@article {676, title = {A stroke prediction score in the elderly: validation and Web-based application.}, journal = {J Clin Epidemiol}, volume = {55}, year = {2002}, month = {2002 Feb}, pages = {129-36}, abstract = {

The objective of this study was to construct a prediction model for predicting stroke in an elderly U.S. population, and to assess the accuracy in this population of other previously published prediction models. The subjects were participants in the Cardiovascular Health Study: 2,495 men and 3,393 women age 65 years and older at baseline, and followed for 6.3 years. Among 5,711 participants free of baseline stroke, 399 strokes occurred. Sex-specific prediction equations were constructed using study variables that were most importantly related to incident stroke: age, systolic blood pressure, diabetes, ECG diagnosis of atrial fibrillation or left ventricular hypertrophy, confirmed history of cardiovascular disease, diabetes, time to walk 15 ft, and serum creatinine. The prediction rule was implemented as a risk score and in a Web-based interactive Java applet. Overall, the model predicted 5-year stroke risks ranging from less than 1 to 59\%. The 20\% of subjects in the highest predicted risk group had a 5-year actual stroke incidence rate of 15\%, while the 20\% lowest risk group had a 1\% incidence. Risk scores from two other studies performed well in these study participants. Effective discrimination between low and high stroke risk in the elderly was possible in this cohort with data that are easy to obtain. Evaluation of the generalizability and clinical usefulness of this prediction model requires further research.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Female, Follow-Up Studies, Humans, Incidence, Male, Models, Cardiovascular, Predictive Value of Tests, Risk Factors, ROC Curve, Stroke, United States}, issn = {0895-4356}, doi = {10.1016/s0895-4356(01)00434-6}, author = {Lumley, Thomas and Kronmal, Richard A and Cushman, Mary and Manolio, Teri A and Goldstein, Steven} } @article {708, title = {Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Nov 11}, pages = {2325-32}, abstract = {

BACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.

OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.

RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37\% at baseline to 49\% in 1999. The 51\% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5\% in 1990 to 51.1\% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.

CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.

}, keywords = {Age Factors, Aged, Antihypertensive Agents, Awareness, Cohort Studies, Drug Therapy, Female, Health Knowledge, Attitudes, Practice, Humans, Hypertension, Male, Prospective Studies, Time Factors}, issn = {0003-9926}, doi = {10.1001/archinte.162.20.2325}, author = {Psaty, Bruce M and Manolio, Teri A and Smith, Nicholas L and Heckbert, Susan R and Gottdiener, John S and Burke, Gregory L and Weissfeld, Joel and Enright, Paul and Lumley, Thomas and Powe, Neil and Furberg, Curt D} } @article {738, title = {The association between time since last meal and blood pressure in older adults: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {51}, year = {2003}, month = {2003 Jun}, pages = {824-8}, abstract = {

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.

}, keywords = {Aged, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Eating, Female, Humans, Hypotension, Male, Postprandial Period, Prospective Studies, Risk Factors, Time Factors}, issn = {0002-8614}, doi = {10.1046/j.1365-2389.2003.51264.x}, author = {Smith, Nicholas L and Psaty, Bruce M and Rutan, Gale H and Lumley, Thomas and Yanez, David and Chaves, Paulo H M and Kronmal, Richard A} } @article {733, title = {Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Apr 22}, pages = {2021-4}, abstract = {

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95\% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95\% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Cohort Studies, Comorbidity, Coronary Disease, European Continental Ancestry Group, Follow-Up Studies, Gene Frequency, Humans, Incidence, Linkage Disequilibrium, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Assessment, Stroke, United States}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000065231.07729.92}, author = {Heckbert, Susan R and Hindorff, Lucia A and Edwards, Karen L and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Tang, Zhonghua and Durda, J Peter and Kronmal, Richard A and Tracy, Russell P} } @article {803, title = {The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Oct}, pages = {1639-47}, abstract = {

OBJECTIVES: To assess the association between lipid levels and cardiovascular events in older adults.

DESIGN: A prospective population-based study.

SETTING: Four field centers in U.S. communities.

PARTICIPANTS: A total of 5,201 adults aged 65 and older living in U.S. communities, plus a recruitment of 687 African Americans 3 years later.

MEASUREMENTS: Fasting lipid measures included low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides.

RESULTS: At baseline, 1,954 men and 2,931 women were at risk for an incident myocardial infarction (MI) or stroke. During an average 7.5-year follow-up, 436 subjects had a coronary event, 332 had an ischemic stroke, 104 a hemorrhagic stroke, and 1,096 died. After adjustment, lipid measures were not major predictors of the outcomes of MI, ischemic stroke, hemorrhagic stroke, and total mortality. For total cholesterol and LDL-C, the associations with MI and ischemic stroke were only marginally significant. HDL-C was inversely associated with MI risk (hazard ratio=0.85 per standard deviation of 15.7 mg/dL, 95\% confidence interval=0.76-0.96). For the outcome of ischemic stroke, high levels of HDL-C were associated with a decreased risk in men but not women. Lipid measures were generally only weakly associated with the risks of hemorrhagic stroke or total mortality.

