A1 - Abecasis, G. R. A1 - Meigs, J. B. A1 - Hovingh, G. K. A1 - Lindstr?m, J. A1 - Wilson, J. F. A1 - Wright, A. F. A1 - Dedoussis, G. V. A1 - Bornstein, S. R. A1 - Schwarz, P. E. H. A1 - T?njes, A. A1 - Winkelmann, B. R. A1 - Boehm, B. O. A1 - M?rz, W. A1 - Metspalu, A. A1 - Price, J. F. A1 - Deloukas, P. A1 - K?rner, A. A1 - Lakka, T. A. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Saaristo, T. E. A1 - Bergman, R. N. A1 - Tuomilehto, J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - M?nnist?, S. A1 - Franks, P. W. A1 - Hayward, C. A1 - Vitart, V. A1 - Kaprio, J. A1 - Visvikis-Siest, S. A1 - Balkau, B. A1 - Altshuler, D. A1 - Rudan, I. A1 - Stumvoll, M. A1 - Campbell, H. A1 - van Duijn, C. M. A1 - Gieger, C. A1 - Illig, T. A1 - Ferrucci, L. A1 - Pedersen, N. L. A1 - Pramstaller, P. P. A1 - Boehnke, M. A1 - Frayling, T. M. A1 - Shuldiner, A. R. A1 - Peyser, P. A. A1 - Kardia, S. L. R. A1 - Palmer, L. J. A1 - Penninx, B. W. A1 - Meneton, P. A1 - Harris, T. B. A1 - Navis, G. A1 - Harst, P. V. A1 - Smith, G. D. A1 - Forouhi, N. G. A1 - Loos, R. J. F. A1 - Salomaa, V. A1 - Soranzo, N. A1 - Boomsma, D. I. A1 - Groop, L. A1 - Tuomi, T. A1 - Hofman, A. A1 - Munroe, P. B. A1 - Gudnason, V. A1 - Siscovick, D. S. A1 - Watkins, H. A1 - Lecoeur, C. A1 - Vollenweider, P. A1 - Franco-Cereceda, A. A1 - Eriksson, P. A1 - Jarvelin, M. R. A1 - Stefansson, K. A1 - Hamsten, A. A1 - Nicholson, G. A1 - Karpe, F. A1 - Dermitzakis, E. T. A1 - Lindgren, C. M. A1 - McCarthy, M. I. A1 - Froguel, P. A1 - Kaakinen, M. A. A1 - Lyssenko, V. A1 - Watanabe, R. M. A1 - Ingelsson, E. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Barroso, I. A1 - Morris, A. P. A1 - Prokopenko, I. AB - Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. VL - 12 ER - TY - JOUR T1 - {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability JF - Nat Commun Y1 - 2021 A1 - Lagou, V. A1 - Mägi, R. A1 - Hottenga, J. J. A1 - Grallert, H. A1 - Perry, J. R. B. A1 - Bouatia-Naji, N. A1 - Marullo, L. A1 - Rybin, D. A1 - Jansen, R. A1 - Min, J. L. A1 - Dimas, A. S. A1 - Ulrich, A. A1 - Zudina, L. A1 - Gådin, J. R. A1 - Jiang, L. A1 - Faggian, A. A1 - Bonnefond, A. A1 - Fadista, J. A1 - Stathopoulou, M. G. A1 - Isaacs, A. A1 - Willems, S. M. A1 - Navarro, P. A1 - Tanaka, T. A1 - Jackson, A. U. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Bielak, L. F. A1 - Webster, R. J. A1 - Saxena, R. A1 - Stafford, J. M. A1 - Pourcain, B. S. A1 - Timpson, N. J. A1 - Salo, P. A1 - Shin, S. Y. A1 - Amin, N. A1 - Smith, A. V. A1 - Li, G. A1 - Verweij, N. A1 - Goel, A. A1 - Ford, I. A1 - Johnson, P. C. D. A1 - Johnson, T. A1 - Kapur, K. A1 - Thorleifsson, G. A1 - Strawbridge, R. J. A1 - Rasmussen-Torvik, L. J. A1 - Esko, T. A1 - Mihailov, E. A1 - Fall, T. A1 - Fraser, R. M. A1 - Mahajan, A. A1 - Kanoni, S. A1 - Giedraitis, V. A1 - Kleber, M. E. A1 - Silbernagel, G. A1 - Meyer, J. A1 - Müller-Nurasyid, M. A1 - Ganna, A. A1 - Sarin, A. P. A1 - Yengo, L. A1 - Shungin, D. A1 - Luan, J. A1 - Horikoshi, M. A1 - An, P. A1 - Sanna, S. A1 - Boettcher, Y. A1 - Rayner, N. W. A1 - Nolte, I. M. A1 - Zemunik, T. A1 - Iperen, E. V. A1 - Kovacs, P. A1 - Hastie, N. D. A1 - Wild, S. H. A1 - McLachlan, S. A1 - Campbell, S. A1 - Polasek, O. A1 - Carlson, O. A1 - Egan, J. A1 - Kiess, W. A1 - Willemsen, G. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Dimitriou, M. A1 - Hicks, A. A. A1 - Rauramaa, R. A1 - Bandinelli, S. A1 - Thorand, B. A1 - Liu, Y. A1 - Miljkovic, I. A1 - Lind, L. A1 - Doney, A. A1 - Perola, M. A1 - Hingorani, A. A1 - Kivimaki, M. A1 - Kumari, M. A1 - Bennett, A. J. A1 - Groves, C. J. A1 - Herder, C. A1 - Koistinen, H. A. A1 - Kinnunen, L. A1 - Faire, U. A1 - Bakker, S. J. L. A1 - Uusitupa, M. A1 - Palmer, C. N. A. A1 - Jukema, J. W. A1 - Sattar, N. A1 - Pouta, A. A1 - Snieder, H. A1 - Boerwinkle, E. A1 - Pankow, J. S. A1 - Magnusson, P. K. A1 - Krus, U. A1 - Scapoli, C. A1 - de Geus, E. J. C. N. A1 - Blüher, M. A1 - Wolffenbuttel, B. H. R. A1 - Province, M. A. A1 - Abecasis, G. R. A1 - Meigs, J. B. A1 - Hovingh, G. K. A1 - Lindström, J. A1 - Wilson, J. F. A1 - Wright, A. F. A1 - Dedoussis, G. V. A1 - Bornstein, S. R. A1 - Schwarz, P. E. H. A1 - Tonjes, A. A1 - Winkelmann, B. R. A1 - Boehm, B. O. A1 - März, W. A1 - Metspalu, A. A1 - Price, J. F. A1 - Deloukas, P. A1 - Körner, A. A1 - Lakka, T. A. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Saaristo, T. E. A1 - Bergman, R. N. A1 - Tuomilehto, J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Männistö, S. A1 - Franks, P. W. A1 - Hayward, C. A1 - Vitart, V. A1 - Kaprio, J. A1 - Visvikis-Siest, S. A1 - Balkau, B. A1 - Altshuler, D. A1 - Rudan, I. A1 - Stumvoll, M. A1 - Campbell, H. A1 - van Duijn, C. M. A1 - Gieger, C. A1 - Illig, T. A1 - Ferrucci, L. A1 - Pedersen, N. L. A1 - Pramstaller, P. P. A1 - Boehnke, M. A1 - Frayling, T. M. A1 - Shuldiner, A. R. A1 - Peyser, P. A. A1 - Kardia, S. L. R. A1 - Palmer, L. J. A1 - Penninx, B. W. A1 - Meneton, P. A1 - Harris, T. B. A1 - Navis, G. A1 - Harst, P. V. A1 - Smith, G. D. A1 - Forouhi, N. G. A1 - Loos, R. J. F. A1 - Salomaa, V. A1 - Soranzo, N. A1 - Boomsma, D. I. A1 - Groop, L. A1 - Tuomi, T. A1 - Hofman, A. A1 - Munroe, P. B. A1 - Gudnason, V. A1 - Siscovick, D. S. A1 - Watkins, H. A1 - Lecoeur, C. A1 - Vollenweider, P. A1 - Franco-Cereceda, A. A1 - Eriksson, P. A1 - Jarvelin, M. R. A1 - Stefansson, K. A1 - Hamsten, A. A1 - Nicholson, G. A1 - Karpe, F. A1 - Dermitzakis, E. T. A1 - Lindgren, C. M. A1 - McCarthy, M. I. A1 - Froguel, P. A1 - Kaakinen, M. A. A1 - Lyssenko, V. A1 - Watanabe, R. M. A1 - Ingelsson, E. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Barroso, I. A1 - Morris, A. P. A1 - Prokopenko, I. AB - Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. VL - 12 ER - TY - JOUR T1 - Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations. JF - Circ Genom Precis Med Y1 - 2021 A1 - Haslam, Danielle E A1 - Peloso, Gina M A1 - Guirette, Melanie A1 - Imamura, Fumiaki A1 - Bartz, Traci M A1 - Pitsillides, Achilleas N A1 - Wang, Carol A A1 - Li-Gao, Ruifang A1 - Westra, Jason M A1 - Pitkänen, Niina A1 - Young, Kristin L A1 - Graff, Mariaelisa A1 - Wood, Alexis C A1 - Braun, Kim V E A1 - Luan, Jian'an A1 - Kähönen, Mika A1 - Kiefte-de Jong, Jessica C A1 - Ghanbari, Mohsen A1 - Tintle, Nathan A1 - Lemaitre, Rozenn N A1 - Mook-Kanamori, Dennis O A1 - North, Kari A1 - Helminen, Mika A1 - Mossavar-Rahmani, Yasmin A1 - Snetselaar, Linda A1 - Martin, Lisa W A1 - Viikari, Jorma S A1 - Oddy, Wendy H A1 - Pennell, Craig E A1 - Rosendall, Frits R A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Livingston, Kara A A1 - Voortman, Trudy A1 - Forouhi, Nita G A1 - Wareham, Nick J A1 - de Mutsert, Renée A1 - Rich, Steven S A1 - Manson, JoAnn E A1 - Mora, Samia A1 - Ridker, Paul M A1 - Merino, Jordi A1 - Meigs, James B A1 - Dashti, Hassan S A1 - Chasman, Daniel I A1 - Lichtenstein, Alice H A1 - Smith, Caren E A1 - Dupuis, Josée A1 - Herman, Mark A A1 - McKeown, Nicola M AB -

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

VL - 14 IS - 4 ER - TY - JOUR T1 - Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. JF - J Am Coll Cardiol Y1 - 2021 A1 - Yu, Bing A1 - Roberts, Mary B A1 - Raffield, Laura M A1 - Zekavat, Seyedeh Maryam A1 - Nguyen, Ngoc Quynh H A1 - Biggs, Mary L A1 - Brown, Michael R A1 - Griffin, Gabriel A1 - Desai, Pinkal A1 - Correa, Adolfo A1 - Morrison, Alanna C A1 - Shah, Amil M A1 - Niroula, Abhishek A1 - Uddin, Md Mesbah A1 - Honigberg, Michael C A1 - Ebert, Benjamin L A1 - Psaty, Bruce M A1 - Whitsel, Eric A A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Bick, Alexander G A1 - Ballantyne, Christie M A1 - Reiner, Alex P A1 - Natarajan, Pradeep A1 - Eaton, Charles B KW - Aged KW - Clonal Hematopoiesis KW - Correlation of Data KW - Demography KW - DNA-Binding Proteins KW - Female KW - Heart Failure KW - Humans KW - Janus Kinase 2 KW - Male KW - Middle Aged KW - Mutation KW - Proportional Hazards Models KW - Proto-Oncogene Proteins KW - Repressor Proteins KW - Risk Factors KW - Stroke Volume KW - Ventricular Dysfunction, Left KW - Whole Exome Sequencing AB -

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

VL - 78 IS - 1 ER - TY - JOUR T1 - A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. JF - Am J Epidemiol Y1 - 2021 A1 - Stilp, Adrienne M A1 - Emery, Leslie S A1 - Broome, Jai G A1 - Buth, Erin J A1 - Khan, Alyna T A1 - Laurie, Cecelia A A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Chen, Dongquan A1 - D'Augustine, Catherine M A1 - Heard-Costa, Nancy L A1 - Hohensee, Chancellor R A1 - Johnson, William Craig A1 - Juarez, Lucia D A1 - Liu, Jingmin A1 - Mutalik, Karen M A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - de Vries, Paul S A1 - Kelly, Tanika N A1 - Kooperberg, Charles A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Reiner, Alex P A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Barnes, Kathleen C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Chen, Ming-Huei A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - de Andrade, Mariza A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Gan, Weiniu A1 - Ganesh, Santhi K A1 - Graffelman, Jan A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hawley, Nicola L A1 - Hsu, Wan-Ling A1 - Jackson, Rebecca D A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Lee, Jiwon A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - North, Kari E A1 - Nouraie, Seyed Mehdi A1 - Oelsner, Elizabeth C A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Weiss, Scott T A1 - Wilson, Carla G A1 - Yanek, Lisa R A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Laurie, Cathy C AB -

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

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A1 - Chai, X. A1 - Chang, L. C. A1 - Chen, C. H. A1 - Chen, B. H. A1 - Chitrala, K. N. A1 - Chiu, Y. F. A1 - de Haan, H. G. A1 - Delgado, G. E. A1 - Demirkan, A. A1 - Duan, Q. A1 - Engmann, J. A1 - Fatumo, S. A. A1 - Gayán, J. A1 - Giulianini, F. A1 - Gong, J. H. A1 - Gustafsson, S. A1 - Hai, Y. A1 - Hartwig, F. P. A1 - He, J. A1 - Heianza, Y. A1 - Huang, T. A1 - Huerta-Chagoya, A. A1 - Hwang, M. Y. A1 - Jensen, R. A. A1 - Kawaguchi, T. A1 - Kentistou, K. A. A1 - Kim, Y. J. A1 - Kleber, M. E. A1 - Kooner, I. K. A1 - Lai, S. A1 - Lange, L. A. A1 - Langefeld, C. D. A1 - Lauzon, M. A1 - Li, M. A1 - Ligthart, S. A1 - Liu, J. A1 - Loh, M. A1 - Long, J. A1 - Lyssenko, V. A1 - Mangino, M. A1 - Marzi, C. A1 - Montasser, M. E. A1 - Nag, A. A1 - Nakatochi, M. A1 - Noce, D. A1 - Noordam, R. A1 - Pistis, G. A1 - Preuss, M. A1 - Raffield, L. A1 - Rasmussen-Torvik, L. J. A1 - Rich, S. S. A1 - Robertson, N. R. A1 - Rueedi, R. A1 - Ryan, K. A1 - Sanna, S. A1 - Saxena, R. A1 - Schraut, K. E. A1 - Sennblad, B. A1 - Setoh, K. A1 - Smith, A. V. A1 - Sparsø, T. A1 - Strawbridge, R. J. A1 - Takeuchi, F. A1 - Tan, J. A1 - Trompet, S. A1 - van den Akker, E. A1 - van der Most, P. J. A1 - Verweij, N. A1 - Vogel, M. A1 - Wang, H. A1 - Wang, C. A1 - Wang, N. A1 - Warren, H. R. A1 - Wen, W. A1 - Wilsgaard, T. A1 - Wong, A. A1 - Wood, A. R. A1 - Xie, T. A1 - Zafarmand, M. H. A1 - Zhao, J. H. A1 - Zhao, W. A1 - Amin, N. A1 - Arzumanyan, Z. A1 - Astrup, A. A1 - Bakker, S. J. L. A1 - Baldassarre, D. A1 - Beekman, M. A1 - Bergman, R. N. A1 - Bertoni, A. A1 - Blüher, M. A1 - Bonnycastle, L. L. A1 - Bornstein, S. R. A1 - Bowden, D. W. A1 - Cai, Q. A1 - Campbell, A. A1 - Campbell, H. A1 - Chang, Y. C. A1 - de Geus, E. J. C. A1 - Dehghan, A. A1 - Du, S. A1 - Eiriksdottir, G. A1 - Farmaki, A. E. A1 - Frånberg, M. A1 - Fuchsberger, C. A1 - Gao, Y. A1 - Gjesing, A. P. A1 - Goel, A. A1 - Han, S. A1 - Hartman, C. A. A1 - Herder, C. A1 - Hicks, A. A. A1 - Hsieh, C. H. A1 - Hsueh, W. A. A1 - Ichihara, S. A1 - Igase, M. A1 - Ikram, M. A. A1 - Johnson, W. C. A1 - Jørgensen, M. E. A1 - Joshi, P. K. A1 - Kalyani, R. R. A1 - Kandeel, F. R. A1 - Katsuya, T. A1 - Khor, C. C. A1 - Kiess, W. A1 - Kolcic, I. A1 - Kuulasmaa, T. A1 - Kuusisto, J. A1 - Läll, K. A1 - Lam, K. A1 - Lawlor, D. A. A1 - Lee, N. R. A1 - Lemaitre, R. N. A1 - Li, H. A1 - Lin, S. Y. A1 - Lindström, J. A1 - Linneberg, A. A1 - Liu, J. A1 - Lorenzo, C. A1 - Matsubara, T. A1 - Matsuda, F. A1 - Mingrone, G. A1 - Mooijaart, S. A1 - Moon, S. A1 - Nabika, T. A1 - Nadkarni, G. N. A1 - Nadler, J. L. A1 - Nelis, M. A1 - Neville, M. J. A1 - Norris, J. M. A1 - Ohyagi, Y. A1 - Peters, A. A1 - Peyser, P. A. A1 - Polasek, O. A1 - Qi, Q. A1 - Raven, D. A1 - Reilly, D. F. A1 - Reiner, A. A1 - Rivideneira, F. A1 - Roll, K. A1 - Rudan, I. A1 - Sabanayagam, C. A1 - Sandow, K. A1 - Sattar, N. A1 - Schürmann, A. A1 - Shi, J. A1 - Stringham, H. M. A1 - Taylor, K. D. A1 - Teslovich, T. M. A1 - Thuesen, B. A1 - Timmers, P. R. H. J. A1 - Tremoli, E. A1 - Tsai, M. Y. A1 - Uitterlinden, A. A1 - van Dam, R. M. A1 - van Heemst, D. A1 - van Hylckama Vlieg, A. A1 - Van Vliet-Ostaptchouk, J. V. A1 - Vangipurapu, J. A1 - Vestergaard, H. A1 - Wang, T. A1 - Willems van Dijk, K. A1 - Zemunik, T. A1 - Abecasis, G. R. A1 - Adair, L. S. A1 - Aguilar-Salinas, C. A. A1 - Alarcón-Riquelme, M. E. A1 - An, P. A1 - Aviles-Santa, L. A1 - Becker, D. M. A1 - Beilin, L. J. A1 - Bergmann, S. A1 - Bisgaard, H. A1 - Black, C. A1 - Boehnke, M. A1 - Boerwinkle, E. A1 - Böhm, B. O. A1 - Bønnelykke, K. A1 - Boomsma, D. I. A1 - Bottinger, E. P. A1 - Buchanan, T. A. A1 - Canouil, M. A1 - Caulfield, M. J. A1 - Chambers, J. C. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Cheng, C. Y. A1 - Collins, F. S. A1 - Correa, A. A1 - Cucca, F. A1 - de Silva, H. J. A1 - Dedoussis, G. A1 - Elmståhl, S. A1 - Evans, M. K. A1 - Ferrannini, E. A1 - Ferrucci, L. A1 - Florez, J. C. A1 - Franks, P. W. A1 - Frayling, T. M. A1 - Froguel, P. A1 - Gigante, B. A1 - Goodarzi, M. O. A1 - Gordon-Larsen, P. A1 - Grallert, H. A1 - Grarup, N. A1 - Grimsgaard, S. A1 - Groop, L. A1 - Gudnason, V. A1 - Guo, X. A1 - Hamsten, A. A1 - Hansen, T. A1 - Hayward, C. A1 - Heckbert, S. R. A1 - Horta, B. L. A1 - Huang, W. A1 - Ingelsson, E. A1 - James, P. S. A1 - Jarvelin, M. R. A1 - Jonas, J. B. A1 - Jukema, J. W. A1 - Kaleebu, P. A1 - Kaplan, R. A1 - Kardia, S. L. R. A1 - Kato, N. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Kim, B. J. A1 - Kivimaki, M. A1 - Koistinen, H. A. A1 - Kooner, J. S. A1 - Körner, A. A1 - Kovacs, P. A1 - Kuh, D. A1 - Kumari, M. A1 - Kutalik, Z. A1 - Laakso, M. A1 - Lakka, T. A. A1 - Launer, L. J. A1 - Leander, K. A1 - Li, H. A1 - Lin, X. A1 - Lind, L. A1 - Lindgren, C. A1 - Liu, S. A1 - Loos, R. J. F. A1 - Magnusson, P. K. E. A1 - Mahajan, A. A1 - Metspalu, A. A1 - Mook-Kanamori, D. O. A1 - Mori, T. A. A1 - Munroe, P. B. A1 - Njølstad, I. A1 - O'Connell, J. R. A1 - Oldehinkel, A. J. A1 - Ong, K. K. A1 - Padmanabhan, S. A1 - Palmer, C. N. A. A1 - Palmer, N. D. A1 - Pedersen, O. A1 - Pennell, C. E. A1 - Porteous, D. J. A1 - Pramstaller, P. P. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Qi, L. A1 - Raffel, L. J. A1 - Rauramaa, R. A1 - Redline, S. A1 - Ridker, P. M. A1 - Rosendaal, F. R. A1 - Saaristo, T. E. A1 - Sandhu, M. A1 - Saramies, J. A1 - Schneiderman, N. A1 - Schwarz, P. A1 - Scott, L. J. A1 - Selvin, E. A1 - Sever, P. A1 - Shu, X. O. A1 - Slagboom, P. E. A1 - Small, K. S. A1 - Smith, B. H. A1 - Snieder, H. A1 - Sofer, T. A1 - Sørensen, T. I. A. A1 - Spector, T. D. A1 - Stanton, A. A1 - Steves, C. J. A1 - Stumvoll, M. A1 - Sun, L. A1 - Tabara, Y. A1 - Tai, E. S. A1 - Timpson, N. J. A1 - Tonjes, A. A1 - Tuomilehto, J. A1 - Tusie, T. A1 - Uusitupa, M. A1 - van der Harst, P. A1 - van Duijn, C. A1 - Vitart, V. A1 - Vollenweider, P. A1 - Vrijkotte, T. G. M. A1 - Wagenknecht, L. E. A1 - Walker, M. A1 - Wang, Y. X. A1 - Wareham, N. J. A1 - Watanabe, R. M. A1 - Watkins, H. A1 - Wei, W. B. A1 - Wickremasinghe, A. R. A1 - Willemsen, G. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Wu, J. Y. A1 - Xiang, A. H. A1 - Yanek, L. R. A1 - Yengo, L. A1 - Yokota, M. A1 - Zeggini, E. A1 - Zheng, W. A1 - Zonderman, A. B. A1 - Rotter, J. I. A1 - Gloyn, A. L. A1 - McCarthy, M. I. A1 - Dupuis, J. A1 - Meigs, J. B. A1 - Scott, R. A. A1 - Prokopenko, I. A1 - Leong, A. A1 - Liu, C. T. A1 - Parker, S. C. J. A1 - Mohlke, K. L. A1 - Langenberg, C. A1 - Wheeler, E. A1 - Morris, A. P. A1 - Barroso, I. A1 - de Haan, H. G. A1 - van den Akker, E. A1 - van der Most, P. J. A1 - de Geus, E. J. C. A1 - van Dam, R. M. A1 - van Heemst, D. A1 - van Hylckama Vlieg, A. A1 - van Willems van Dijk, K. A1 - de Silva, H. J. A1 - van der Harst, P. A1 - van Duijn, C. AB - 10.1038/s41588-021-00852-9Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. VL - 53 ER - TY - JOUR T1 - Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. JF - EBioMedicine Y1 - 2021 A1 - Lin, Bridget M A1 - Grinde, Kelsey E A1 - Brody, Jennifer A A1 - Breeze, Charles E A1 - Raffield, Laura M A1 - Mychaleckyj, Josyf C A1 - Thornton, Timothy A A1 - Perry, James A A1 - Baier, Leslie J A1 - de Las Fuentes, Lisa A1 - Guo, Xiuqing A1 - Heavner, Benjamin D A1 - Hanson, Robert L A1 - Hung, Yi-Jen A1 - Qian, Huijun A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Irvin, Margaret R A1 - Jain, Deepti A1 - Kelly, Tanika N A1 - Kobes, Sayuko A1 - Lange, Leslie A1 - Lash, James P A1 - Li, Yun A1 - Liu, Xiaoming A1 - Mi, Xuenan A1 - Musani, Solomon K A1 - Papanicolaou, George J A1 - Parsa, Afshin A1 - Reiner, Alex P A1 - Salimi, Shabnam A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tin, Adrienne A1 - Vaidya, Dhananjay A1 - Wallace, Robert B A1 - Yamamoto, Kenichi A1 - Sakaue, Saori A1 - Matsuda, Koichi A1 - Kamatani, Yoichiro A1 - Momozawa, Yukihide A1 - Yanek, Lisa R A1 - Young, Betsi A A1 - Zhao, Wei A1 - Okada, Yukinori A1 - Abecasis, Gonzalo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Cai, Jianwen A1 - Yii-Der Chen, Ida A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - He, Jiang A1 - Kardia, Sharon Lr A1 - Kooperberg, Charles A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Nickerson, Deborah A A1 - Turner, Steve T A1 - Vasan, Ramachandran S A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Rich, Stephen S A1 - Lin, Dan-Yu A1 - Browning, Sharon R A1 - Franceschini, Nora AB -

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

VL - 63 ER - TY - JOUR T1 - Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative. JF - Hum Mol Genet Y1 - 2021 A1 - Little, Amarise A1 - Hu, Yao A1 - Sun, Quan A1 - Jain, Deepti A1 - Broome, Jai A1 - Chen, Ming-Huei A1 - Thibord, Florian A1 - McHugh, Caitlin A1 - Surendran, Praveen A1 - Blackwell, Thomas W A1 - Brody, Jennifer A A1 - Bhan, Arunoday A1 - Chami, Nathalie A1 - Vries, Paul S A1 - Ekunwe, Lynette A1 - Heard-Costa, Nancy A1 - Hobbs, Brian D A1 - Manichaikul, Ani A1 - Moon, Jee-Young A1 - Preuss, Michael H A1 - Ryan, Kathleen A1 - Wang, Zhe A1 - Wheeler, Marsha A1 - Yanek, Lisa R A1 - Abecasis, Goncalo R A1 - Almasy, Laura A1 - Beaty, Terri H A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Butterworth, Adam S A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Faraday, Nauder A1 - Fornage, Myriam A1 - Glahn, David C A1 - Hou, Lifang A1 - Jorgenson, Eric A1 - Kooperberg, Charles A1 - Lewis, Joshua P A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Min, Nancy A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Nickerson, Debbie A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Pankratz, Nathan A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Albert V A1 - Smith, Nicholas L A1 - Tang, Hua A1 - Tracy, Russell P A1 - Conomos, Matthew P A1 - Laurie, Cecelia A A1 - Mathias, Rasika A A1 - Li, Yun A1 - Auer, Paul L A1 - Thornton, Timothy A1 - Reiner, Alexander P A1 - Johnson, Andrew D A1 - Raffield, Laura M AB -

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

ER - TY - JOUR T1 - Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2021 A1 - Hu, Yao A1 - Stilp, Adrienne M A1 - McHugh, Caitlin P A1 - Rao, Shuquan A1 - Jain, Deepti A1 - Zheng, Xiuwen A1 - Lane, John A1 - Méric de Bellefon, Sébastian A1 - Raffield, Laura M A1 - Chen, Ming-Huei A1 - Yanek, Lisa R A1 - Wheeler, Marsha A1 - Yao, Yao A1 - Ren, Chunyan A1 - Broome, Jai A1 - Moon, Jee-Young A1 - de Vries, Paul S A1 - Hobbs, Brian D A1 - Sun, Quan A1 - Surendran, Praveen A1 - Brody, Jennifer A A1 - Blackwell, Thomas W A1 - Choquet, Helene A1 - Ryan, Kathleen A1 - Duggirala, Ravindranath A1 - Heard-Costa, Nancy A1 - Wang, Zhe A1 - Chami, Nathalie A1 - Preuss, Michael H A1 - Min, Nancy A1 - Ekunwe, Lynette A1 - Lange, Leslie A A1 - Cushman, Mary A1 - Faraday, Nauder A1 - Curran, Joanne E A1 - Almasy, Laura A1 - Kundu, Kousik A1 - Smith, Albert V A1 - Gabriel, Stacey A1 - Rotter, Jerome I A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Vasan, Ramachandran S A1 - Smith, Nicholas L A1 - North, Kari E A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Lewis, Joshua P A1 - Abecasis, Goncalo R A1 - Hou, Lifang A1 - O'Connell, Jeffrey R A1 - Morrison, Alanna C A1 - Beaty, Terri H A1 - Kaplan, Robert A1 - Correa, Adolfo A1 - Blangero, John A1 - Jorgenson, Eric A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Walton, Russell T A1 - Kleinstiver, Benjamin P A1 - Tang, Hua A1 - Loos, Ruth J F A1 - Soranzo, Nicole A1 - Butterworth, Adam S A1 - Nickerson, Debbie A1 - Rich, Stephen S A1 - Mitchell, Braxton D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Li, Yun A1 - Mathias, Rasika A A1 - Lettre, Guillaume A1 - Pankratz, Nathan A1 - Laurie, Cathy C A1 - Laurie, Cecelia A A1 - Bauer, Daniel E A1 - Conomos, Matthew P A1 - Reiner, Alexander P KW - Adult KW - Aged KW - Chromosomes, Human, Pair 16 KW - Datasets as Topic KW - Erythrocytes KW - Female KW - Gene Editing KW - Genetic Variation KW - Genome-Wide Association Study KW - HEK293 Cells KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Phenotype KW - Quality Control KW - Reproducibility of Results KW - United States AB -

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

VL - 108 IS - 5 ER - TY - JOUR T1 - Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2021 A1 - Mikhaylova, Anna V A1 - McHugh, Caitlin P A1 - Polfus, Linda M A1 - Raffield, Laura M A1 - Boorgula, Meher Preethi A1 - Blackwell, Thomas W A1 - Brody, Jennifer A A1 - Broome, Jai A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Conomos, Matthew P A1 - Cox, Corey A1 - Curran, Joanne E A1 - Daya, Michelle A1 - Ekunwe, Lynette A1 - Glahn, David C A1 - Heard-Costa, Nancy A1 - Highland, Heather M A1 - Hobbs, Brian D A1 - Ilboudo, Yann A1 - Jain, Deepti A1 - Lange, Leslie A A1 - Miller-Fleming, Tyne W A1 - Min, Nancy A1 - Moon, Jee-Young A1 - Preuss, Michael H A1 - Rosen, Jonathon A1 - Ryan, Kathleen A1 - Smith, Albert V A1 - Sun, Quan A1 - Surendran, Praveen A1 - de Vries, Paul S A1 - Walter, Klaudia A1 - Wang, Zhe A1 - Wheeler, Marsha A1 - Yanek, Lisa R A1 - Zhong, Xue A1 - Abecasis, Goncalo R A1 - Almasy, Laura A1 - Barnes, Kathleen C A1 - Beaty, Terri H A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Butterworth, Adam S A1 - Chavan, Sameer A1 - Cho, Michael H A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Cox, Nancy A1 - DeMeo, Dawn L A1 - Faraday, Nauder A1 - Fornage, Myriam A1 - Gerszten, Robert E A1 - Hou, Lifang A1 - Johnson, Andrew D A1 - Jorgenson, Eric A1 - Kaplan, Robert A1 - Kooperberg, Charles A1 - Kundu, Kousik A1 - Laurie, Cecelia A A1 - Lettre, Guillaume A1 - Lewis, Joshua P A1 - Li, Bingshan A1 - Li, Yun A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani A1 - Meyers, Deborah A A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Ngo, Debby A1 - Nickerson, Deborah A A1 - Nongmaithem, Suraj A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Ortega, Victor E A1 - Pankratz, Nathan A1 - Perry, James A A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Soranzo, Nicole A1 - Rotter, Jerome I A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Tang, Hua A1 - Tracy, Russell P A1 - Thornton, Timothy A A1 - Vasan, Ramachandran S A1 - Zein, Joe A1 - Mathias, Rasika A A1 - Reiner, Alexander P A1 - Auer, Paul L KW - Asthma KW - Biomarkers KW - Dermatitis, Atopic KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Leukocytes KW - National Heart, Lung, and Blood Institute (U.S.) KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Proteome KW - Pulmonary Disease, Chronic Obstructive KW - Quantitative Trait Loci KW - United Kingdom KW - United States KW - Whole Genome Sequencing AB -

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

VL - 108 IS - 10 ER - TY - JOUR T1 - Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. JF - Nat Genet Y1 - 2022 A1 - Wainschtein, Pierrick A1 - Jain, Deepti A1 - Zheng, Zhili A1 - Cupples, L Adrienne A1 - Shadyab, Aladdin H A1 - McKnight, Barbara A1 - Shoemaker, Benjamin M A1 - Mitchell, Braxton D A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Albert, Christine M A1 - Roden, Dan A1 - Chasman, Daniel I A1 - Darbar, Dawood A1 - Lloyd-Jones, Donald M A1 - Arnett, Donna K A1 - Regan, Elizabeth A A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - O'Connell, Jeffrey R A1 - Yanek, Lisa R A1 - de Andrade, Mariza A1 - Allison, Matthew A A1 - McDonald, Merry-Lynn N A1 - Chung, Mina K A1 - Fornage, Myriam A1 - Chami, Nathalie A1 - Smith, Nicholas L A1 - Ellinor, Patrick T A1 - Vasan, Ramachandran S A1 - Mathias, Rasika A A1 - Loos, Ruth J F A1 - Rich, Stephen S A1 - Lubitz, Steven A A1 - Heckbert, Susan R A1 - Redline, Susan A1 - Guo, Xiuqing A1 - Chen, Y -D Ida A1 - Laurie, Cecelia A A1 - Hernandez, Ryan D A1 - McGarvey, Stephen T A1 - Goddard, Michael E A1 - Laurie, Cathy C A1 - North, Kari E A1 - Lange, Leslie A A1 - Weir, Bruce S A1 - Yengo, Loic A1 - Yang, Jian A1 - Visscher, Peter M AB -

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

VL - 54 IS - 3 ER - TY - JOUR T1 - Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. JF - J Alzheimers Dis Y1 - 2022 A1 - Frenzel, Stefan A1 - Bis, Josh C A1 - Gudmundsson, Elias F A1 - O'Donnell, Adrienne A1 - Simino, Jeannette A1 - Yaqub, Amber A1 - Bartz, Traci M A1 - Brusselle, Guy G O A1 - Bülow, Robin A1 - DeCarli, Charles S A1 - Ewert, Ralf A1 - Gharib, Sina A A1 - Ghosh, Saptaparni A1 - Gireud-Goss, Monica A1 - Gottesman, Rebecca F A1 - Ikram, M Arfan A1 - Knopman, David S A1 - Launer, Lenore J A1 - London, Stephanie J A1 - Longstreth, W T A1 - Lopez, Oscar L A1 - Melo van Lent, Debora A1 - O'Connor, George A1 - Satizabal, Claudia L A1 - Shrestha, Srishti A1 - Sigurdsson, Sigurdur A1 - Stubbe, Beate A1 - Talluri, Rajesh A1 - Vasan, Ramachandran S A1 - Vernooij, Meike W A1 - Völzke, Henry A1 - Wiggins, Kerri L A1 - Yu, Bing A1 - Beiser, Alexa S A1 - Gudnason, Vilmundur A1 - Mosley, Thomas A1 - Psaty, Bruce M A1 - Wolters, Frank J A1 - Grabe, Hans J A1 - Seshadri, Sudha AB -

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

ER - TY - JOUR T1 - Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. JF - Stroke Y1 - 2022 A1 - Bhattacharya, Romit A1 - Zekavat, Seyedeh M A1 - Haessler, Jeffrey A1 - Fornage, Myriam A1 - Raffield, Laura A1 - Uddin, Md Mesbah A1 - Bick, Alexander G A1 - Niroula, Abhishek A1 - Yu, Bing A1 - Gibson, Christopher A1 - Griffin, Gabriel A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Longstreth, William T A1 - Bis, Joshua C A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tracy, Russell P A1 - Correa, Adolfo A1 - Seshadri, Sudha A1 - Johnson, Andrew A1 - Collins, Jason M A1 - Hayden, Kathleen M A1 - Madsen, Tracy E A1 - Ballantyne, Christie M A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Whitsel, Eric A A1 - Natarajan, Pradeep A1 - Reiner, Alexander P AB -

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.

RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.

CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

VL - 53 IS - 3 ER - TY - JOUR T1 - {Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease JF - Nat Commun Y1 - 2022 A1 - Uddin, M. D. M. A1 - Nguyen, N. Q. H. A1 - Yu, B. A1 - Brody, J. A. A1 - Pampana, A. A1 - Nakao, T. A1 - Fornage, M. A1 - Bressler, J. A1 - Sotoodehnia, N. A1 - Weinstock, J. S. A1 - Honigberg, M. C. A1 - Nachun, D. A1 - Bhattacharya, R. A1 - Griffin, G. K. A1 - Chander, V. A1 - Gibbs, R. A. A1 - Rotter, J. I. A1 - Liu, C. A1 - Baccarelli, A. A. A1 - Chasman, D. I. A1 - Whitsel, E. A. A1 - Kiel, D. P. A1 - Murabito, J. M. A1 - Boerwinkle, E. A1 - Ebert, B. L. A1 - Jaiswal, S. A1 - Floyd, J. S. A1 - Bick, A. G. A1 - Ballantyne, C. M. A1 - Psaty, B. M. A1 - Natarajan, P. A1 - Conneely, K. N. AB - Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD. VL - 13 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

VL - 5 IS - 1 ER - TY - JOUR T1 - Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. JF - Brain Y1 - 2022 A1 - Yang, Yunju A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Mishra, Aniket A1 - Liu, Dan A1 - Luciano, Michelle A1 - Teumer, Alexander A1 - Armstrong, Nicola A1 - Bis, Joshua C A1 - Jhun, Min A A1 - Li, Shuo A1 - Adams, Hieab H H A1 - Aziz, Nasir Ahmad A1 - Bastin, Mark E A1 - Bourgey, Mathieu A1 - Brody, Jennifer A A1 - Frenzel, Stefan A1 - Gottesman, Rebecca F A1 - Hosten, Norbert A1 - Hou, Lifang A1 - Kardia, Sharon L R A1 - Lohner, Valerie A1 - Marquis, Pascale A1 - Maniega, Susana Muñoz A1 - Satizabal, Claudia L A1 - Sorond, Farzaneh A A1 - Valdés Hernández, Maria C A1 - van Duijn, Cornelia M A1 - Vernooij, Meike W A1 - Wittfeld, Katharina A1 - Yang, Qiong A1 - Zhao, Wei A1 - Boerwinkle, Eric A1 - Levy, Daniel A1 - Deary, Ian J A1 - Jiang, Jiyang A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Sachdev, Perminder S A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - DeCarli, Charles S A1 - Breteler, Monique M B A1 - Arfan Ikram, M A1 - Grabe, Hans J A1 - Wardlaw, Joanna A1 - Longstreth, W T A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Debette, Stephanie A1 - Fornage, Myriam AB -

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.

ER - TY - JOUR T1 - eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data. JF - Brief Bioinform Y1 - 2022 A1 - Yang, Yingxi A1 - Sun, Quan A1 - Huang, Le A1 - Broome, Jai G A1 - Correa, Adolfo A1 - Reiner, Alexander A1 - Raffield, Laura M A1 - Yang, Yuchen A1 - Li, Yun KW - Genome KW - Genome-Wide Association Study KW - Genomics KW - Regulatory Sequences, Nucleic Acid KW - Whole Genome Sequencing AB -

Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.