CONCLUSION: In this population-based study of older adults, most lipid measures were weakly associated with cardiovascular events. The association between low HDL-C and increased MI risk was nonetheless strong and consistent.

}, keywords = {African Americans, African Continental Ancestry Group, Aged, Female, Health Surveys, Humans, Incidence, Lipids, Male, Mortality, Myocardial Infarction, Population Surveillance, Prospective Studies, Risk Factors, Stroke, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52455.x}, author = {Psaty, Bruce M and Anderson, Melissa and Kronmal, Richard A and Tracy, Russell P and Orchard, Trevor and Fried, Linda P and Lumley, Thomas and Robbins, John and Burke, Greg and Newman, Anne B and Furberg, Curt D} } @article {802, title = {Survival associated with two sets of diagnostic criteria for congestive heart failure.}, journal = {Am J Epidemiol}, volume = {160}, year = {2004}, month = {2004 Oct 01}, pages = {628-35}, abstract = {

Congestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54\% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31\% fulfilled only the Framingham criteria (Framingham only), and 15\% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95\% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95\% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Diagnosis, Differential, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Prognosis, Severity of Illness Index, Survival Analysis}, issn = {0002-9262}, doi = {10.1093/aje/kwh268}, author = {Schellenbaum, Gina D and Rea, Thomas D and Heckbert, Susan R and Smith, Nicholas L and Lumley, Thomas and Roger, Veronique L and Kitzman, Dalane W and Taylor, Herman A and Levy, Daniel and Psaty, Bruce M} } @article {807, title = {Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure.}, journal = {Am Heart J}, volume = {148}, year = {2004}, month = {2004 Oct}, pages = {710-7}, abstract = {

BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.

METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.

RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95\% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45\%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.

CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.

}, keywords = {Adrenergic beta-Antagonists, Aged, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Cohort Studies, Drug Therapy, Drug Therapy, Combination, Female, Heart Failure, Humans, Male, Multivariate Analysis, Prevalence}, issn = {1097-6744}, doi = {10.1016/j.ahj.2004.04.002}, author = {Smith, Nicholas L and Chan, Jeannie D and Rea, Thomas D and Wiggins, Kerri L and Gottdiener, John S and Lumley, Thomas and Psaty, Bruce M} } @article {856, title = {Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {150}, year = {2005}, month = {2005 Sep}, pages = {464-70}, abstract = {

BACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF.

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF.

RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95\% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40\% and those with ejection fraction of > or = 40\% (HR 0.56, 95\% CI 0.27-1.13; HR 0.82, 95\% CI 0.56-1.22, respectively; interaction P = .34).

CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.

}, keywords = {Adrenergic beta-Antagonists, Age Factors, Aged, Aged, 80 and over, Female, Follow-Up Studies, Heart Failure, Humans, Male}, issn = {1097-6744}, doi = {10.1016/j.ahj.2004.12.022}, author = {Chan, Jeannie D and Rea, Thomas D and Smith, Nicholas L and Siscovick, David and Heckbert, Susan R and Lumley, Thomas and Chaves, Paulo and Furberg, Curt D and Kuller, Lewis and Psaty, Bruce M} } @article {825, title = {beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.}, journal = {Am J Hypertens}, volume = {18}, year = {2005}, month = {2005 Mar}, pages = {392-7}, abstract = {

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.

METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.

RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95\% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95\% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95\% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95\% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.

CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.

}, keywords = {African Americans, Antihypertensive Agents, Arteriosclerosis, Coronary Artery Disease, European Continental Ancestry Group, Female, Genotype, Homozygote, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Factors}, issn = {0895-7061}, doi = {10.1016/j.amjhyper.2004.10.014}, author = {Hindorff, Lucia A and Heckbert, Susan R and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Herrington, David M and Edwards, Karen L and Tracy, Russell P} } @article {842, title = {Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study.}, journal = {Atherosclerosis}, volume = {181}, year = {2005}, month = {2005 Jul}, pages = {175-83}, abstract = {

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

}, keywords = {Aged, Aging, Carboxypeptidase B2, Cause of Death, Cohort Studies, Female, Genotype, Health Status, Humans, Inflammation, Longevity, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Polymorphism, Genetic, Promoter Regions, Genetic, Prospective Studies, Risk Factors, Thrombosis}, issn = {0021-9150}, doi = {10.1016/j.atherosclerosis.2005.01.028}, author = {Reiner, Alexander P and Diehr, Paula and Browner, Warren S and Humphries, Stephen E and Jenny, Nancy S and Cushman, Mary and Tracy, Russell P and Walston, Jeremy and Lumley, Thomas and Newman, Anne B and Kuller, Lewis H and Psaty, Bruce M} } @article {868, title = {Weight loss, muscle strength, and angiotensin-converting enzyme inhibitors in older adults with congestive heart failure or hypertension.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Nov}, pages = {1996-2000}, abstract = {

OBJECTIVES: To determine whether angiotensin-converting enzyme (ACE) inhibitor use may be associated with weight maintenance and sustained muscle strength (measured by grip strength) in older adults.