VL - 23 IS - 1 ER - TY - JOUR T1 - A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. JF - Nat Methods Y1 - 2022 A1 - Li, Zilin A1 - Li, Xihao A1 - Zhou, Hufeng A1 - Gaynor, Sheila M A1 - Selvaraj, Margaret Sunitha A1 - Arapoglou, Theodore A1 - Quick, Corbin A1 - Liu, Yaowu A1 - Chen, Han A1 - Sun, Ryan A1 - Dey, Rounak A1 - Arnett, Donna K A1 - Auer, Paul L A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blackwell, Thomas W A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Conomos, Matthew P A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Duggirala, Ravindranath A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Göring, Harald H H A1 - Guo, Xiuqing A1 - Kalyani, Rita R A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Lange, Leslie A A1 - Lin, Bridget M A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Meigs, James B A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Taub, Margaret A A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Lin, Xihong KW - Genetic Variation KW - Genome KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Whole Genome Sequencing AB -

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

VL - 19 IS - 12 ER - TY - JOUR T1 - {Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy JF - Am J Ophthalmol Y1 - 2022 A1 - Sobrin, L. A1 - Susarla, G. A1 - Stanwyck, L. A1 - Rouhana, J. M. A1 - Li, A. A1 - Pollack, S. A1 - Igo, R. P. A1 - Jensen, R. A. A1 - Li, X. A1 - Ng, M. C. Y. A1 - Smith, A. V. A1 - Kuo, J. Z. A1 - Taylor, K. D. A1 - Freedman, B. I. A1 - Bowden, D. W. A1 - Penman, A. A1 - Chen, C. J. A1 - Craig, J. E. A1 - Adler, S. G. A1 - Chew, E. Y. A1 - Cotch, M. F. A1 - Yaspan, B. A1 - Mitchell, P. A1 - Wang, J. J. A1 - Klein, B. E. K. A1 - Wong, T. Y. A1 - Rotter, J. I. A1 - Burdon, K. P. A1 - Iyengar, S. K. A1 - Segrè, A. V. AB - {To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.\ .05.\ .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment VL - 233 ER - TY - JOUR T1 - {Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate JF - Brain Y1 - 2022 A1 - Mishra, A. A1 - Duplaà, C. A1 - Vojinovic, D. A1 - Suzuki, H. A1 - Sargurupremraj, M. A1 - Zilhao, N. R. A1 - Li, S. A1 - Bartz, T. M. A1 - Jian, X. A1 - Zhao, W. A1 - Hofer, E. A1 - Wittfeld, K. A1 - Harris, S. E. A1 - van der Auwera-Palitschka, S. A1 - Luciano, M. A1 - Bis, J. C. A1 - Adams, H. H. H. A1 - Satizabal, C. L. A1 - Gottesman, R. F. A1 - Gampawar, P. G. A1 - Bülow, R. A1 - Weiss, S. A1 - Yu, M. A1 - Bastin, M. E. A1 - Lopez, O. L. A1 - Vernooij, M. W. A1 - Beiser, A. S. A1 - Völker, U. A1 - Kacprowski, T. A1 - Soumare, A. A1 - Smith, J. A. A1 - Knopman, D. S. A1 - Morris, Z. A1 - Zhu, Y. A1 - Rotter, J. I. A1 - Dufouil, C. A1 - Valdés Hernández, M. A1 - Muñoz Maniega, S. A1 - Lathrop, M. A1 - Boerwinkle, E. A1 - Schmidt, R. A1 - Ihara, M. A1 - Mazoyer, B. A1 - Yang, Q. A1 - Joutel, A. A1 - Tournier-Lasserve, E. A1 - Launer, L. J. A1 - Deary, I. J. A1 - Mosley, T. H. A1 - Amouyel, P. A1 - DeCarli, C. S. A1 - Psaty, B. M. A1 - Tzourio, C. A1 - Kardia, S. L. R. A1 - Grabe, H. J. A1 - Teumer, A. A1 - van Duijn, C. M. A1 - Schmidt, H. A1 - Wardlaw, J. M. A1 - Ikram, M. A. A1 - Fornage, M. A1 - Gudnason, V. A1 - Seshadri, S. A1 - Matthews, P. M. A1 - Longstreth, W. T. A1 - Couffinhal, T. A1 - Debette, S. AB - Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work. VL - 145 ER - TY - JOUR T1 - {Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways JF - Nat Commun Y1 - 2022 A1 - Young, W. J. A1 - Lahrouchi, N. A1 - Isaacs, A. A1 - Duong, T. A1 - Foco, L. A1 - Ahmed, F. A1 - Brody, J. A. A1 - Salman, R. A1 - Noordam, R. A1 - Benjamins, J. W. A1 - Haessler, J. A1 - Lyytikäinen, L. P. A1 - Repetto, L. A1 - Concas, M. P. A1 - van den Berg, M. E. A1 - Weiss, S. A1 - Baldassari, A. R. A1 - Bartz, T. M. A1 - Cook, J. P. A1 - Evans, D. S. A1 - Freudling, R. A1 - Hines, O. A1 - Isaksen, J. L. A1 - Lin, H. A1 - Mei, H. A1 - Moscati, A. A1 - Müller-Nurasyid, M. A1 - Nursyifa, C. A1 - Qian, Y. A1 - Richmond, A. A1 - Roselli, C. A1 - Ryan, K. A. A1 - Tarazona-Santos, E. A1 - Thériault, S. A1 - van Duijvenboden, S. A1 - Warren, H. R. A1 - Yao, J. A1 - Raza, D. A1 - Aeschbacher, S. A1 - Ahlberg, G. A1 - Alonso, A. A1 - Andreasen, L. A1 - Bis, J. C. A1 - Boerwinkle, E. A1 - Campbell, A. A1 - Catamo, E. A1 - Cocca, M. A1 - Cutler, M. J. A1 - Darbar, D. A1 - De Grandi, A. A1 - De Luca, A. A1 - Ding, J. A1 - Ellervik, C. A1 - Ellinor, P. T. A1 - Felix, S. B. A1 - Froguel, P. A1 - Fuchsberger, C. A1 - Gögele, M. A1 - Graff, C. A1 - Graff, M. A1 - Guo, X. A1 - Hansen, T. A1 - Heckbert, S. R. A1 - Huang, P. L. A1 - Huikuri, H. V. A1 - Hutri-Kähönen, N. A1 - Ikram, M. A. A1 - Jackson, R. D. A1 - Junttila, J. A1 - Kavousi, M. A1 - Kors, J. A. A1 - Leal, T. P. A1 - Lemaitre, R. N. A1 - Lin, H. J. A1 - Lind, L. A1 - Linneberg, A. A1 - Liu, S. A1 - Macfarlane, P. W. A1 - Mangino, M. A1 - Meitinger, T. A1 - Mezzavilla, M. A1 - Mishra, P. P. A1 - Mitchell, R. N. A1 - Mononen, N. A1 - Montasser, M. E. A1 - Morrison, A. C. A1 - Nauck, M. A1 - Nauffal, V. A1 - Navarro, P. A1 - Nikus, K. A1 - Pare, G. A1 - Patton, K. K. A1 - Pelliccione, G. A1 - Pittman, A. A1 - Porteous, D. J. A1 - Pramstaller, P. P. A1 - Preuss, M. H. A1 - Raitakari, O. T. A1 - Reiner, A. P. A1 - Ribeiro, A. L. P. A1 - Rice, K. M. A1 - Risch, L. A1 - Schlessinger, D. A1 - Schotten, U. A1 - Schurmann, C. A1 - Shen, X. A1 - Shoemaker, M. B. A1 - Sinagra, G. A1 - Sinner, M. F. A1 - Soliman, E. Z. A1 - Stoll, M. A1 - Strauch, K. A1 - Tarasov, K. A1 - Taylor, K. D. A1 - Tinker, A. A1 - Trompet, S. A1 - Uitterlinden, A. A1 - Völker, U. A1 - Völzke, H. A1 - Waldenberger, M. A1 - Weng, L. C. A1 - Whitsel, E. A. A1 - Wilson, J. G. A1 - Avery, C. L. A1 - Conen, D. A1 - Correa, A. A1 - Cucca, F. A1 - Dörr, M. A1 - Gharib, S. A. A1 - Girotto, G. A1 - Grarup, N. A1 - Hayward, C. A1 - Jamshidi, Y. A1 - Jarvelin, M. R. A1 - Jukema, J. W. A1 - Kääb, S. A1 - Kähönen, M. A1 - Kanters, J. K. A1 - Kooperberg, C. A1 - Lehtimäki, T. A1 - Lima-Costa, M. F. A1 - Liu, Y. A1 - Loos, R. J. F. A1 - Lubitz, S. A. A1 - Mook-Kanamori, D. O. A1 - Morris, A. P. A1 - O'Connell, J. R. A1 - Olesen, M. S. A1 - Orini, M. A1 - Padmanabhan, S. A1 - Pattaro, C. A1 - Peters, A. A1 - Psaty, B. M. A1 - Rotter, J. I. A1 - Stricker, B. A1 - van der Harst, P. A1 - van Duijn, C. M. A1 - Verweij, N. A1 - Wilson, J. F. A1 - Arking, D. E. A1 - Ramirez, J. A1 - Lambiase, P. D. A1 - Sotoodehnia, N. A1 - Mifsud, B. A1 - Newton-Cheh, C. A1 - Munroe, P. B. AB - 250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization. VL - 13 ER - TY - JOUR T1 - {Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study JF - Hum Mol Genet Y1 - 2022 A1 - Portilla-Fernandez, E. A1 - Klarin, D. A1 - Hwang, S. J. A1 - Biggs, M. L. A1 - Bis, J. C. A1 - Weiss, S. A1 - Rospleszcz, S. A1 - Natarajan, P. A1 - Hoffmann, U. A1 - Rogers, I. S. A1 - Truong, Q. A. A1 - lker, U. A1 - rr, M. A1 - low, R. A1 - Criqui, M. H. A1 - Allison, M. A1 - Ganesh, S. K. A1 - Yao, J. A1 - Waldenberger, M. A1 - Bamberg, F. A1 - Rice, K. M. A1 - Essers, J. A1 - Kapteijn, D. M. C. A1 - van der Laan, S. W. A1 - de Knegt, R. J. A1 - Ghanbari, M. A1 - Felix, J. F. A1 - Ikram, M. A. A1 - Kavousi, M. A1 - Uitterlinden, A. G. A1 - Roks, A. J. M. A1 - Danser, A. H. J. A1 - Tsao, P. S. A1 - Damrauer, S. M. A1 - Guo, X. A1 - Rotter, J. I. A1 - Psaty, B. M. A1 - Kathiresan, S. A1 - lzke, H. A1 - Peters, A. A1 - Johnson, C. A1 - Strauch, K. A1 - Meitinger, T. A1 - O'Donnell, C. J. A1 - Dehghan, A. AB - 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases. VL - 31 ER - TY - JOUR T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. JF - Kidney Int Y1 - 2022 A1 - Gorski, Mathias A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Thomas, Laurent F A1 - Graham, Sarah E A1 - Sveinbjornsson, Gardar A1 - Winkler, Thomas W A1 - Günther, Felix A1 - Stark, Klaus J A1 - Chai, Jin-Fang A1 - Tayo, Bamidele O A1 - Wuttke, Matthias A1 - Li, Yong A1 - Tin, Adrienne A1 - Ahluwalia, Tarunveer S A1 - Arnlöv, Johan A1 - Åsvold, Bjørn Olav A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Böhnke, Michael A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Carroll, Robert J A1 - Chaker, Layal A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Chu, Audrey Y A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Cook, James P A1 - Coresh, Josef A1 - Cusi, Daniele A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Feitosa, Mary F A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Fuchsberger, Christian A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hishida, Asahi A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Karabegović, Irma A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Li, Man A1 - Lieb, Wolfgang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Matias-Garcia, Pamela R A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Naito, Mariko A1 - Nakatochi, Masahiro A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - O'Donoghue, Michelle L A1 - O'Connell, Jeffrey A1 - Olafsson, Isleifur A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Pirastu, Mario A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Sabanayagam, Charumathi A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scholz, Markus A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Sieber, Karsten B A1 - Sim, Xueling A1 - Sims, Mario A1 - Snieder, Harold A1 - Stanzick, Kira J A1 - Thorsteinsdottir, Unnur A1 - Stocker, Hannah A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Sulem, Patrick A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Thio, Chris H L A1 - Tremblay, Johanne A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Wakai, Kenji A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wallner, Stefan A1 - Wang, Judy A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yerges-Armstrong, Laura M A1 - Zimmermann, Martina A1 - Zonderman, Alan B A1 - Bergler, Tobias A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Heid, Iris M AB -

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

ER - TY - JOUR T1 - {Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation JF - Hum Genet Y1 - 2022 A1 - Longchamps, R. J. A1 - Yang, S. Y. A1 - Castellani, C. A. A1 - Shi, W. A1 - Lane, J. A1 - Grove, M. L. A1 - Bartz, T. M. A1 - Sarnowski, C. A1 - Liu, C. A1 - Burrows, K. A1 - Guyatt, A. L. A1 - Gaunt, T. R. A1 - Kacprowski, T. A1 - Yang, J. A1 - De Jager, P. L. A1 - Yu, L. A1 - Bergman, A. A1 - Xia, R. A1 - Fornage, M. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Kraja, A. T. A1 - Province, M. A. A1 - Amin, N. A1 - Rivadeneira, F. A1 - Tiemeier, H. A1 - Uitterlinden, A. G. A1 - Broer, L. A1 - van Meurs, J. B. J. A1 - van Duijn, C. M. A1 - Raffield, L. M. A1 - Lange, L. A1 - Rich, S. S. A1 - Lemaitre, R. N. A1 - Goodarzi, M. O. A1 - Sitlani, C. M. A1 - Mak, A. C. Y. A1 - Bennett, D. A. A1 - Rodriguez, S. A1 - Murabito, J. M. A1 - Lunetta, K. L. A1 - Sotoodehnia, N. A1 - Atzmon, G. A1 - Ye, K. A1 - Barzilai, N. A1 - Brody, J. A. A1 - Psaty, B. M. A1 - Taylor, K. D. A1 - Rotter, J. I. A1 - Boerwinkle, E. A1 - Pankratz, N. A1 - Arking, D. E. AB - ). VL - 141 ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

ER - TY - JOUR T1 - {Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases JF - JCI Insight Y1 - 2022 A1 - Li, Y. A1 - Cheng, Y. A1 - Consolato, F. A1 - Schiano, G. A1 - Chong, M. R. A1 - Pietzner, M. A1 - Nguyen, N. Q. H. A1 - Scherer, N. A1 - Biggs, M. L. A1 - Kleber, M. E. A1 - Haug, S. A1 - Göçmen, B. A1 - Pigeyre, M. A1 - Sekula, P. A1 - Steinbrenner, I. A1 - Schlosser, P. A1 - Joseph, C. B. A1 - Brody, J. A. A1 - Grams, M. E. A1 - Hayward, C. A1 - Schultheiss, U. T. A1 - Krämer, B. K. A1 - Kronenberg, F. A1 - Peters, A. A1 - Seissler, J. A1 - Steubl, D. A1 - Then, C. A1 - Wuttke, M. A1 - März, W. A1 - Eckardt, K. U. A1 - Gieger, C. A1 - Boerwinkle, E. A1 - Psaty, B. M. A1 - Coresh, J. A1 - Oefner, P. J. A1 - Pare, G. A1 - Langenberg, C. A1 - Scherberich, J. E. A1 - Yu, B. A1 - Akilesh, S. A1 - Devuyst, O. A1 - Rampoldi, L. A1 - Köttgen, A. AB - Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions. VL - 7 ER - TY - JOUR T1 - {Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis JF - Genome Biol Y1 - 2022 A1 - Kanoni, S. A1 - Graham, S. E. A1 - Wang, Y. A1 - Surakka, I. A1 - Ramdas, S. A1 - Zhu, X. A1 - Clarke, S. L. A1 - Bhatti, K. F. A1 - Vedantam, S. A1 - Winkler, T. W. A1 - Locke, A. E. A1 - Marouli, E. A1 - Zajac, G. J. M. A1 - Wu, K. H. A1 - Ntalla, I. A1 - Hui, Q. A1 - Klarin, D. A1 - Hilliard, A. T. A1 - Wang, Z. A1 - Xue, C. A1 - Thorleifsson, G. A1 - Helgadottir, A. A1 - Gudbjartsson, D. F. A1 - Holm, H. A1 - Olafsson, I. A1 - Hwang, M. Y. A1 - Han, S. A1 - Akiyama, M. A1 - Sakaue, S. A1 - Terao, C. A1 - Kanai, M. A1 - Zhou, W. A1 - Brumpton, B. M. A1 - Rasheed, H. A1 - Havulinna, A. S. A1 - Veturi, Y. A1 - Pacheco, J. A. A1 - Rosenthal, E. A. A1 - Lingren, T. A1 - Feng, Q. A1 - Kullo, I. J. A1 - Narita, A. A1 - Takayama, J. A1 - Martin, H. C. A1 - Hunt, K. A. A1 - Trivedi, B. A1 - Haessler, J. A1 - Giulianini, F. A1 - Bradford, Y. A1 - Miller, J. E. A1 - Campbell, A. A1 - Lin, K. A1 - Millwood, I. Y. A1 - Rasheed, A. A1 - Hindy, G. A1 - Faul, J. D. A1 - Zhao, W. A1 - Weir, D. R. A1 - Turman, C. A1 - Huang, H. A1 - Graff, M. A1 - Choudhury, A. A1 - Sengupta, D. A1 - Mahajan, A. A1 - Brown, M. R. A1 - Zhang, W. A1 - Yu, K. A1 - Schmidt, E. M. A1 - Pandit, A. A1 - Gustafsson, S. A1 - Yin, X. A1 - Luan, J. A1 - Zhao, J. H. A1 - Matsuda, F. A1 - Jang, H. M. A1 - Yoon, K. A1 - Medina-Gomez, C. A1 - Pitsillides, A. A1 - Hottenga, J. J. A1 - Wood, A. R. A1 - Ji, Y. A1 - Gao, Z. A1 - Haworth, S. A1 - Yousri, N. A. A1 - Mitchell, R. E. A1 - Chai, J. F. A1 - Aadahl, M. A1 - Bjerregaard, A. A. A1 - Yao, J. A1 - Manichaikul, A. A1 - Hwu, C. M. A1 - Hung, Y. J. A1 - Warren, H. R. A1 - Ramirez, J. A1 - Bork-Jensen, J. A1 - rhus, L. L. A1 - Goel, A. A1 - Sabater-Lleal, M. A1 - Noordam, R. A1 - Mauro, P. A1 - Matteo, F. A1 - McDaid, A. F. A1 - Marques-Vidal, P. A1 - Wielscher, M. A1 - Trompet, S. A1 - Sattar, N. A1 - llehave, L. T. A1 - Munz, M. A1 - Zeng, L. A1 - Huang, J. A1 - Yang, B. A1 - Poveda, A. A1 - Kurbasic, A. A1 - Lamina, C. A1 - Forer, L. A1 - Scholz, M. A1 - Galesloot, T. E. A1 - Bradfield, J. P. A1 - Ruotsalainen, S. E. A1 - Daw, E. A1 - Zmuda, J. M. A1 - Mitchell, J. S. A1 - Fuchsberger, C. A1 - Christensen, H. A1 - Brody, J. A. A1 - Vazquez-Moreno, M. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Wang, Z. A1 - Preuss, M. H. A1 - Mangino, M. A1 - Christofidou, P. A1 - Verweij, N. A1 - Benjamins, J. W. A1 - Engmann, J. A1 - Tsao, N. L. A1 - Verma, A. A1 - Slieker, R. C. A1 - Lo, K. S. A1 - Zilhao, N. R. A1 - Le, P. A1 - Kleber, M. E. A1 - Delgado, G. E. A1 - Huo, S. A1 - Ikeda, D. D. A1 - Iha, H. A1 - Yang, J. A1 - Liu, J. A1 - Demirkan, A. A1 - Leonard, H. L. A1 - Marten, J. A1 - Frank, M. A1 - Schmidt, B. A1 - Smyth, L. J. A1 - adas-Garre, M. A1 - Wang, C. A1 - Nakatochi, M. A1 - Wong, A. A1 - nen, N. A1 - Sim, X. A1 - Xia, R. A1 - Huerta-Chagoya, A. A1 - Fernandez-Lopez, J. C. A1 - Lyssenko, V. A1 - Nongmaithem, S. S. A1 - Bayyana, S. A1 - Stringham, H. M. A1 - Irvin, M. R. A1 - Oldmeadow, C. A1 - Kim, H. N. A1 - Ryu, S. A1 - Timmers, P. R. H. J. A1 - Arbeeva, L. A1 - Dorajoo, R. A1 - Lange, L. A. A1 - Prasad, G. A1 - s-Motta, L. A1 - Pauper, M. A1 - Long, J. A1 - Li, X. A1 - Theusch, E. A1 - Takeuchi, F. A1 - Spracklen, C. N. A1 - Loukola, A. A1 - Bollepalli, S. A1 - Warner, S. C. A1 - Wang, Y. X. A1 - Wei, W. B. A1 - Nutile, T. A1 - Ruggiero, D. A1 - Sung, Y. J. A1 - Chen, S. A1 - Liu, F. A1 - Yang, J. A1 - Kentistou, K. A. A1 - Banas, B. A1 - Nardone, G. G. A1 - Meidtner, K. A1 - Bielak, L. F. A1 - Smith, J. A. A1 - Hebbar, P. A1 - Farmaki, A. E. A1 - Hofer, E. A1 - Lin, M. A1 - Concas, M. P. A1 - Vaccargiu, S. A1 - van der Most, P. J. A1 - nen, N. A1 - Cade, B. E. A1 - van der Laan, S. W. A1 - Chitrala, K. N. A1 - Weiss, S. A1 - Bentley, A. R. A1 - Doumatey, A. P. A1 - Adeyemo, A. A. A1 - Lee, J. Y. A1 - Petersen, E. R. B. A1 - Nielsen, A. A. A1 - Choi, H. S. A1 - Nethander, M. A1 - Freitag-Wolf, S. A1 - Southam, L. A1 - Rayner, N. W. A1 - Wang, C. A. A1 - Lin, S. Y. A1 - Wang, J. S. A1 - Couture, C. A1 - inen, L. P. A1 - Nikus, K. A1 - Cuellar-Partida, G. A1 - Vestergaard, H. A1 - Hidalgo, B. A1 - Giannakopoulou, O. A1 - Cai, Q. A1 - Obura, M. O. A1 - van Setten, J. A1 - Li, X. A1 - Liang, J. A1 - Tang, H. A1 - Terzikhan, N. A1 - Shin, J. H. A1 - Jackson, R. D. A1 - Reiner, A. P. A1 - Martin, L. W. A1 - Chen, Z. A1 - Li, L. A1 - Kawaguchi, T. A1 - Thiery, J. A1 - Bis, J. C. A1 - Launer, L. J. A1 - Li, H. A1 - Nalls, M. A. A1 - Raitakari, O. T. A1 - Ichihara, S. A1 - Wild, S. H. A1 - Nelson, C. P. A1 - Campbell, H. A1 - ger, S. A1 - Nabika, T. A1 - Al-Mulla, F. A1 - Niinikoski, H. A1 - Braund, P. S. A1 - Kolcic, I. A1 - Kovacs, P. A1 - Giardoglou, T. A1 - Katsuya, T. A1 - de Kleijn, D. A1 - de Borst, G. J. A1 - Kim, E. K. A1 - Adams, H. H. H. A1 - Ikram, M. A. A1 - Zhu, X. A1 - Asselbergs, F. W. A1 - Kraaijeveld, A. O. A1 - Beulens, J. W. J. A1 - Shu, X. O. A1 - Rallidis, L. S. A1 - Pedersen, O. A1 - Hansen, T. A1 - Mitchell, P. A1 - Hewitt, A. W. A1 - nen, M. A1 - russe, L. A1 - Bouchard, C. A1 - njes, A. A1 - Chen, Y. I. A1 - Pennell, C. E. A1 - Mori, T. A. A1 - Lieb, W. A1 - Franke, A. A1 - Ohlsson, C. A1 - m, D. A1 - Cho, Y. S. A1 - Lee, H. A1 - Yuan, J. M. A1 - Koh, W. P. A1 - Rhee, S. Y. A1 - Woo, J. T. A1 - Heid, I. M. A1 - Stark, K. J. A1 - Zimmermann, M. E. A1 - lzke, H. A1 - Homuth, G. A1 - Evans, M. K. A1 - Zonderman, A. B. A1 - Polasek, O. A1 - Pasterkamp, G. A1 - Hoefer, I. E. A1 - Redline, S. A1 - Pahkala, K. A1 - Oldehinkel, A. J. A1 - Snieder, H. A1 - Biino, G. A1 - Schmidt, R. A1 - Schmidt, H. A1 - Bandinelli, S. A1 - Dedoussis, G. A1 - Thanaraj, T. A. A1 - Kardia, S. L. R. A1 - Peyser, P. A. A1 - Kato, N. A1 - Schulze, M. B. A1 - Girotto, G. A1 - ger, C. A. A1 - Jung, B. A1 - Joshi, P. K. A1 - Bennett, D. A. A1 - De Jager, P. L. A1 - Lu, X. A1 - Mamakou, V. A1 - Brown, M. A1 - Caulfield, M. J. A1 - Munroe, P. B. A1 - Guo, X. A1 - Ciullo, M. A1 - Jonas, J. B. A1 - Samani, N. J. A1 - Kaprio, J. A1 - Pajukanta, P. A1 - -Luna, T. A1 - Aguilar-Salinas, C. A. A1 - Adair, L. S. A1 - Bechayda, S. A. A1 - de Silva, H. J. A1 - Wickremasinghe, A. R. A1 - Krauss, R. M. A1 - Wu, J. Y. A1 - Zheng, W. A1 - Hollander, A. I. A1 - Bharadwaj, D. A1 - Correa, A. A1 - Wilson, J. G. 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J. A1 - Cruz, M. A1 - Psaty, B. M. A1 - Brandslund, I. A1 - Pramstaller, P. P. A1 - Rotimi, C. N. A1 - Christensen, K. A1 - Ripatti, S. A1 - n, E. A1 - Hakonarson, H. A1 - Grant, S. F. A. A1 - Kiemeney, L. A. L. M. A1 - de Graaf, J. A1 - Loeffler, M. A1 - Kronenberg, F. A1 - Gu, D. A1 - Erdmann, J. A1 - Schunkert, H. A1 - Franks, P. W. A1 - Linneberg, A. A1 - Jukema, J. W. A1 - Khera, A. V. A1 - ö, M. A1 - Jarvelin, M. R. A1 - Kutalik, Z. A1 - Francesco, C. A1 - Mook-Kanamori, D. O. A1 - van Dijk, K. W. A1 - Watkins, H. A1 - Strachan, D. P. A1 - Grarup, N. A1 - Sever, P. A1 - Poulter, N. A1 - Chuang, L. M. A1 - Rotter, J. I. A1 - Dantoft, T. M. A1 - Karpe, F. A1 - Neville, M. J. A1 - Timpson, N. J. A1 - Cheng, C. Y. A1 - Wong, T. Y. A1 - Khor, C. C. A1 - Li, H. A1 - Sabanayagam, C. A1 - Peters, A. A1 - Gieger, C. A1 - Hattersley, A. T. A1 - Pedersen, N. L. A1 - Magnusson, P. K. E. A1 - Boomsma, D. I. A1 - Willemsen, A. H. M. A1 - Cupples, L. A1 - van Meurs, J. B. J. A1 - Ghanbari, M. A1 - Gordon-Larsen, P. A1 - Huang, W. A1 - Kim, Y. J. A1 - Tabara, Y. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Zeggini, E. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Ingelsson, E. A1 - Abecasis, G. A1 - Chambers, J. C. A1 - Kooner, J. S. A1 - de Vries, P. S. A1 - Morrison, A. C. A1 - Hazelhurst, S. A1 - Ramsay, M. A1 - North, K. E. A1 - Daviglus, M. A1 - Kraft, P. A1 - Martin, N. G. A1 - Whitfield, J. B. A1 - Abbas, S. A1 - Saleheen, D. A1 - Walters, R. G. A1 - Holmes, M. V. A1 - Black, C. A1 - Smith, B. H. A1 - Baras, A. A1 - Justice, A. E. A1 - Buring, J. E. A1 - Ridker, P. M. A1 - Chasman, D. I. A1 - Kooperberg, C. A1 - Tamiya, G. A1 - Yamamoto, M. A1 - van Heel, D. A. A1 - Trembath, R. C. A1 - Wei, W. Q. A1 - Jarvik, G. P. A1 - Namjou, B. A1 - Hayes, M. G. A1 - Ritchie, M. D. A1 - Jousilahti, P. A1 - Salomaa, V. A1 - Hveem, K. A1 - svold, B. O. A1 - Kubo, M. A1 - Kamatani, Y. A1 - Okada, Y. A1 - Murakami, Y. A1 - Kim, B. J. A1 - Thorsteinsdottir, U. A1 - Stefansson, K. A1 - Zhang, J. A1 - Chen, Y. A1 - Ho, Y. L. A1 - Lynch, J. A. A1 - Rader, D. J. A1 - Tsao, P. S. A1 - Chang, K. M. A1 - Cho, K. A1 - O'Donnell, C. J. A1 - Gaziano, J. M. A1 - Wilson, P. W. F. A1 - Frayling, T. M. A1 - Hirschhorn, J. N. A1 - Kathiresan, S. A1 - Mohlke, K. L. A1 - Sun, Y. V. A1 - Morris, A. P. A1 - Boehnke, M. A1 - Brown, C. D. A1 - Natarajan, P. A1 - Deloukas, P. A1 - Willer, C. J. A1 - Assimes, T. L. A1 - Peloso, G. M. AB - Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.\ 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.\ Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. VL - 23 ER - TY - JOUR T1 - Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. JF - Hypertension Y1 - 2022 A1 - Kelly, Tanika N A1 - Sun, Xiao A1 - He, Karen Y A1 - Brown, Michael R A1 - Taliun, Sarah A Gagliano A1 - Hellwege, Jacklyn N A1 - Irvin, Marguerite R A1 - Mi, Xuenan A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - de Vries, Paul S A1 - Gao, Yan A1 - Moscati, Arden A1 - Nadkarni, Girish N A1 - Yanek, Lisa R A1 - Elfassy, Tali A1 - Smith, Jennifer A A1 - Chung, Ren-Hua A1 - Beitelshees, Amber L A1 - Patki, Amit A1 - Aslibekyan, Stella A1 - Blobner, Brandon M A1 - Peralta, Juan M A1 - Assimes, Themistocles L A1 - Palmas, Walter R A1 - Liu, Chunyu A1 - Bress, Adam P A1 - Huang, Zhijie A1 - Becker, Lewis C A1 - Hwa, Chii-Min A1 - O'Connell, Jeffrey R A1 - Carlson, Jenna C A1 - Warren, Helen R A1 - Das, Sayantan A1 - Giri, Ayush A1 - Martin, Lisa W A1 - Craig Johnson, W A1 - Fox, Ervin R A1 - Bottinger, Erwin P A1 - Razavi, Alexander C A1 - Vaidya, Dhananjay A1 - Chuang, Lee-Ming A1 - Chang, Yen-Pei C A1 - Naseri, Take A1 - Jain, Deepti A1 - Kang, Hyun Min A1 - Hung, Adriana M A1 - Srinivasasainagendra, Vinodh A1 - Snively, Beverly M A1 - Gu, Dongfeng A1 - Montasser, May E A1 - Reupena, Muagututi'a Sefuiva A1 - Heavner, Benjamin D A1 - LeFaive, Jonathon A1 - Hixson, James E A1 - Rice, Kenneth M A1 - Wang, Fei Fei A1 - Nielsen, Jonas B A1 - Huang, Jianfeng A1 - Khan, Alyna T A1 - Zhou, Wei A1 - Nierenberg, Jovia L A1 - Laurie, Cathy C A1 - Armstrong, Nicole D A1 - Shi, Mengyao A1 - Pan, Yang A1 - Stilp, Adrienne M A1 - Emery, Leslie A1 - Wong, Quenna A1 - Hawley, Nicola L A1 - Minster, Ryan L A1 - Curran, Joanne E A1 - Munroe, Patricia B A1 - Weeks, Daniel E A1 - North, Kari E A1 - Tracy, Russell P A1 - Kenny, Eimear E A1 - Shimbo, Daichi A1 - Chakravarti, Aravinda A1 - Rich, Stephen S A1 - Reiner, Alex P A1 - Blangero, John A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Rao, Dabeeru C A1 - Ida Chen, Yii-Der A1 - Kardia, Sharon L R A1 - Kaplan, Robert C A1 - Mathias, Rasika A A1 - He, Jiang A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Loos, Ruth J F A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Edwards, Todd L A1 - Abecasis, Goncalo R A1 - Zhu, Xiaofeng A1 - Levy, Daniel A1 - Arnett, Donna K A1 - Morrison, Alanna C AB -

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

ER - TY - JOUR T1 - Integrative analysis of clinical and epigenetic biomarkers of mortality. JF - Aging Cell Y1 - 2022 A1 - Huan, Tianxiao A1 - Nguyen, Steve A1 - Colicino, Elena A1 - Ochoa-Rosales, Carolina A1 - Hill, W David A1 - Brody, Jennifer A A1 - Soerensen, Mette A1 - Zhang, Yan A1 - Baldassari, Antoine A1 - Elhadad, Mohamed Ahmed A1 - Toshiko, Tanaka A1 - Zheng, Yinan A1 - Domingo-Relloso, Arce A1 - Lee, Dong Heon A1 - Ma, Jiantao A1 - Yao, Chen A1 - Liu, Chunyu A1 - Hwang, Shih-Jen A1 - Joehanes, Roby A1 - Fornage, Myriam A1 - Bressler, Jan A1 - van Meurs, Joyce B J A1 - Debrabant, Birgit A1 - Mengel-From, Jonas A1 - Hjelmborg, Jacob A1 - Christensen, Kaare A1 - Vokonas, Pantel A1 - Schwartz, Joel A1 - Gahrib, Sina A A1 - Sotoodehnia, Nona A1 - Sitlani, Colleen M A1 - Kunze, Sonja A1 - Gieger, Christian A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Qu, Yishu A1 - Greenland, Philip A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Bandinelli, Stefania A1 - Voortman, Trudy A1 - Hermann, Brenner A1 - Baccarelli, Andrea A1 - Whitsel, Eric A1 - Pankow, James S A1 - Levy, Daniel KW - Biomarkers KW - Cardiovascular Diseases KW - DNA Methylation KW - Epigenesis, Genetic KW - Epigenomics KW - Humans KW - Male KW - Neoplasms AB -

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

VL - 21 IS - 6 ER - TY - JOUR T1 - Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study. JF - Eur Heart J Y1 - 2022 A1 - Eckhardt, Christina M A1 - Balte, Pallavi P A1 - Barr, Robert Graham A1 - Bertoni, Alain G A1 - Bhatt, Surya P A1 - Cuttica, Michael A1 - Cassano, Patricia A A1 - Chaves, Paolo A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Lange, Leslie A1 - Loehr, Laura A1 - London, Stephanie J A1 - O'Connor, George T A1 - Rosamond, Wayne A1 - Sanders, Jason A1 - Schwartz, Joseph E A1 - Shah, Amil A1 - Shah, Sanjiv J A1 - Smith, Lewis A1 - White, Wendy A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Heart Failure KW - Hospitalization KW - Humans KW - Lung KW - National Heart, Lung, and Blood Institute (U.S.) KW - Prognosis KW - Risk Factors KW - Stroke Volume KW - United States AB -

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).

METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.

CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

VL - 43 IS - 23 ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. 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Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

VL - 54 IS - 5 ER - TY - JOUR T1 - A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. JF - Nat Commun Y1 - 2022 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Kelly, Tanika N A1 - Elfassy, Tali A1 - Wiggins, Kerri L A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Taylor, Kent D A1 - Lin, Henry J A1 - Haessler, Jeffrey A1 - Gao, Yan A1 - Shimbo, Daichi A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Feofanova, Elena V A1 - Smit, Roelof A J A1 - Wang, Zhe A1 - Hwang, Shih-Jen A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Lloyd-Jones, Donald M A1 - Rich, Stephen S A1 - Loos, Ruth J F A1 - Redline, Susan A1 - Correa, Adolfo A1 - Kooperberg, Charles A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Morrison, Alanna C A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Sofer, Tamar KW - Adult KW - Diabetes Mellitus, Type 2 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Multifactorial Inheritance KW - Prevalence KW - Risk Factors AB -

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

VL - 13 IS - 1 ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - Holstege, Henne A1 - Vilas, Raquel Huerto A1 - Hulsman, Marc A1 - Humphrey, Jack A1 - Biessels, Geert Jan A1 - Jian, Xueqiu A1 - Johansson, Charlotte A1 - Jun, Gyungah R A1 - Kastumata, Yuriko A1 - Kauwe, John A1 - Kehoe, Patrick G A1 - Kilander, Lena A1 - Ståhlbom, Anne Kinhult A1 - Kivipelto, Miia A1 - Koivisto, Anne A1 - Kornhuber, Johannes A1 - Kosmidis, Mary H A1 - Kukull, Walter A A1 - Kuksa, Pavel P A1 - Kunkle, Brian W A1 - Kuzma, Amanda B A1 - Lage, Carmen A1 - Laukka, Erika J A1 - Launer, Lenore A1 - Lauria, Alessandra A1 - Lee, Chien-Yueh A1 - Lehtisalo, Jenni A1 - Lerch, Ondrej A1 - Lleo, Alberto A1 - Longstreth, William A1 - Lopez, Oscar A1 - de Munain, Adolfo Lopez A1 - Love, Seth A1 - Löwemark, Malin A1 - Luckcuck, Lauren A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Macías, Juan A1 - MacLeod, Catherine A A1 - Maier, Wolfgang A1 - Mangialasche, Francesca A1 - Spallazzi, Marco A1 - Marquié, Marta A1 - Marshall, Rachel A1 - Martin, Eden R A1 - Montes, Angel Martín A1 - Rodríguez, Carmen Martínez A1 - Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

VL - 54 IS - 4 ER - TY - JOUR T1 - {Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol JF - Diabetes Care Y1 - 2022 A1 - Wu, P. A1 - Moon, J. Y. A1 - Daghlas, I. A1 - Franco, G. A1 - Porneala, B. C. A1 - Ahmadizar, F. A1 - Richardson, T. G. A1 - Isaksen, J. L. A1 - Hindy, G. A1 - Yao, J. A1 - Sitlani, C. M. A1 - Raffield, L. M. A1 - Yanek, L. R. A1 - Feitosa, M. F. A1 - Cuadrat, R. R. C. A1 - Qi, Q. A1 - Arfan Ikram, M. A1 - Ellervik, C. A1 - Ericson, U. A1 - Goodarzi, M. O. A1 - Brody, J. A. A1 - Lange, L. A1 - Mercader, J. M. A1 - Vaidya, D. A1 - An, P. A1 - Schulze, M. B. A1 - Masana, L. A1 - Ghanbari, M. A1 - Olesen, M. S. A1 - Cai, J. A1 - Guo, X. A1 - Floyd, J. S. A1 - Jäger, S. A1 - Province, M. A. A1 - Kalyani, R. R. A1 - Psaty, B. M. A1 - Orho-Melander, M. A1 - Ridker, P. M. A1 - Kanters, J. K. A1 - Uitterlinden, A. A1 - Davey Smith, G. A1 - Gill, D. A1 - Kaplan, R. C. A1 - Kavousi, M. A1 - Raghavan, S. A1 - Chasman, D. I. A1 - Rotter, J. I. A1 - Meigs, J. B. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Liu, C. T. A1 - Merino, J. AB - LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.\ We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.\ A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).\ These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications. VL - 45 ER - TY - JOUR T1 - Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2022 A1 - Hu, Xiaowei A1 - Qiao, Dandi A1 - Kim, Wonji A1 - Moll, Matthew A1 - Balte, Pallavi P A1 - Lange, Leslie A A1 - Bartz, Traci M A1 - Kumar, Rajesh A1 - Li, Xingnan A1 - Yu, Bing A1 - Cade, Brian E A1 - Laurie, Cecelia A A1 - Sofer, Tamar A1 - Ruczinski, Ingo A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Gabriel, Stacy A1 - Gupta, Namrata A1 - Dugan-Perez, Shannon A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Jain, Deepti A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Morrison, Alanna C A1 - Vasan, Ramachandran S A1 - Washko, George A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Bleecker, Eugene A1 - Kaplan, Robert C A1 - Kalhan, Ravi A1 - Redline, Susan A1 - Gharib, Sina A A1 - Meyers, Deborah A1 - Ortega, Victor A1 - Dupuis, Josée A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Thornton, Timothy A A1 - Wheeler, Heather E A1 - Cho, Michael H A1 - Im, Hae Kyung A1 - Manichaikul, Ani AB -

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

ER - TY - JOUR T1 - Pooled Cohort Probability Score for Subclinical Airflow Obstruction. JF - Ann Am Thorac Soc Y1 - 2022 A1 - Bhatt, Surya P A1 - Balte, Pallavi P A1 - Schwartz, Joseph E A1 - Jaeger, Byron C A1 - Cassano, Patricia A A1 - Chaves, Paulo H A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kaplan, Robert A1 - Lloyd-Jones, Donald A1 - Newman, Anne B A1 - O'Connor, George A1 - Sanders, Jason L A1 - Smith, Benjamin M A1 - Sun, Yifei A1 - Umans, Jason G A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Female KW - Forced Expiratory Volume KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Nutrition Surveys KW - Pulmonary Disease, Chronic Obstructive KW - Risk Factors KW - Spirometry KW - Vital Capacity AB -

Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.

VL - 19 IS - 8 ER - TY - JOUR T1 - {A population-based meta-analysis of circulating GFAP for cognition and dementia risk JF - Ann Clin Transl Neurol Y1 - 2022 A1 - Gonzales, M. M. A1 - Wiedner, C. A1 - Wang, C. P. A1 - Liu, Q. A1 - Bis, J. C. A1 - Li, Z. A1 - Himali, J. J. A1 - Ghosh, S. A1 - Thomas, E. A. A1 - Parent, D. M. A1 - Kautz, T. F. A1 - Pase, M. P. A1 - Aparicio, H. J. A1 - Djousse, L. A1 - Mukamal, K. J. A1 - Psaty, B. M. A1 - Longstreth, W. T. A1 - Mosley, T. H. A1 - Gudnason, V. A1 - Mbangdadji, D. A1 - Lopez, O. L. A1 - Yaffe, K. A1 - Sidney, S. A1 - Bryan, R. N. A1 - Nasrallah, I. M. A1 - DeCarli, C. S. A1 - Beiser, A. S. A1 - Launer, L. J. A1 - Fornage, M. A1 - Tracy, R. P. A1 - Seshadri, S. A1 - Satizabal, C. L. AB - Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings.\ Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models.\ 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up.\ Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings. VL - 9 ER - TY - JOUR T1 - Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. JF - Am J Hum Genet Y1 - 2022 A1 - Hindy, George A1 - Dornbos, Peter A1 - Chaffin, Mark D A1 - Liu, Dajiang J A1 - Wang, Minxian A1 - Selvaraj, Margaret Sunitha A1 - Zhang, David A1 - Park, Joseph A1 - Aguilar-Salinas, Carlos A A1 - Antonacci-Fulton, Lucinda A1 - Ardissino, Diego A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Atzmon, Gil A1 - Ballantyne, Christie M A1 - Barajas-Olmos, Francisco A1 - Barzilai, Nir A1 - Becker, Lewis C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bottinger, Erwin A1 - Bowden, Donald W A1 - Bown, Matthew J A1 - Brody, Jennifer A A1 - Broome, Jai G A1 - Burtt, Noel P A1 - Cade, Brian E A1 - Centeno-Cruz, Federico A1 - Chan, Edmund A1 - Chang, Yi-Cheng A1 - Chen, Yii-der I A1 - Cheng, Ching-Yu A1 - Choi, Won Jung A1 - Chowdhury, Rajiv A1 - Contreras-Cubas, Cecilia A1 - Córdova, Emilio J A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Danesh, John A1 - de Vries, Paul S A1 - DeFronzo, Ralph A A1 - Doddapaneni, Harsha A1 - Duggirala, Ravindranath A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Florez, Jose C A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Fuster, Valentin A1 - Garay-Sevilla, Ma Eugenia A1 - García-Ortiz, Humberto A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Gieger, Christian A1 - Glaser, Benjamin A1 - Gonzalez, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Graff, Mariaelisa A1 - Graham, Sarah E A1 - Grarup, Niels A1 - Groop, Leif C A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Han, Sohee A1 - Hanis, Craig L A1 - Hansen, Torben A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Irvin, Marguerite R A1 - Islas-Andrade, Sergio A1 - Jarvik, Gail P A1 - Kang, Hyun Min A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kenny, Eimear E A1 - Khan, Alyna T A1 - Kim, Bong-Jo A1 - Kim, Ryan W A1 - Kim, Young Jin A1 - Koistinen, Heikki A A1 - Kooperberg, Charles A1 - Kuusisto, Johanna A1 - Kwak, Soo Heon A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lee, Jiwon A1 - Lee, Juyoung A1 - Lee, Seonwook A1 - Lehman, Donna M A1 - Lemaitre, Rozenn N A1 - Linneberg, Allan A1 - Liu, Jianjun A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Lyssenko, Valeriya A1 - Ma, Ronald C W A1 - Martin, Lisa Warsinger A1 - Martínez-Hernández, Angélica A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - McPherson, Ruth A1 - Meigs, James B A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mendoza-Caamal, Elvia A1 - Metcalf, Ginger A A1 - Mi, Xuenan A1 - Mohlke, Karen L A1 - Montasser, May E A1 - Moon, Jee-Young A1 - Moreno-Macias, Hortensia A1 - Morrison, Alanna C A1 - Muzny, Donna M A1 - Nelson, Sarah C A1 - Nilsson, Peter M A1 - O'Connell, Jeffrey R A1 - Orho-Melander, Marju A1 - Orozco, Lorena A1 - Palmer, Colin N A A1 - Palmer, Nicholette D A1 - Park, Cheol Joo A1 - Park, Kyong Soo A1 - Pedersen, Oluf A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Post, Wendy S A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qi, Qibin A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Revilla-Monsalve, Cristina A1 - Rich, Stephen S A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Schurmann, Claudia A1 - Seo, Daekwan A1 - Seo, Jeong-Sun A1 - Sim, Xueling A1 - Sladek, Rob A1 - Small, Kerrin S A1 - So, Wing Yee A1 - Stilp, Adrienne M A1 - Tai, E Shyong A1 - Tam, Claudia H T A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Thameem, Farook A1 - Tomlinson, Brian A1 - Tsai, Michael Y A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - van Dam, Rob M A1 - Vasan, Ramachandran S A1 - Viaud Martinez, Karine A A1 - Wang, Fei Fei A1 - Wang, Xuzhi A1 - Watkins, Hugh A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Witte, Daniel R A1 - Wong, Tien-Yin A1 - Yanek, Lisa R A1 - Kathiresan, Sekar A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Flannick, Jason A A1 - Khera, Amit V A1 - Peloso, Gina M KW - Alleles KW - Blood Glucose KW - Case-Control Studies KW - Computational Biology KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Molecular Sequence Annotation KW - Multifactorial Inheritance KW - Open Reading Frames KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

VL - 109 IS - 1 ER - TY - JOUR T1 - Rare genetic variants explain missing heritability in smoking. JF - Nat Hum Behav Y1 - 2022 A1 - Jang, Seon-Kyeong A1 - Evans, Luke A1 - Fialkowski, Allison A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Blangero, John A1 - Bleecker, Eugene R A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Jenkins, Brenda W Campbell A1 - Carson, April P A1 - Chavan, Sameer A1 - Cupples, L Adrienne A1 - Custer, Brian A1 - Damrauer, Scott M A1 - David, Sean P A1 - de Andrade, Mariza A1 - Dinardo, Carla L A1 - Fingerlin, Tasha E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Glahn, David C A1 - Haessler, Jeffrey A1 - Heckbert, Susan R A1 - Hokanson, John E A1 - Hou, Lifang A1 - Hwang, Shih-Jen A1 - Hyman, Matthew C A1 - Judy, Renae A1 - Justice, Anne E A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Kim, Wonji A1 - Kooperberg, Charles A1 - Levy, Daniel A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani W A1 - Gladwin, Mark T A1 - Martin, Lisa Warsinger A1 - Nouraie, Mehdi A1 - Melander, Olle A1 - Meyers, Deborah A A1 - Montgomery, Courtney G A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Palmer, Nicholette D A1 - Payton, Marinelle A1 - Peljto, Anna L A1 - Peyser, Patricia A A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qiao, Dandi A1 - Rader, Daniel J A1 - Rafaels, Nicholas A1 - Redline, Susan A1 - Reed, Robert M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Smith, J Gustav A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Vasan, Ramachandran S A1 - Gordeuk, Victor R A1 - Wang, Zhe A1 - Wiggins, Kerri L A1 - Yanek, Lisa R A1 - Yang, Ivana V A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhang, Yingze A1 - Liu, Dajiang J A1 - Keller, Matthew C A1 - Vrieze, Scott AB -

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

ER - TY - JOUR T1 - {A saturated map of common genetic variants associated with human height JF - Nature Y1 - 2022 A1 - Yengo, L. A1 - Vedantam, S. A1 - Marouli, E. A1 - Sidorenko, J. A1 - Bartell, E. A1 - Sakaue, S. A1 - Graff, M. A1 - Eliasen, A. U. A1 - Jiang, Y. A1 - Raghavan, S. A1 - Miao, J. A1 - Arias, J. D. A1 - Graham, S. E. A1 - Mukamel, R. E. A1 - Spracklen, C. N. A1 - Yin, X. A1 - Chen, S. H. A1 - Ferreira, T. A1 - Highland, H. H. A1 - Ji, Y. A1 - Karaderi, T. A1 - Lin, K. A1 - ll, K. A1 - Malden, D. E. A1 - Medina-Gomez, C. A1 - Machado, M. A1 - Moore, A. A1 - eger, S. A1 - Sim, X. A1 - Vrieze, S. A1 - Ahluwalia, T. S. A1 - Akiyama, M. A1 - Allison, M. A. A1 - Alvarez, M. A1 - Andersen, M. K. A1 - Ani, A. A1 - Appadurai, V. A1 - Arbeeva, L. A1 - Bhaskar, S. A1 - Bielak, L. F. A1 - Bollepalli, S. A1 - Bonnycastle, L. L. A1 - Bork-Jensen, J. A1 - Bradfield, J. P. A1 - Bradford, Y. A1 - Braund, P. S. A1 - Brody, J. A. A1 - Burgdorf, K. S. A1 - Cade, B. E. A1 - Cai, H. A1 - Cai, Q. A1 - Campbell, A. A1 - adas-Garre, M. A1 - Catamo, E. A1 - Chai, J. F. A1 - Chai, X. A1 - Chang, L. C. A1 - Chang, Y. C. A1 - Chen, C. H. A1 - Chesi, A. A1 - Choi, S. H. A1 - Chung, R. H. A1 - Cocca, M. A1 - Concas, M. P. A1 - Couture, C. A1 - Cuellar-Partida, G. A1 - Danning, R. A1 - Daw, E. W. A1 - Degenhard, F. A1 - Delgado, G. E. A1 - Delitala, A. A1 - Demirkan, A. A1 - Deng, X. A1 - Devineni, P. A1 - Dietl, A. A1 - Dimitriou, M. A1 - Dimitrov, L. A1 - Dorajoo, R. A1 - Ekici, A. B. A1 - Engmann, J. E. A1 - Fairhurst-Hunter, Z. A1 - Farmaki, A. E. A1 - Faul, J. D. A1 - Fernandez-Lopez, J. C. A1 - Forer, L. A1 - Francescatto, M. A1 - Freitag-Wolf, S. A1 - Fuchsberger, C. A1 - Galesloot, T. E. A1 - Gao, Y. A1 - Gao, Z. A1 - Geller, F. A1 - Giannakopoulou, O. A1 - Giulianini, F. A1 - Gjesing, A. P. A1 - Goel, A. A1 - Gordon, S. D. A1 - Gorski, M. A1 - Grove, J. A1 - Guo, X. A1 - Gustafsson, S. A1 - Haessler, J. A1 - Hansen, T. F. A1 - Havulinna, A. S. A1 - Haworth, S. J. 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A1 - Tuomilehto, J. A1 - -Luna, M. T. A1 - Uitterlinden, A. G. A1 - van Dam, R. M. A1 - van der Harst, P. A1 - Van der Velde, N. A1 - van Duijn, C. M. A1 - van Schoor, N. M. A1 - Vitart, V. A1 - lker, U. A1 - Vollenweider, P. A1 - lzke, H. A1 - Wacher-Rodarte, N. H. A1 - Walker, M. A1 - Wang, Y. X. A1 - Wareham, N. J. A1 - Watanabe, R. M. A1 - Watkins, H. A1 - Weir, D. R. A1 - Werge, T. M. A1 - Widén, E. A1 - Wilkens, L. R. A1 - Willemsen, G. A1 - Willett, W. C. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Woo, J. T. A1 - Wright, A. F. A1 - Wu, J. Y. A1 - Xu, H. A1 - Yajnik, C. S. A1 - Yokota, M. A1 - Yuan, J. M. A1 - Zeggini, E. A1 - Zemel, B. S. A1 - Zheng, W. A1 - Zhu, X. A1 - Zmuda, J. M. A1 - Zonderman, A. B. A1 - Zwart, J. A. A1 - Chasman, D. I. A1 - Cho, Y. S. A1 - Heid, I. M. A1 - McCarthy, M. I. A1 - Ng, M. C. Y. A1 - O'Donnell, C. J. A1 - Rivadeneira, F. A1 - Thorsteinsdottir, U. A1 - Sun, Y. V. A1 - Tai, E. S. A1 - Boehnke, M. A1 - Deloukas, P. A1 - Justice, A. E. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. A1 - North, K. E. A1 - Stefansson, K. A1 - Walters, R. G. A1 - Winkler, T. W. A1 - Young, K. L. A1 - Loh, P. R. A1 - Yang, J. A1 - Esko, T. A1 - Assimes, T. L. A1 - Auton, A. A1 - Abecasis, G. R. A1 - Willer, C. J. A1 - Locke, A. E. A1 - Berndt, S. I. A1 - Lettre, G. A1 - Frayling, T. M. A1 - Okada, Y. A1 - Wood, A. R. A1 - Visscher, P. M. A1 - Hirschhorn, J. N. A1 - Partida, G. C. A1 - Sun, Y. A1 - Croteau-Chonka, D. A1 - Vonk, J. M. A1 - Chanock, S. A1 - Le Marchand, L. AB - ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries. VL - 610 ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

ER - TY - JOUR T1 - The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. JF - Front Endocrinol (Lausanne) Y1 - 2022 A1 - Wang, Zhe A1 - Choi, Shing Wan A1 - Chami, Nathalie A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Redline, Susan A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Kim, Wonji A1 - McDonald, Merry-Lynn N A1 - Regan, Elizabeth A A1 - Silverman, Edwin K A1 - Liu, Ching-Ti A1 - Vasan, Ramachandran S A1 - Kalyani, Rita R A1 - Mathias, Rasika A A1 - Yanek, Lisa R A1 - Arnett, Donna K A1 - Justice, Anne E A1 - North, Kari E A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Lange, Leslie A A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Ellinor, Patrick T A1 - Lubitz, Steven A A1 - Blangero, John A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Gladwin, Mark T A1 - Albert, Christine M A1 - Chasman, Daniel I A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - O'Reilly, Paul F A1 - Loos, Ruth J F KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Whole Genome Sequencing AB -

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

VL - 13 ER - TY - JOUR T1 - Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. JF - Commun Biol Y1 - 2022 A1 - DiCorpo, Daniel A1 - Gaynor, Sheila M A1 - Russell, Emily M A1 - Westerman, Kenneth E A1 - Raffield, Laura M A1 - Majarian, Timothy D A1 - Wu, Peitao A1 - Sarnowski, Chloe A1 - Highland, Heather M A1 - Jackson, Anne A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Brody, Jennifer A A1 - Hidalgo, Bertha A1 - Guo, Xiuqing A1 - Perry, James A A1 - O'Connell, Jeffrey R A1 - Lent, Samantha A1 - Montasser, May E A1 - Cade, Brian E A1 - Jain, Deepti A1 - Wang, Heming A1 - D'Oliveira Albanus, Ricardo A1 - Varshney, Arushi A1 - Yanek, Lisa R A1 - Lange, Leslie A1 - Palmer, Nicholette D A1 - Almeida, Marcio A1 - Peralta, Juan M A1 - Aslibekyan, Stella A1 - Baldridge, Abigail S A1 - Bertoni, Alain G A1 - Bielak, Lawrence F A1 - Chen, Chung-Shiuan A1 - Chen, Yii-Der Ida A1 - Choi, Won Jung A1 - Goodarzi, Mark O A1 - Floyd, James S A1 - Irvin, Marguerite R A1 - Kalyani, Rita R A1 - Kelly, Tanika N A1 - Lee, Seonwook A1 - Liu, Ching-Ti A1 - Loesch, Douglas A1 - Manson, JoAnn E A1 - Minster, Ryan L A1 - Naseri, Take A1 - Pankow, James S A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Selvin, Elizabeth A1 - Smith, Jennifer A A1 - Weeks, Daniel E A1 - Xu, Huichun A1 - Yao, Jie A1 - Zhao, Wei A1 - Parker, Stephen A1 - Alonso, Alvaro A1 - Arnett, Donna K A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Duggirala, Ravindranath A1 - He, Jiang A1 - Heckbert, Susan R A1 - Kardia, Sharon L R A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Liu, Simin A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Florez, Jose C A1 - Wilson, James G A1 - Sladek, Robert A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Dupuis, Josée A1 - Meigs, James B A1 - Wessel, Jennifer A1 - Manning, Alisa K KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Glucose KW - Humans KW - Insulin KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Precision Medicine KW - Receptors, Immunologic KW - United States AB -

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

VL - 5 IS - 1 ER - TY - JOUR T1 - Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. JF - Nat Commun Y1 - 2022 A1 - Wheeler, Marsha M A1 - Stilp, Adrienne M A1 - Rao, Shuquan A1 - Halldorsson, Bjarni V A1 - Beyter, Doruk A1 - Wen, Jia A1 - Mihkaylova, Anna V A1 - McHugh, Caitlin P A1 - Lane, John A1 - Jiang, Min-Zhi A1 - Raffield, Laura M A1 - Jun, Goo A1 - Sedlazeck, Fritz J A1 - Metcalf, Ginger A1 - Yao, Yao A1 - Bis, Joshua B A1 - Chami, Nathalie A1 - de Vries, Paul S A1 - Desai, Pinkal A1 - Floyd, James S A1 - Gao, Yan A1 - Kammers, Kai A1 - Kim, Wonji A1 - Moon, Jee-Young A1 - Ratan, Aakrosh A1 - Yanek, Lisa R A1 - Almasy, Laura A1 - Becker, Lewis C A1 - Blangero, John A1 - Cho, Michael H A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tang, Hua A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Abecasis, Goncalo R A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Conomos, Matthew P A1 - Li, Yun A1 - Þorsteinsdottir, Unnur A1 - Magnússon, Magnús K A1 - Stefansson, Kari A1 - Pankratz, Nathan D A1 - Bauer, Daniel E A1 - Auer, Paul L A1 - Reiner, Alex P KW - Blood Cells KW - Genome-Wide Association Study KW - Humans KW - Whole Genome Sequencing AB -

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

VL - 13 IS - 1 ER - TY - JOUR T1 - Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. JF - Hum Mol Genet Y1 - 2022 A1 - Pan, Yang A1 - Sun, Xiao A1 - Mi, Xuenan A1 - Huang, Zhijie A1 - Hsu, Yenchih A1 - Hixson, James E A1 - Munzy, Donna A1 - Metcalf, Ginger A1 - Franceschini, Nora A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Francis, Michael A1 - Brody, Jennifer A A1 - Kestenbaum, Bryan A1 - Sitlani, Colleen M A1 - Mychaleckyj, Josyf C A1 - Kramer, Holly A1 - Lange, Leslie A A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Irvin, Marguerite R A1 - Smith, Jennifer A A1 - Yanek, Lisa R A1 - Vaidya, Dhananjay A1 - Chen, Yii-Der Ida A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Cupple, L Adrienne A1 - Levy, Daniel A1 - Kaplan, Robert C A1 - North, Kari E A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Gibbs, Richard A A1 - Morrison, Alanna C A1 - Feldman, Harold A1 - Boerwinkle, Eric A1 - He, Jiang A1 - Kelly, Tanika N AB -

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

ER - TY - JOUR T1 - Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. JF - Nature Y1 - 2023 A1 - Weinstock, Joshua S A1 - Gopakumar, Jayakrishnan A1 - Burugula, Bala Bharathi A1 - Uddin, Md Mesbah A1 - Jahn, Nikolaus A1 - Belk, Julia A A1 - Bouzid, Hind A1 - Daniel, Bence A1 - Miao, Zhuang A1 - Ly, Nghi A1 - Mack, Taralynn M A1 - Luna, Sofia E A1 - Prothro, Katherine P A1 - Mitchell, Shaneice R A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Sinner, Moritz F A1 - von Falkenhausen, Aenne S A1 - Kääb, Stefan A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Redline, Susan A1 - Cade, Brian E A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - DeMeo, Dawn L A1 - Vasan, Ramachandran S A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - He, Jiang A1 - Rienstra, Michiel A1 - van der Harst, Pim A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Cutler, Michael J A1 - Knight, Stacey A1 - Muhlestein, J Brent A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Smith, J Gustav A1 - Melander, Olle A1 - Nilsson, Peter M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - McGarvey, Stephen A1 - Williams, L Keoki A1 - Xiao, Shujie A1 - Yang, Mao A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Marcus, Gregory M A1 - Kane, John P A1 - Pullinger, Clive R A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan M A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Zhou, Ying A1 - Manson, JoAnn E A1 - Desai, Pinkal A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Satpathy, Ansuman T A1 - Natarajan, Pradeep A1 - Kitzman, Jacob O A1 - Whitsel, Eric A A1 - Reiner, Alexander P A1 - Bick, Alexander G A1 - Jaiswal, Siddhartha KW - Alleles KW - Animals KW - Clonal Hematopoiesis KW - Genome-Wide Association Study KW - Hematopoiesis KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Mutation KW - Promoter Regions, Genetic AB -

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

VL - 616 IS - 7958 ER - TY - JOUR T1 - Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study. JF - J Transl Med Y1 - 2023 A1 - Yi, Jiayi A1 - Wang, Lili A1 - Guo, Xinli A1 - Ren, Xiangpeng KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence.

METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD.

RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD.

CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.

VL - 21 IS - 1 ER - TY - JOUR T1 - Association Between Acute Myocardial Infarction and Cognition. JF - JAMA Neurol Y1 - 2023 A1 - Johansen, Michelle C A1 - Ye, Wen A1 - Gross, Alden A1 - Gottesman, Rebecca F A1 - Han, Dehua A1 - Whitney, Rachael A1 - Briceño, Emily M A1 - Giordani, Bruno J A1 - Shore, Supriya A1 - Elkind, Mitchell S V A1 - Manly, Jennifer J A1 - Sacco, Ralph L A1 - Fohner, Alison A1 - Griswold, Michael A1 - Psaty, Bruce M A1 - Sidney, Stephen A1 - Sussman, Jeremy A1 - Yaffe, Kristine A1 - Moran, Andrew E A1 - Heckbert, Susan A1 - Hughes, Timothy M A1 - Galecki, Andrzej A1 - Levine, Deborah A AB -

IMPORTANCE: The magnitude of cognitive change after incident myocardial infarction (MI) is unclear.

OBJECTIVE: To assess whether incident MI is associated with changes in cognitive function after adjusting for pre-MI cognitive trajectories.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adults without MI, dementia, or stroke and with complete covariates from the following US population-based cohort studies conducted from 1971 to 2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Data were analyzed from July 2021 to January 2022.

EXPOSURES: Incident MI.

MAIN OUTCOMES AND MEASURES: The main outcome was change in global cognition. Secondary outcomes were changes in memory and executive function. Outcomes were standardized as mean (SD) T scores of 50 (10); a 1-point difference represented a 0.1-SD difference in cognition. Linear mixed-effects models estimated changes in cognition at the time of MI (change in the intercept) and the rate of cognitive change over the years after MI (change in the slope), controlling for pre-MI cognitive trajectories and participant factors, with interaction terms for race and sex.

RESULTS: The study included 30 465 adults (mean [SD] age, 64 [10] years; 56% female), of whom 1033 had 1 or more MI event, and 29 432 did not have an MI event. Median follow-up was 6.4 years (IQR, 4.9-19.7 years). Overall, incident MI was not associated with an acute decrease in global cognition (-0.18 points; 95% CI, -0.52 to 0.17 points), executive function (-0.17 points; 95% CI, -0.53 to 0.18 points), or memory (0.62 points; 95% CI, -0.07 to 1.31 points). However, individuals with incident MI vs those without MI demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21 to -0.10 points per year), memory (-0.13 points per year; 95% CI, -0.22 to -0.04 points per year), and executive function (-0.14 points per year; 95% CI, -0.20 to -0.08 points per year) over the years after MI compared with pre-MI slopes. The interaction analysis suggested that race and sex modified the degree of change in the decline in global cognition after MI (race × post-MI slope interaction term, P = .02; sex × post-MI slope interaction term, P = .04), with a smaller change in the decline over the years after MI in Black individuals than in White individuals (difference in slope change, 0.22 points per year; 95% CI, 0.04-0.40 points per year) and in females than in males (difference in slope change, 0.12 points per year; 95% CI, 0.01-0.23 points per year).

CONCLUSIONS: This cohort study using pooled data from 6 cohort studies found that incident MI was not associated with a decrease in global cognition, memory, or executive function at the time of the event compared with no MI but was associated with faster declines in global cognition, memory, and executive function over time. These findings suggest that prevention of MI may be important for long-term brain health.

ER - TY - JOUR T1 - Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. JF - J Am Heart Assoc Y1 - 2023 A1 - Liu, Xue A1 - Sun, Xianbang A1 - Zhang, Yuankai A1 - Jiang, Wenqing A1 - Lai, Meng A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Haessler, Jeffrey A1 - Zheng, Yinan A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Qian, Yong A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Carson, April P A1 - Abecasis, Goncalo A1 - Dupuis, Josée A1 - Reiner, Alexander A1 - Kooperberg, Charles A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

ER - TY - JOUR T1 - Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. JF - Neurology Y1 - 2023 A1 - Zhang, Yuankai A1 - Liu, Xue A1 - Wiggins, Kerri L A1 - Kurniansyah, Nuzulul A1 - Guo, Xiuqing A1 - Rodrigue, Amanda L A1 - Zhao, Wei A1 - Yanek, Lisa R A1 - Ratliff, Scott M A1 - Pitsillides, Achilleas A1 - Aguirre Patiño, Juan Sebastian A1 - Sofer, Tamar A1 - Arking, Dan E A1 - Austin, Thomas R A1 - Beiser, Alexa S A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Curran, Joanne E A1 - Hou, Lifang A1 - Hughes, Timothy M A1 - Kardia, Sharon L A1 - Launer, Lenore A1 - Levy, Daniel A1 - Mosley, Tom H A1 - Nasrallah, Ilya M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Tarraf, Wassim A1 - González, Kevin A A1 - Ramachandran, Vasan A1 - Yaffe, Kristine A1 - Nyquist, Paul A A1 - Psaty, Bruce M A1 - DeCarli, Charles S A1 - Smith, Jennifer A A1 - Glahn, David C A1 - González, Hector M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Heckbert, Susan R A1 - Fitzpatrick, Annette L A1 - Liu, Chunyu A1 - Satizabal, Claudia L AB -

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

ER - TY - JOUR T1 - Association of Obesity With Cognitive Decline in Black and White Americans. JF - Neurology Y1 - 2023 A1 - Quaye, Emmanuel A1 - Galecki, Andrzej T A1 - Tilton, Nicholas A1 - Whitney, Rachael A1 - Briceño, Emily M A1 - Elkind, Mitchell S V A1 - Fitzpatrick, Annette L A1 - Gottesman, Rebecca F A1 - Griswold, Michael A1 - Gross, Alden L A1 - Heckbert, Susan R A1 - Hughes, Timothy M A1 - Longstreth, W T A1 - Sacco, Ralph L A1 - Sidney, Stephen A1 - Windham, B Gwen A1 - Yaffe, Kristine A1 - Levine, Deborah A KW - Aged KW - Black or African American KW - Cognition KW - Cognitive Dysfunction KW - Female KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Risk Factors KW - United States KW - White AB -

BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.

METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).

RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34).

DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

VL - 100 IS - 2 ER - TY - JOUR T1 - Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. JF - BMJ Y1 - 2023 A1 - Ong, Kwok Leung A1 - Marklund, Matti A1 - Huang, Liping A1 - Rye, Kerry-Anne A1 - Hui, Nicholas A1 - Pan, Xiong-Fei A1 - Rebholz, Casey M A1 - Kim, Hyunju A1 - Steffen, Lyn M A1 - van Westing, Anniek C A1 - Geleijnse, Johanna M A1 - Hoogeveen, Ellen K A1 - Chen, Yun-Yu A1 - Chien, Kuo-Liong A1 - Fretts, Amanda M A1 - Lemaitre, Rozenn N A1 - Imamura, Fumiaki A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Birukov, Anna A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Schulze, Matthias B A1 - de Mello, Vanessa Derenji A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Lindström, Jaana A1 - Tintle, Nathan A1 - Harris, William S A1 - Yamasaki, Keisuke A1 - Hirakawa, Yoichiro A1 - Ninomiya, Toshiharu A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Virtanen, Jyrki K A1 - Voutilainen, Ari A1 - Jayasena, Tharusha A1 - Thalamuthu, Anbupalam A1 - Poljak, Anne A1 - Bustamante, Sonia A1 - Sachdev, Perminder S A1 - Senn, Mackenzie K A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Wood, Alexis C A1 - Laakso, Markku A1 - Lankinen, Maria A1 - Yang, Xiaowei A1 - Sun, Liang A1 - Li, Huaixing A1 - Lin, Xu A1 - Nowak, Christoph A1 - Arnlöv, Johan A1 - Riserus, Ulf A1 - Lind, Lars A1 - Le Goff, Mélanie A1 - Samieri, Cecilia A1 - Helmer, Catherine A1 - Qian, Frank A1 - Micha, Renata A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Mozaffarian, Dariush A1 - Wu, Jason HY KW - alpha-Linolenic Acid KW - Fatty Acids, Omega-3 KW - Fatty Acids, Unsaturated KW - Humans KW - Middle Aged KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

VL - 380 ER - TY - JOUR T1 - Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. JF - medRxiv Y1 - 2023 A1 - Georgakis, Marios K A1 - Malik, Rainer A1 - Hasbani, Natalie R A1 - Shakt, Gabrielle A1 - Morrison, Alanna C A1 - Tsao, Noah L A1 - Judy, Renae A1 - Mitchell, Braxton D A1 - Xu, Huichun A1 - Montasser, May E A1 - Do, Ron A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Terry, James G A1 - Carr, John Jeffrey A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Young, Kendra A A1 - Lutz, Sharon M A1 - Cho, Michael H A1 - Broome, Jai A1 - Khan, Alyna T A1 - Wang, Fei Fei A1 - Heard-Costa, Nancy A1 - Seshadri, Sudha A1 - Vasan, Ramachandran S A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Yanek, Lisa R A1 - Kral, Brian G A1 - Becker, Lewis C A1 - Peyser, Patricia A A1 - Bielak, Lawrence F A1 - Ammous, Farah A1 - Carson, April P A1 - Hall, Michael E A1 - Raffield, Laura M A1 - Rich, Stephen S A1 - Post, Wendy S A1 - Tracy, Russel P A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Mahaney, Michael C A1 - Curran, Joanne E A1 - Blangero, John A1 - Clarke, Shoa L A1 - Haessler, Jeffrey W A1 - Hu, Yao A1 - Assimes, Themistocles L A1 - Kooperberg, Charles A1 - Damrauer, Scott M A1 - Rotter, Jerome I A1 - de Vries, Paul S A1 - Dichgans, Martin AB -

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

ER - TY - JOUR T1 - Clonal hematopoiesis is associated with protection from Alzheimer's disease. JF - Nat Med Y1 - 2023 A1 - Bouzid, Hind A1 - Belk, Julia A A1 - Jan, Max A1 - Qi, Yanyan A1 - Sarnowski, Chloe A1 - Wirth, Sara A1 - Ma, Lisa A1 - Chrostek, Matthew R A1 - Ahmad, Herra A1 - Nachun, Daniel A1 - Yao, Winnie A1 - Beiser, Alexa A1 - Bick, Alexander G A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Longstreth, William T A1 - Lopez, Oscar L A1 - Natarajan, Pradeep A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Weinstock, Joshua A1 - Larson, Eric B A1 - Crane, Paul K A1 - Keene, C Dirk A1 - Seshadri, Sudha A1 - Satpathy, Ansuman T A1 - Montine, Thomas J A1 - Jaiswal, Siddhartha AB -

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

VL - 29 IS - 7 ER - TY - JOUR T1 - Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. JF - medRxiv Y1 - 2023 A1 - Sargurupremraj, Muralidharan A1 - Soumaré, Aïcha A1 - Bis, Joshua C A1 - Surakka, Ida A1 - Jürgenson, Tuuli A1 - Joly, Pierre A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Yang, Qiong A1 - Satizabal, Claudia L A1 - Gudjonsson, Alexander A1 - Mishra, Aniket A1 - Bouteloup, Vincent A1 - Phuah, Chia-Ling A1 - van Duijn, Cornelia M A1 - Cruchaga, Carlos A1 - Dufouil, Carole A1 - Chene, Geneviève A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Tzourio, Christophe A1 - Amouyel, Philippe A1 - Adams, Hieab H A1 - Jacqmin-Gadda, Hélène A1 - Ikram, Mohammad Arfan A1 - Gudnason, Vilmundur A1 - Milani, Lili A1 - Winsvold, Bendik S A1 - Hveem, Kristian A1 - Matthews, Paul M A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Debette, Stephanie AB -

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

ER - TY - JOUR T1 - Determinants of mosaic chromosomal alteration fitness. JF - medRxiv Y1 - 2023 A1 - Pershad, Yash A1 - Mack, Taralynn A1 - Poisner, Hannah A1 - Jakubek, Yasminka A A1 - Stilp, Adrienne M A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Loos, Ruth J A1 - Chami, Nathalie A1 - Wang, Zhe A1 - Barnes, Kathleen A1 - Pankratz, Nathan A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Shojaie, Ali A1 - Silverman, Edwin K A1 - Cho, Michael H A1 - Yun, Jeong A1 - DeMeo, Dawn A1 - Levy, Daniel A1 - Johnson, Andrew A1 - Mathias, Rasika A1 - Taub, Margaret A1 - Arnett, Donna A1 - North, Kari A1 - Raffield, Laura M A1 - Carson, April A1 - Doyle, Margaret F A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Guo, Xiuqing A1 - Cox, Nancy A1 - Roden, Dan M A1 - Franceschini, Nora A1 - Desai, Pinkal A1 - Reiner, Alex A1 - Auer, Paul L A1 - Scheet, Paul A1 - Jaiswal, Siddhartha A1 - Weinstock, Joshua S A1 - Bick, Alexander G AB -

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

ER - TY - JOUR T1 - {Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease? JF - Alzheimers Dement (Amst) Y1 - 2023 A1 - Mantyh, W. G. A1 - Cochran, J. N. A1 - Taylor, J. W. A1 - Broce, I. J. A1 - Geier, E. G. A1 - Bonham, L. W. A1 - Anderson, A. G. A1 - Sirkis, D. W. A1 - Joie, R. A1 - Iaccarino, L. A1 - Chaudhary, K. A1 - Edwards, L. A1 - Strom, A. A1 - Grant, H. A1 - Allen, I. E. A1 - Miller, Z. A. A1 - Gorno-Tempini, M. L. A1 - Kramer, J. H. A1 - Miller, B. L. A1 - Desikan, R. S. A1 - Rabinovici, G. D. A1 - Yokoyama, J. S. AB - There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity. VL - 15 ER - TY - JOUR T1 - Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. JF - Nat Commun Y1 - 2023 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Khan, Alyna T A1 - Wang, Jiongming A1 - Feofanova, Elena A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Kelly, Tanika A1 - Elfassy, Tali A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Lin, Henry J A1 - Hwang, Shih-Jen A1 - Gao, Yan A1 - Young, Kendra A1 - Kinney, Gregory L A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Zhu, Xiaofeng A1 - Chen, Yii-Der Ida A1 - Lee, I-Te A1 - Gu, C Charles A1 - Lloyd-Jones, Donald M A1 - Zöllner, Sebastian A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - Correa, Adolfo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Isasi, Carmen R A1 - Rich, Stephen S A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Sofer, Tamar KW - Blood Pressure KW - Ethnicity KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Multifactorial Inheritance KW - Population Health KW - Risk Factors AB -

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

VL - 14 IS - 1 ER - TY - JOUR T1 - Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses. JF - Ann Intern Med Y1 - 2023 A1 - Marriott, Ross J A1 - Murray, Kevin A1 - Adams, Robert J A1 - Antonio, Leen A1 - Ballantyne, Christie M A1 - Bauer, Douglas C A1 - Bhasin, Shalender A1 - Biggs, Mary L A1 - Cawthon, Peggy M A1 - Couper, David J A1 - Dobs, Adrian S A1 - Flicker, Leon A1 - Handelsman, David J A1 - Hankey, Graeme J A1 - Hannemann, Anke A1 - Haring, Robin A1 - Hsu, Benjumin A1 - Karlsson, Magnus A1 - Martin, Sean A A1 - Matsumoto, Alvin M A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - O'Neill, Terence W A1 - Orwoll, Eric S A1 - Quartagno, Matteo A1 - Shores, Molly M A1 - Steveling, Antje A1 - Tivesten, Åsa A1 - Travison, Thomas G A1 - Vanderschueren, Dirk A1 - Wittert, Gary A A1 - Wu, Frederick C W A1 - Yeap, Bu B AB -

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.

PURPOSE: To clarify factors associated with variations in sex hormone concentrations.

DATA SOURCES: Systematic literature searches (to July 2019).

STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.

DATA EXTRACTION: Individual participant data (IPD) (9 studies;  = 21 074) and aggregate data (2 studies;  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.

DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.

LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.

CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.

PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. JF - Front Genet Y1 - 2023 A1 - de Las Fuentes, Lisa A1 - Schwander, Karen L A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Winkler, Thomas W A1 - Sung, Yun Ju A1 - Munroe, Patricia B A1 - Miller, Clint L A1 - Aschard, Hugo A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chai, Jin Fang A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Feitosa, Mary F A1 - Guo, Xiuqing A1 - Hartwig, Fernando P A1 - Horimoto, Andrea A1 - Kolcic, Ivana A1 - Lim, Elise A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Noordam, Raymond A1 - Padmanabhan, Sandosh A1 - Rankinen, Tuomo A1 - Richard, Melissa A A1 - Ridker, Paul M A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Zonderman, Alan B A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Christensen, Kaare A1 - Freedman, Barry I A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhan, Yiqiang A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chai, Xiaoran A1 - Chen, Yii-Der Ida A1 - Chen, Xu A1 - Chitrala, Kumaraswamy Naidu A1 - Concas, Maria Pina A1 - de Faire, Ulf A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Do, Ahn A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Floyd, James S A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Girotto, Giorgia A1 - Gu, C Charles A1 - Hallmans, Göran A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Homuth, Georg A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Langefeld, Carl D A1 - Liang, Jingjing A1 - Liu, Kiang A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pereira, Alexandre C A1 - Perls, Thomas A1 - Peters, Annette A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Sabanayagam, Charumathi A1 - Schreiner, Pamela J A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bonnefond, Amélie A1 - Bowden, Donald W A1 - Cooper, Richard S A1 - Deary, Ian J A1 - Divers, Jasmin A1 - Esko, Tõnu A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Penninx, Brenda A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Spedicati, Beatrice A1 - van der Harst, Pim A1 - Völzke, Henry A1 - Wagenknecht, Lynne E A1 - Weir, David R A1 - Wojczynski, Mary K A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Chasman, Daniel I A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Krieger, Jose Eduardo A1 - Mook-Kanamori, Dennis O A1 - Peyser, Patricia A A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Rudan, Igor A1 - Sim, Xueling A1 - Smith, Blair H A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Arnett, Donna K A1 - Rao, Dabeeru C A1 - Gauderman, James A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Fornage, Myriam AB -

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

VL - 14 ER - TY - JOUR T1 - Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. JF - Nat Commun Y1 - 2023 A1 - Young, William J A1 - Haessler, Jeffrey A1 - Benjamins, Jan-Walter A1 - Repetto, Linda A1 - Yao, Jie A1 - Isaacs, Aaron A1 - Harper, Andrew R A1 - Ramirez, Julia A1 - Garnier, Sophie A1 - Van Duijvenboden, Stefan A1 - Baldassari, Antoine R A1 - Concas, Maria Pina A1 - Duong, ThuyVy A1 - Foco, Luisa A1 - Isaksen, Jonas L A1 - Mei, Hao A1 - Noordam, Raymond A1 - Nursyifa, Casia A1 - Richmond, Anne A1 - Santolalla, Meddly L A1 - Sitlani, Colleen M A1 - Soroush, Negin A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Aeschbacher, Stefanie A1 - Ahmadizar, Fariba A1 - Alonso, Alvaro A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Correa, Adolfo A1 - Darbar, Dawood A1 - De Luca, Antonio A1 - Deleuze, Jean-Francois A1 - Ellervik, Christina A1 - Fuchsberger, Christian A1 - Goel, Anuj A1 - Grace, Christopher A1 - Guo, Xiuqing A1 - Hansen, Torben A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Kors, Jan A A1 - Lima-Costa, Maria Fernanda A1 - Linneberg, Allan A1 - Macfarlane, Peter W A1 - Morrison, Alanna C A1 - Navarro, Pau A1 - Porteous, David J A1 - Pramstaller, Peter P A1 - Reiner, Alexander P A1 - Risch, Lorenz A1 - Schotten, Ulrich A1 - Shen, Xia A1 - Sinagra, Gianfranco A1 - Soliman, Elsayed Z A1 - Stoll, Monika A1 - Tarazona-Santos, Eduardo A1 - Tinker, Andrew A1 - Trajanoska, Katerina A1 - Villard, Eric A1 - Warren, Helen R A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Arking, Dan E A1 - Avery, Christy L A1 - Conen, David A1 - Girotto, Giorgia A1 - Grarup, Niels A1 - Hayward, Caroline A1 - Jukema, J Wouter A1 - Mook-Kanamori, Dennis O A1 - Olesen, Morten Salling A1 - Padmanabhan, Sandosh A1 - Psaty, Bruce M A1 - Pattaro, Cristian A1 - Ribeiro, Antonio Luiz P A1 - Rotter, Jerome I A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Wilson, James G A1 - Orini, Michele A1 - Charron, Philippe A1 - Watkins, Hugh A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Wilson, James F A1 - Kanters, Jørgen K A1 - Sotoodehnia, Nona A1 - Mifsud, Borbala A1 - Lambiase, Pier D A1 - Tereshchenko, Larisa G A1 - Munroe, Patricia B KW - Arrhythmias, Cardiac KW - Atrioventricular Block KW - Biomarkers KW - Cardiovascular Diseases KW - Electrocardiography KW - Genome-Wide Association Study KW - Humans KW - Risk Factors AB -

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

VL - 14 IS - 1 ER - TY - JOUR T1 - The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. JF - Sci Adv Y1 - 2023 A1 - Weinstock, Joshua S A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Redline, Susan A1 - Cade, Brian E A1 - Gilliland, Frank D A1 - Chen, Zhanghua A1 - Gauderman, W James A1 - Kumar, Rajesh A1 - Grammer, Leslie A1 - Schleimer, Robert P A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Weiss, Scott T A1 - Lasky-Su, Jessica A1 - DeMeo, Dawn L A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - Vasan, Ramachandran S A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon A1 - He, Jiang A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Manichaikul, Ani W A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - Gui, Hongsheng A1 - Xiao, Shujie A1 - Williams, L Keoki A1 - Meyers, Deborah A A1 - Li, Xingnan A1 - Ortega, Victor A1 - McGarvey, Stephen A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Desai, Pinkal A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Mathias, Rasika A1 - Natarajan, Pradeep A1 - Jaiswal, Siddhartha A1 - Reiner, Alexander P A1 - Bick, Alexander G KW - Germ-Line Mutation KW - Hematopoiesis KW - Humans KW - Middle Aged KW - Mutation KW - Mutation, Missense KW - Phenotype AB -

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

VL - 9 IS - 17 ER - TY - JOUR T1 - Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts. JF - Res Sq Y1 - 2023 A1 - Yang, Chaojie A1 - Veenstra, Jenna A1 - Bartz, Traci A1 - Pahl, Matthew A1 - Hallmark, Brian A1 - Chen, Yii-Der Ida A1 - Westra, Jason A1 - Steffen, Lyn A1 - Brown, Christopher A1 - Siscovick, David A1 - Tsai, Michael A1 - Wood, Alexis A1 - Rich, Stephen A1 - Smith, Caren A1 - O'Connor, Timothy A1 - Mozaffarian, Dariush A1 - Grant, Struan A1 - Chilton, Floyd A1 - Tintle, Nathan A1 - Lemaitre, Rozenn A1 - Manichaikul, Ani AB -

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of  < 5 x 10 , we confirmed association of the signal and found evidence of two additional signals (in and ) within 200 kb of the originally reported signal. Outside of the region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including , , and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

ER - TY - JOUR T1 - {Identification of circulating proteins associated with general cognitive function among middle-aged and older adults JF - Commun Biol Y1 - 2023 A1 - Tin, A. A1 - Fohner, A. E. A1 - Yang, Q. A1 - Brody, J. A. A1 - Davies, G. A1 - Yao, J. A1 - Liu, D. A1 - Caro, I. A1 - Lindbohm, J. V. A1 - Duggan, M. R. A1 - Meirelles, O. A1 - Harris, S. E. A1 - Gudmundsdottir, V. A1 - Taylor, A. M. A1 - Henry, A. A1 - Beiser, A. S. A1 - Shojaie, A. A1 - Coors, A. A1 - Fitzpatrick, A. L. A1 - Langenberg, C. A1 - Satizabal, C. L. A1 - Sitlani, C. M. A1 - Wheeler, E. A1 - Tucker-Drob, E. M. A1 - Bressler, J. A1 - Coresh, J. A1 - Bis, J. C. A1 - Candia, J. A1 - Jennings, L. L. A1 - Pietzner, M. A1 - Lathrop, M. A1 - Lopez, O. L. A1 - Redmond, P. A1 - Gerszten, R. E. A1 - Rich, S. S. A1 - Heckbert, S. R. A1 - Austin, T. R. A1 - Hughes, T. M. A1 - Tanaka, T. A1 - Emilsson, V. A1 - Vasan, R. S. A1 - Guo, X. A1 - Zhu, Y. A1 - Tzourio, C. A1 - Rotter, J. I. A1 - Walker, K. A. A1 - Ferrucci, L. A1 - ki, M. A1 - Breteler, M. M. B. A1 - Cox, S. R. A1 - Debette, S. A1 - Mosley, T. H. A1 - Gudnason, V. G. A1 - Launer, L. J. A1 - Psaty, B. M. A1 - Seshadri, S. A1 - Fornage, M. AB - 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets. VL - 6 ER - TY - JOUR T1 - loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology JF - medRxiv Y1 - 2023 A1 - Chemparathy, A. A1 - Guen, Y. L. A1 - Chen, S. A1 - Lee, E. G. A1 - Leong, L. A1 - Gorzynski, J. A1 - Xu, G. A1 - Belloy, M. A1 - Kasireddy, N. A1 - Tauber, A. P. A1 - Williams, K. A1 - Stewart, I. A1 - Wingo, T. A1 - Lah, J. A1 - Jayadev, S. A1 - Hales, C. A1 - Peskind, E. A1 - Child, D. D. A1 - Keene, C. D. A1 - Cong, L. A1 - Ashley, E. A1 - Yu, C. E. A1 - Greicius, M. D. AB - 4 or its protein product as a viable therapeutic option. ER - TY - JOUR T1 - Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. JF - Nat Genet Y1 - 2023 A1 - Jakubek, Yasminka A A1 - Zhou, Ying A1 - Stilp, Adrienne A1 - Bacon, Jason A1 - Wong, Justin W A1 - Ozcan, Zuhal A1 - Arnett, Donna A1 - Barnes, Kathleen A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Jiawen A1 - Cho, Michael A1 - Conomos, Matthew P A1 - Cox, Nancy A1 - Doyle, Margaret F A1 - Fornage, Myriam A1 - Guo, Xiuqing A1 - Kardia, Sharon L R A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Ma, Xiaolong A1 - Machiela, Mitchell J A1 - Mack, Taralynn M A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mychaleckyj, Josyf C A1 - North, Kari A1 - Pankratz, Nathan A1 - Peyser, Patricia A A1 - Preuss, Michael H A1 - Psaty, Bruce A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Silverman, Edwin K A1 - Smith, Jennifer A A1 - Smith, Aaron P A1 - Taub, Margaret A1 - Taylor, Kent D A1 - Yun, Jeong A1 - Li, Yun A1 - Desai, Pinkal A1 - Bick, Alexander G A1 - Reiner, Alexander P A1 - Scheet, Paul A1 - Auer, Paul L KW - Black People KW - Genome, Human KW - Genome-Wide Association Study KW - Hispanic or Latino KW - Humans KW - Mosaicism KW - Precision Medicine AB -

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

VL - 55 IS - 11 ER - TY - JOUR T1 - Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. JF - Nat Genet Y1 - 2023 A1 - Kavousi, Maryam A1 - Bos, Maxime M A1 - Barnes, Hanna J A1 - Lino Cardenas, Christian L A1 - Wong, Doris A1 - Lu, Haojie A1 - Hodonsky, Chani J A1 - Landsmeer, Lennart P L A1 - Turner, Adam W A1 - Kho, Minjung A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Bowden, Donald W A1 - Chopade, Sandesh A1 - Deelen, Joris A1 - Benavente, Ernest Diez A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Hwang, Shih-Jen A1 - Lutz, Sharon M A1 - Lyytikäinen, Leo-Pekka A1 - Slenders, Lotte A1 - Smith, Albert V A1 - Stanislawski, Maggie A A1 - van Setten, Jessica A1 - Wong, Quenna A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Beekman, Marian A1 - Budoff, Matthew J A1 - Feitosa, Mary F A1 - Finan, Chris A1 - Hilliard, Austin T A1 - Kardia, Sharon L R A1 - Kovacic, Jason C A1 - Kral, Brian G A1 - Langefeld, Carl D A1 - Launer, Lenore J A1 - Malik, Shaista A1 - Hoesein, Firdaus A A Mohamed A1 - Mokry, Michal A1 - Schmidt, Reinhold A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Terry, James G A1 - van der Grond, Jeroen A1 - van Meurs, Joyce A1 - Vliegenthart, Rozemarijn A1 - Xu, Jianzhao A1 - Young, Kendra A A1 - Zilhão, Nuno R A1 - Zweiker, Robert A1 - Assimes, Themistocles L A1 - Becker, Lewis C A1 - Bos, Daniel A1 - Carr, J Jeffrey A1 - Cupples, L Adrienne A1 - de Kleijn, Dominique P V A1 - de Winther, Menno A1 - den Ruijter, Hester M A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Hokanson, John E A1 - Ikram, M Arfan A1 - Išgum, Ivana A1 - Jacobs, David R A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Pasterkamp, Gerard A1 - Raitakari, Olli T A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Bis, Joshua C A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Björkegren, Johan L M A1 - O'Donnell, Christopher J A1 - Bielak, Lawrence F A1 - Peyser, Patricia A A1 - Malhotra, Rajeev A1 - van der Laan, Sander W A1 - Miller, Clint L AB -

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

VL - 55 IS - 10 ER - TY - JOUR T1 - Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. JF - medRxiv Y1 - 2023 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Ana Luiza de, S V Arruda A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Alaine Broadaway, K A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - Janaka de Silva, H A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lithgart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Project, Biobank Japan A1 - BioBank, Penn Medicine A1 - Center, Regeneron Genetics A1 - Consortium, eMERGE A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Geoffrey Hayes, M A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

ER - TY - JOUR T1 - Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. JF - Nat Genet Y1 - 2023 A1 - Chen, Fang A1 - Wang, Xingyan A1 - Jang, Seon-Kyeong A1 - Quach, Bryan C A1 - Weissenkampen, J Dylan A1 - Khunsriraksakul, Chachrit A1 - Yang, Lina A1 - Sauteraud, Renan A1 - Albert, Christine M A1 - Allred, Nicholette D D A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Barr, R Graham A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boorgula, Meher Preethi A1 - Chasman, Daniel I A1 - Chavan, Sameer A1 - Chen, Yii-der I A1 - Chuang, Lee-Ming A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - David, Sean P A1 - Fuentes, Lisa de Las A1 - Deka, Ranjan A1 - Duggirala, Ravindranath A1 - Faul, Jessica D A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - Hawley, Nicola L A1 - He, Jiang A1 - Hobbs, Brian D A1 - Hokanson, John E A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Hyde, Thomas M A1 - Irvin, Marguerite R A1 - Jaffe, Andrew E A1 - Johnson, Eric O A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kaufman, Joel D A1 - Kelly, Tanika N A1 - Kleinman, Joel E A1 - Kooperberg, Charles A1 - Lee, I-Te A1 - Levy, Daniel A1 - Lutz, Sharon M A1 - Manichaikul, Ani W A1 - Martin, Lisa W A1 - Marx, Olivia A1 - McGarvey, Stephen T A1 - Minster, Ryan L A1 - Moll, Matthew A1 - Moussa, Karine A A1 - Naseri, Take A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Rafaels, Nicholas A1 - Raffield, Laura M A1 - Reupena, Muagututi'a Sefuiva A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Sheu, Wayne H-H A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sun, Xiao A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Watson, Harold A1 - Weeks, Daniel E A1 - Weir, David R A1 - Yanek, Lisa R A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhao, Wei A1 - Hancock, Dana B A1 - Jiang, Bibo A1 - Vrieze, Scott A1 - Liu, Dajiang J KW - Biology KW - Drug Repositioning KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Tobacco Use KW - Transcriptome AB -

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

VL - 55 IS - 2 ER - TY - JOUR T1 - Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. JF - Nat Genet Y1 - 2023 A1 - Li, Xihao A1 - Quick, Corbin A1 - Zhou, Hufeng A1 - Gaynor, Sheila M A1 - Liu, Yaowu A1 - Chen, Han A1 - Selvaraj, Margaret Sunitha A1 - Sun, Ryan A1 - Dey, Rounak A1 - Arnett, Donna K A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Duggirala, Ravindranath A1 - Freedman, Barry I A1 - Göring, Harald H H A1 - Guo, Xiuqing A1 - Haessler, Jeffrey A1 - Kalyani, Rita R A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Martin, Lisa W A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Willer, Cristen J A1 - Wilson, James G A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Li, Zilin A1 - Lin, Xihong KW - Exome Sequencing KW - Genome-Wide Association Study KW - Lipids KW - Phenotype KW - Whole Genome Sequencing AB -

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

VL - 55 IS - 1 ER - TY - JOUR T1 - Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. JF - medRxiv Y1 - 2023 A1 - Wang, Yuxuan A1 - Selvaraj, Margaret Sunitha A1 - Li, Xihao A1 - Li, Zilin A1 - Holdcraft, Jacob A A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Cade, Brian E A1 - Carlson, Jenna C A1 - Carson, April P A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Floyd, James S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Guo, Xiuqing A1 - He, Jiang A1 - Heard-Costa, Nancy A1 - Hildalgo, Bertha A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Joehanes, Roby A1 - Kaplan, Robert C A1 - Kardia, Sharon Lr A1 - Kelly, Tanika N A1 - Kim, Ryan A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Levy, Daniel A1 - Li, Changwei A1 - Liu, Chunyu A1 - Lloyd-Jone, Don A1 - Loos, Ruth Jf A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Ruepena, Muagututi'a Sefuiva A1 - Sheu, Wayne H-H A1 - Smith, Jennifer A A1 - Smith, Albert A1 - Tiwari, Hemant K A1 - Tsai, Michael Y A1 - Viaud-Martinez, Karine A A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Natarajan, Pradeep A1 - Peloso, Gina M AB -

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

ER - TY - JOUR T1 - Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. JF - JAMA Netw Open Y1 - 2023 A1 - Pase, Matthew P A1 - Harrison, Stephanie A1 - Misialek, Jeffrey R A1 - Kline, Christopher E A1 - Cavuoto, Marina A1 - Baril, Andree-Ann A1 - Yiallourou, Stephanie A1 - Bisson, Alycia A1 - Himali, Dibya A1 - Leng, Yue A1 - Yang, Qiong A1 - Seshadri, Sudha A1 - Beiser, Alexa A1 - Gottesman, Rebecca F A1 - Redline, Susan A1 - Lopez, Oscar A1 - Lutsey, Pamela L A1 - Yaffe, Kristine A1 - Stone, Katie L A1 - Purcell, Shaun M A1 - Himali, Jayandra J AB -

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

VL - 6 IS - 7 ER - TY - JOUR T1 - A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. JF - bioRxiv Y1 - 2023 A1 - Li, Xihao A1 - Chen, Han A1 - Selvaraj, Margaret Sunitha A1 - Van Buren, Eric A1 - Zhou, Hufeng A1 - Wang, Yuxuan A1 - Sun, Ryan A1 - McCaw, Zachary R A1 - Yu, Zhi A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Carson, April P A1 - Carlson, Jenna C A1 - Chami, Nathalie A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Gu, Charles A1 - Heard-Costa, Nancy L A1 - He, Jiang A1 - Hou, Lifang A1 - Hung, Yi-Jen A1 - Irvin, Marguerite R A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Konigsberg, Iain A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Li, Changwei A1 - Loos, Ruth J F A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Tiwari, Hemant A1 - Vasan, Ramachandran S A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Yu, Bing A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Li, Zilin A1 - Liu, Zhonghua A1 - Lin, Xihong AB -

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

ER - TY - JOUR T1 - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. JF - medRxiv Y1 - 2023 A1 - Kwak, Soo Heon A1 - Hernandez-Cancela, Ryan B A1 - DiCorpo, Daniel A A1 - Condon, David E A1 - Merino, Jordi A1 - Wu, Peitao A1 - Brody, Jennifer A A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Ahmadizar, Fariba A1 - Meyer, Mariah A1 - Sincan, Murat A1 - Mercader, Josep M A1 - Lee, Sujin A1 - Haessler, Jeffrey A1 - Vy, Ha My T A1 - Lin, Zhaotong A1 - Armstrong, Nicole D A1 - Gu, Shaopeng A1 - Tsao, Noah L A1 - Lange, Leslie A A1 - Wang, Ningyuan A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Liu, Simin A1 - Loos, Ruth J F A1 - Judy, Renae A1 - Schroeder, Philip H A1 - Hasbani, Natalie R A1 - Bos, Maxime M A1 - Morrison, Alanna C A1 - Jackson, Rebecca D A1 - Reiner, Alexander P A1 - Manson, JoAnn E A1 - Chaudhary, Ninad S A1 - Carmichael, Lynn K A1 - Chen, Yii-Der Ida A1 - Taylor, Kent D A1 - Ghanbari, Mohsen A1 - van Meurs, Joyce A1 - Pitsillides, Achilleas N A1 - Psaty, Bruce M A1 - Noordam, Raymond A1 - Do, Ron A1 - Park, Kyong Soo A1 - Jukema, J Wouter A1 - Kavousi, Maryam A1 - Correa, Adolfo A1 - Rich, Stephen S A1 - Damrauer, Scott M A1 - Hajek, Catherine A1 - Cho, Nam H A1 - Irvin, Marguerite R A1 - Pankow, James S A1 - Nadkarni, Girish N A1 - Sladek, Robert A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Dupuis, Josée A1 - Malhotra, Rajeev A1 - de Vries, Paul S A1 - Liu, Ching-Ti A1 - Rotter, Jerome I A1 - Meigs, James B AB -

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

ER - TY - JOUR T1 - Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. JF - Circ Genom Precis Med Y1 - 2023 A1 - Hasbani, Natalie R A1 - Westerman, Kenneth E A1 - Heon Kwak, Soo A1 - Chen, Han A1 - Li, Xihao A1 - DiCorpo, Daniel A1 - Wessel, Jennifer A1 - Bis, Joshua C A1 - Sarnowski, Chloe A1 - Wu, Peitao A1 - Bielak, Lawrence F A1 - Guo, Xiuqing A1 - Heard-Costa, Nancy A1 - Kinney, Gregory A1 - Mahaney, Michael C A1 - Montasser, May E A1 - Palmer, Nicholette D A1 - Raffield, Laura M A1 - Terry, James G A1 - Yanek, Lisa R A1 - Bon, Jessica A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Duggirala, Ravindranath A1 - Jacobs, David R A1 - Kalyani, Rita R A1 - Lange, Leslie A A1 - Mitchell, Braxton D A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Carson, April A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Gibbs, Richard A A1 - Gupta, Namrata A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Momin, Zeineen A1 - Newman, Anne B A1 - Post, Wendy S A1 - Viaud-Martinez, Karine A A1 - Young, Kendra A A1 - Becker, Lewis C A1 - Bertoni, Alain A1 - Blangero, John A1 - Carr, John J A1 - Pratte, Katherine A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Wu, Joseph C A1 - Malhotra, Rajeev A1 - Peyser, Patricia A A1 - Morrison, Alanna C A1 - Vasan, Ramachandran S A1 - Lin, Xihong A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Manning, Alisa K A1 - de Vries, Paul S AB -

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

ER - TY - JOUR T1 - Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease. JF - J Alzheimers Dis Y1 - 2023 A1 - Ukraintseva, Svetlana A1 - Duan, Matt A1 - Simanek, Amanda M A1 - Holmes, Rachel A1 - Bagley, Olivia A1 - Rajendrakumar, Aravind L A1 - Yashkin, Arseniy P A1 - Akushevich, Igor A1 - Tropsha, Alexander A1 - Whitson, Heather A1 - Yashin, Anatoliy A1 - Arbeev, Konstantin AB -

Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer's disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

ER - TY - JOUR T1 - Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. JF - medRxiv Y1 - 2023 A1 - Huffman, Jennifer E A1 - Nicolas, Jayna A1 - Hahn, Julie A1 - Heath, Adam S A1 - Raffield, Laura M A1 - Yanek, Lisa R A1 - Brody, Jennifer A A1 - Thibord, Florian A1 - Almasy, Laura A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Bowler, Russell P A1 - Carrasquilla, Germán D A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Emmert, David B A1 - Ghanbari, Mohsen A1 - Haessle, Jeffery A1 - Hottenga, Jouke-Jan A1 - Kleber, Marcus E A1 - Le, Ngoc-Quynh A1 - Lee, Jiwon A1 - Lewis, Joshua P A1 - Li-Gao, Ruifang A1 - Luan, Jian'an A1 - Malmberg, Anni A1 - Mangino, Massimo A1 - Marioni, Riccardo E A1 - Martinez-Perez, Angel A1 - Pankratz, Nathan A1 - Polasek, Ozren A1 - Richmond, Anne A1 - Rodriguez, Benjamin At A1 - Rotter, Jerome I A1 - Steri, Maristella A1 - Suchon, Pierre A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Zare, Marjan A1 - Auer, Paul A1 - Cho, Michael H A1 - Christofidou, Paraskevi A1 - Davies, Gail A1 - de Geus, Eco A1 - Deleuze, Jean-Francois A1 - Delgado, Graciela E A1 - Ekunwe, Lynette A1 - Faraday, Nauder A1 - Gögele, Martin A1 - Greinacher, Andreas A1 - He, Gao A1 - Howard, Tom A1 - Joshi, Peter K A1 - Kilpeläinen, Tuomas O A1 - Lahti, Jari A1 - Linneberg, Allan A1 - Naitza, Silvia A1 - Noordam, Raymond A1 - Paüls-Vergés, Ferran A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Ryan, Kathleen A A1 - Souto, Juan Carlos A1 - van Rooij, Frank Ja A1 - Wang, Heming A1 - Zhao, Wei A1 - Becker, Lewis C A1 - Beswick, Andrew A1 - Brown, Michael R A1 - Cade, Brian E A1 - Campbell, Harry A1 - Cho, Kelly A1 - Crapo, James D A1 - Curran, Joanne E A1 - de Maat, Moniek Pm A1 - Doyle, Margaret A1 - Elliott, Paul A1 - Floyd, James S A1 - Fuchsberger, Christian A1 - Grarup, Niels A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Hou, Lifang A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Menni, Cristina A1 - Nauck, Matthias A1 - O'Connell, Jeffrey R A1 - Orrù, Valeria A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Smith, Jennifer A A1 - Soria, José Manuel A1 - Stott, David J A1 - van Hylckama Vlieg, Astrid A1 - Watkins, Hugh A1 - Willemsen, Gonneke A1 - Wilson, Peter A1 - Ben-Shlomo, Yoav A1 - Blangero, John A1 - Boomsma, Dorret A1 - Cox, Simon R A1 - Dehghan, Abbas A1 - Eriksson, Johan G A1 - Fiorillo, Edoardo A1 - Fornage, Myriam A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon Lr A1 - Lange, Leslie A A1 - März, Winfried A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mook-Kanamori, Dennis O A1 - Morange, Pierre-Emmanuel A1 - Pedersen, Oluf A1 - Pramstaller, Peter P A1 - Redline, Susan A1 - Reiner, Alexander A1 - Ridker, Paul M A1 - Silverman, Edwin K A1 - Spector, Tim D A1 - Völker, Uwe A1 - Wareham, Nick A1 - Wilson, James F A1 - Yao, Jie A1 - Trégouët, David-Alexandre A1 - Johnson, Andrew D A1 - Wolberg, Alisa S A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

ER - TY - JOUR T1 - WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. JF - medRxiv Y1 - 2023 A1 - Zhang, Xinruo A1 - Brody, Jennifer A A1 - Graff, Mariaelisa A1 - Highland, Heather M A1 - Chami, Nathalie A1 - Xu, Hanfei A1 - Wang, Zhe A1 - Ferrier, Kendra A1 - Chittoor, Geetha A1 - Josyula, Navya S A1 - Li, Xihao A1 - Li, Zilin A1 - Allison, Matthew A A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Broome, Jai G A1 - Buth, Erin J A1 - Carlson, Christopher S A1 - Chang, Kyong-Mi A1 - Chavan, Sameer A1 - Chiu, Yen-Feng A1 - Chuang, Lee-Ming A1 - Conomos, Matthew P A1 - DeMeo, Dawn L A1 - Du, Margaret A1 - Duggirala, Ravindranath A1 - Eng, Celeste A1 - Fohner, Alison E A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Guo, Xiuqing A1 - Haiman, Chris A1 - Heavner, Benjamin D A1 - Hidalgo, Bertha A1 - Hixson, James E A1 - Ho, Yuk-Lam A1 - Hobbs, Brian D A1 - Hu, Donglei A1 - Hui, Qin A1 - Hwu, Chii-Min A1 - Jackson, Rebecca D A1 - Jain, Deepti A1 - Kalyani, Rita R A1 - Kardia, Sharon L R A1 - Kelly, Tanika N A1 - Lange, Ethan M A1 - LeNoir, Michael A1 - Li, Changwei A1 - Marchand, Loic Le A1 - McDonald, Merry-Lynn N A1 - McHugh, Caitlin P A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey A1 - O'Donnell, Christopher J A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Perry, James A A1 - Peters, Ulrike A1 - Preuss, Michael H A1 - Rao, D C A1 - Regan, Elizabeth A A1 - Reupena, Sefuiva M A1 - Roden, Dan M A1 - Rodriguez-Santana, Jose A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Tiwari, Hemant K A1 - Vasan, Ramachandran S A1 - Wang, Zeyuan A1 - Weeks, Daniel E A1 - Wessel, Jennifer A1 - Wiggins, Kerri L A1 - Wilkens, Lynne R A1 - Wilson, Peter W F A1 - Yanek, Lisa R A1 - Yoneda, Zachary T A1 - Zhao, Wei A1 - Zöllner, Sebastian A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Burchard, Esteban G A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Gordeuk, Victor R A1 - He, Jiang A1 - Heckbert, Susan R A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Kooperberg, Charles A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Nouraie, Mehdi A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Weiss, Scott T A1 - Zhang, Yingze A1 - Costa, Nancy Heard- A1 - Sun, Yan V A1 - Lin, Xihong A1 - Cupples, L Adrienne A1 - Lange, Leslie A A1 - Liu, Ching-Ti A1 - Loos, Ruth J F A1 - North, Kari E A1 - Justice, Anne E AB -

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

ER - TY - JOUR T1 - Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. JF - bioRxiv Y1 - 2023 A1 - Jiang, Min-Zhi A1 - Gaynor, Sheila M A1 - Li, Xihao A1 - Van Buren, Eric A1 - Stilp, Adrienne A1 - Buth, Erin A1 - Wang, Fei Fei A1 - Manansala, Regina A1 - Gogarten, Stephanie M A1 - Li, Zilin A1 - Polfus, Linda M A1 - Salimi, Shabnam A1 - Bis, Joshua C A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Durda, Peter A1 - Tracy, Russell P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Psaty, Bruce M A1 - Pratte, Katherine A A1 - Silverman, Edwin K A1 - Kaplan, Robert C A1 - Avery, Christy A1 - North, Kari A1 - Mathias, Rasika A A1 - Faraday, Nauder A1 - Lin, Honghuang A1 - Wang, Biqi A1 - Carson, April P A1 - Norwood, Arnita F A1 - Gibbs, Richard A A1 - Kooperberg, Charles A1 - Lundin, Jessica A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Hou, Lifang A1 - Fornage, Myriam A1 - Benjamin, Emelia J A1 - Reiner, Alexander P A1 - Bowler, Russell P A1 - Lin, Xihong A1 - Auer, Paul L A1 - Raffield, Laura M AB -

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

ER - TY - JOUR T1 - Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations. JF - Nat Commun Y1 - 2023 A1 - Feofanova, Elena V A1 - Brown, Michael R A1 - Alkis, Taryn A1 - Manuel, Astrid M A1 - Li, Xihao A1 - Tahir, Usman A A1 - Li, Zilin A1 - Mendez, Kevin M A1 - Kelly, Rachel S A1 - Qi, Qibin A1 - Chen, Han A1 - Larson, Martin G A1 - Lemaitre, Rozenn N A1 - Morrison, Alanna C A1 - Grieser, Charles A1 - Wong, Kari E A1 - Gersztern, Robert E A1 - Zhao, Zhongming A1 - Lasky-Su, Jessica A1 - Yu, Bing KW - Ethnicity KW - Genome-Wide Association Study KW - Humans KW - Metabolome KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

VL - 14 IS - 1 ER - TY - JOUR T1 - Association analysis of mitochondrial DNA heteroplasmic variants: methods and application. JF - medRxiv Y1 - 2024 A1 - Sun, Xianbang A1 - Bulekova, Katia A1 - Yang, Jian A1 - Lai, Meng A1 - Pitsillides, Achilleas N A1 - Liu, Xue A1 - Zhang, Yuankai A1 - Guo, Xiuqing A1 - Yong, Qian A1 - Raffield, Laura M A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Abecasis, Goncalo A1 - Carson, April P A1 - Vasan, Ramachandran S A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fitzpatrick, Annette L A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Ding, Jun A1 - Levy, Daniel A1 - Liu, Chunyu AB -

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

ER - TY - JOUR T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. 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Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Ahlqvist, Emma A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Marston, Nicholas A A1 - Ruff, Christian T A1 - van Heel, David A A1 - Finer, Sarah A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

ER - TY - JOUR T1 - Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. JF - Alzheimers Res Ther Y1 - 2024 A1 - Mei, Hao A1 - Simino, Jeannette A1 - Li, Lianna A1 - Jiang, Fan A1 - Bis, Joshua C A1 - Davies, Gail A1 - Hill, W David A1 - Xia, Charley A1 - Gudnason, Vilmundur A1 - Yang, Qiong A1 - Lahti, Jari A1 - Smith, Jennifer A A1 - Kirin, Mirna A1 - De Jager, Philip A1 - Armstrong, Nicola J A1 - Ghanbari, Mohsen A1 - Kolcic, Ivana A1 - Moran, Christopher A1 - Teumer, Alexander A1 - Sargurupremraj, Murali A1 - Mahmud, Shamsed A1 - Fornage, Myriam A1 - Zhao, Wei A1 - Satizabal, Claudia L A1 - Polasek, Ozren A1 - Räikkönen, Katri A1 - Liewald, David C A1 - Homuth, Georg A1 - Callisaya, Michele A1 - Mather, Karen A A1 - Windham, B Gwen A1 - Zemunik, Tatijana A1 - Palotie, Aarno A1 - Pattie, Alison A1 - van der Auwera, Sandra A1 - Thalamuthu, Anbupalam A1 - Knopman, David S A1 - Rudan, Igor A1 - Starr, John M A1 - Wittfeld, Katharina A1 - Kochan, Nicole A A1 - Griswold, Michael E A1 - Vitart, Veronique A1 - Brodaty, Henry A1 - Gottesman, Rebecca A1 - Cox, Simon R A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Sachdev, Perminder S A1 - Srikanth, Velandai A1 - Hayward, Caroline A1 - Wilson, James F A1 - Eriksson, Johan G A1 - Kardia, Sharon L R A1 - Grabe, Hans J A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Bressler, Jan A1 - Debette, Stephanie A1 - Mosley, Thomas H KW - Aged KW - Cognition KW - Genome-Wide Association Study KW - Humans KW - Memory KW - MicroRNAs KW - Multiomics KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

VL - 16 IS - 1 ER - TY - JOUR T1 - {Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications JF - Nat Commun Y1 - 2024 A1 - Sterenborg, R. B. T. M. A1 - Steinbrenner, I. A1 - Li, Y. A1 - Bujnis, M. N. A1 - Naito, T. A1 - Marouli, E. A1 - Galesloot, T. E. A1 - Babajide, O. A1 - Andreasen, L. A1 - Astrup, A. A1 - svold, B. O. A1 - Bandinelli, S. A1 - Beekman, M. A1 - Beilby, J. P. A1 - Bork-Jensen, J. A1 - Boutin, T. A1 - Brody, J. A. A1 - Brown, S. J. A1 - Brumpton, B. A1 - Campbell, P. J. A1 - Cappola, A. R. A1 - Ceresini, G. A1 - Chaker, L. A1 - Chasman, D. I. A1 - Concas, M. P. A1 - Coutinho de Almeida, R. A1 - Cross, S. M. A1 - Cucca, F. A1 - Deary, I. J. A1 - Kjaergaard, A. D. A1 - Echouffo Tcheugui, J. B. A1 - Ellervik, C. A1 - Eriksson, J. G. A1 - Ferrucci, L. A1 - Freudenberg, J. A1 - Fuchsberger, C. A1 - Gieger, C. A1 - Giulianini, F. A1 - gele, M. A1 - Graham, S. E. A1 - Grarup, N. A1 - ä, I. A1 - Hansen, T. A1 - Harding, B. N. A1 - Harris, S. E. A1 - ø, S. A1 - Hayward, C. A1 - Hui, J. A1 - Ittermann, T. A1 - Jukema, J. W. A1 - Kajantie, E. A1 - Kanters, J. K. A1 - rhus, L. L. A1 - Kiemeney, L. A. L. M. A1 - Kloppenburg, M. A1 - hnel, B. A1 - Lahti, J. A1 - Langenberg, C. A1 - Lapauw, B. A1 - Leese, G. A1 - Li, S. A1 - Liewald, D. C. M. A1 - Linneberg, A. A1 - Lominchar, J. V. T. A1 - Luan, J. A1 - Martin, N. G. A1 - Matana, A. A1 - Meima, M. E. A1 - Meitinger, T. A1 - Meulenbelt, I. A1 - Mitchell, B. D. A1 - llehave, L. T. A1 - Mora, S. A1 - Naitza, S. A1 - Nauck, M. A1 - Netea-Maier, R. T. A1 - Noordam, R. A1 - Nursyifa, C. A1 - Okada, Y. A1 - Onano, S. A1 - Papadopoulou, A. A1 - Palmer, C. N. A. A1 - Pattaro, C. A1 - Pedersen, O. A1 - Peters, A. A1 - Pietzner, M. A1 - ek, O. A1 - Pramstaller, P. P. A1 - Psaty, B. M. A1 - Punda, A. A1 - Ray, D. A1 - Redmond, P. A1 - Richards, J. B. A1 - Ridker, P. M. A1 - Russ, T. C. A1 - Ryan, K. A. A1 - Olesen, M. S. A1 - Schultheiss, U. T. A1 - Selvin, E. A1 - Siddiqui, M. K. A1 - Sidore, C. A1 - Slagboom, P. E. A1 - rensen, T. I. A. A1 - Soto-Pedre, E. A1 - Spector, T. D. A1 - Spedicati, B. A1 - Srinivasan, S. A1 - Starr, J. M. A1 - Stott, D. J. A1 - Tanaka, T. A1 - Torlak, V. A1 - Trompet, S. A1 - Tuhkanen, J. A1 - Uitterlinden, A. G. A1 - van den Akker, E. B. A1 - van den Eynde, T. A1 - van der Klauw, M. M. A1 - van Heemst, D. A1 - Verroken, C. A1 - Visser, W. E. A1 - Vojinovic, D. A1 - lzke, H. A1 - Waldenberger, M. A1 - Walsh, J. P. A1 - Wareham, N. J. A1 - Weiss, S. A1 - Willer, C. J. A1 - Wilson, S. G. A1 - Wolffenbuttel, B. H. R. A1 - Wouters, H. J. C. M. A1 - Wright, M. J. A1 - Yang, Q. A1 - Zemunik, T. A1 - Zhou, W. A1 - Zhu, G. A1 - llner, S. A1 - Smit, J. W. A. A1 - Peeters, R. P. A1 - ttgen, A. A1 - Teumer, A. A1 - Medici, M. AB - T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases. VL - 15 ER - TY - JOUR T1 - A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure. JF - ESC Heart Fail Y1 - 2024 A1 - Alkis, Taryn A1 - Luo, Xi A1 - Wall, Katherine A1 - Brody, Jennifer A1 - Bartz, Traci A1 - Chang, Patricia P A1 - Norby, Faye L A1 - Hoogeveen, Ron C A1 - Morrison, Alanna C A1 - Ballantyne, Christie M A1 - Coresh, Josef A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Shah, Amil M A1 - Yu, Bing AB -

AIMS: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations.

METHODS AND RESULTS: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS .

CONCLUSIONS: The PRS was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.

ER - TY - JOUR T1 - Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. JF - Circulation Y1 - 2024 A1 - Laguzzi, Federica A1 - Åkesson, Agneta A1 - Marklund, Matti A1 - Qian, Frank A1 - Gigante, Bruna A1 - Bartz, Traci M A1 - Bassett, Julie K A1 - Birukov, Anna A1 - Campos, Hannia A1 - Hirakawa, Yoichiro A1 - Imamura, Fumiaki A1 - Jäger, Susanne A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Senn, Mackenzie A1 - Tanaka, Toshiko A1 - Tintle, Nathan A1 - Virtanen, Jyrki K A1 - Yamagishi, Kazumasa A1 - Allison, Matthew A1 - Brouwer, Ingeborg A A1 - de Faire, Ulf A1 - Eiriksdottir, Gudny A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Geleijnse, Johanna M A1 - Hodge, Allison M A1 - Kimura, Hitomi A1 - Laakso, Markku A1 - Riserus, Ulf A1 - van Westing, Anniek C A1 - Bandinelli, Stefania A1 - Baylin, Ana A1 - Giles, Graham G A1 - Gudnason, Vilmundur A1 - Iso, Hiroyasu A1 - Lemaitre, Rozenn N A1 - Ninomiya, Toshiharu A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Salonen, Jukka T A1 - Schulze, Matthias B A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wareham, Nicholas J A1 - Oh, Seung-Won A1 - Wood, Alexis C A1 - Harris, William S A1 - Siscovick, David A1 - Mozaffarian, Dariush A1 - Leander, Karin KW - Animals KW - Biomarkers KW - Cardiovascular Diseases KW - Docosahexaenoic Acids KW - Fatty Acids, Omega-3 KW - Risk Factors AB -

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

VL - 149 IS - 4 ER - TY - JOUR T1 - Trajectory of Cognitive Function After Incident Heart Failure. JF - medRxiv Y1 - 2024 A1 - Shore, Supriya A1 - Li, Hanyu A1 - Zhang, Min A1 - Whitney, Rachael A1 - Gross, Alden L A1 - Bhatt, Ankeet S A1 - Nallamothu, Brahmajee K A1 - Giordani, Bruno A1 - Briceño, Emily M A1 - Sussman, Jeremy B A1 - Gutierrez, Jose A1 - Yaffe, Kristine A1 - Griswold, Michael A1 - Johansen, Michelle C A1 - Lopez, Oscar L A1 - Gottesman, Rebecca F A1 - Sidney, Stephen A1 - Heckbert, Susan R A1 - Rundek, Tatjana A1 - Hughes, Timothy M A1 - Longstreth, William T A1 - Levine, Deborah A AB -

BACKGROUND: The size/magnitude of cognitive changes after incident heart failure (HF) are unclear. We assessed whether incident HF is associated with changes in cognitive function after accounting for pre-HF cognitive trajectories and known determinants of cognition.

METHODS: This pooled cohort study included adults without HF, stroke, or dementia from six US population-based cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), controlling for pre-HF cognitive trajectories and participant factors. Change in global cognition was the primary outcome. Change in executive function and memory were secondary outcomes. Cognitive outcomes were standardized to a -score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition.

RESULTS: The study included 29,614 adults (mean [SD] age was 61.1 [10.5] years, 55% female, 70.3% White, 22.2% Black 7.5% Hispanic). During a median follow-up of 6.6 (Q1-Q3: 5-19.8) years, 1,407 (4.7%) adults developed incident HF. Incident HF was associated with an acute decrease in global cognition (-1.08 points; 95% CI -1.36, -0.80) and executive function (-0.65 points; 95% CI -0.96, -0.34) but not memory (-0.51 points; 95% CI -1.37, 0.35) at the time of the event. Greater acute decreases in global cognition after HF were seen in those with older age, female sex and White race. Individuals with incident HF, compared to HF-free individuals, demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21, -0.09) and executive function (-0.16 points per year; 95% CI -0.23, -0.09) but not memory ( -0.11 points per year; 95% CI -0.26, 0.04) compared with pre-HF slopes.

CONCLUSIONS: In this pooled cohort study, incident HF was associated with an acute decrease in global cognition and executive function at the time of the event and faster declines in global cognition and executive function over the following years.

ER -