DESIGN: Data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults, were used.

SETTING: Subjects were recruited from four U.S. sites beginning in 1989; this analysis included data through 2001.

PARTICIPANTS: CHS participants with congestive heart failure (CHF) or treated hypertension.

MEASUREMENTS: The exposure, current ACE inhibitor use, was ascertained by medication inventory at annual clinic visits; the outcomes were weight change and grip-strength change during the following year. Multivariate linear regression was used, accounting for correlations between observations on the same participant over time.

RESULTS: The average annual weight change was -0.38 kg in 2,834 participants (14,443 person-years) with treated hypertension and -0.62 kg in 342 participants (980 person-years) with CHF. ACE inhibitor use was associated with less annual weight loss after adjustment for potential confounders: a difference of 0.17 kg (95\% confidence interval (CI)=0.05-0.29) in those with treated hypertension and 0.29 kg (95\% CI=-0.25-0.83) in those with CHF. There was no evidence of association between ACE inhibitor use and grip-strength change.

CONCLUSION: ACE inhibitor use may be associated with weight maintenance, but not maintenance of muscle strength, in older adults with treated hypertension.

}, keywords = {Aged, Aged, 80 and over, Angiotensin-Converting Enzyme Inhibitors, Female, Hand Strength, Heart Failure, Humans, Hypertension, Male, Multivariate Analysis, Outcome Assessment, Health Care, Prospective Studies, Statistics as Topic, United States, Weight Loss}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53568.x}, author = {Schellenbaum, Gina D and Smith, Nicholas L and Heckbert, Susan R and Lumley, Thomas and Rea, Thomas D and Furberg, Curt D and Lyles, Mary F and Psaty, Bruce M} } @article {941, title = {Alcohol consumption in older adults and Medicare costs.}, journal = {Health Care Financ Rev}, volume = {27}, year = {2006}, month = {2006 Spring}, pages = {49-61}, abstract = {

We determined the relationship of alcohol consumption and Medicare costs among 4,392 participants in the Cardiovascular Health Study (CHS), a longitudinal, population-based cohort study of adults age 65 or over in four U.S. communities. We assessed 5-year Parts A and B costs and self-reported intake of beer, wine, and liquor at baseline. Among both sexes, total costs were approximately $2,000 lower among consumers of > 1-6 drinks per week than abstainers. The lower costs associated with moderate drinking were most apparent among participants with cardiovascular disease (CVD) and for hospitalization costs for CVD among healthy participants. Former drinkers had the highest costs.

}, keywords = {Aged, Alcohol Drinking, Cardiovascular Diseases, Female, Health Expenditures, Hospitalization, Humans, Longitudinal Studies, Male, Medicare, United States}, issn = {0195-8631}, author = {Mukamal, Kenneth J and Lumley, Thomas and Luepker, Russell V and Lapin, Pauline and Mittleman, Murray A and McBean, A Marshall and Crum, Rosa M and Siscovick, David S} } @article {844, title = {Congestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses.}, journal = {Ann Epidemiol}, volume = {16}, year = {2006}, month = {2006 Feb}, pages = {115-22}, abstract = {

PURPOSE: We compared hospitalized congestive heart failure (CHF) incidence and prognosis estimates using hospital discharge diagnoses or central adjudication.

METHODS: We used the Cardiovascular Health Study (CHS), a population-based cohort study of 5888 elderly adults. A physician committee adjudicated potential CHF events, confirmed by signs, symptoms, clinical tests, and/or medical therapy. A CHF discharge diagnosis included any of these ICD-9 codes in any position: 428, 425, 398.91, 402.01, 402.11, 402.91, and 997.1. We constructed an inception cohort of 1209 hospitalized, nonfatal, incident CHF cases, identified by discharge diagnosis, adjudication, or both.

RESULTS: Incidence rates for hospitalized CHF were 24.6 per 1000 person-years using discharge diagnoses and 17.1 per 1000 person-years using central adjudication. Compared to the group identified as having CHF by both methods, the group with only a discharge diagnosis (hazard ratio=0.77, 95\% confidence interval=0.65-0.91) and the group with central adjudication only (hazard ratio=0.72, 95\% confidence interval=0.55-0.94) had lower mortality rates.

CONCLUSIONS: In the elderly, studies using only discharge diagnoses, as compared to central adjudication, may estimate higher rates of incident hospitalized CHF. Mortality following CHF onset may be similar for these methods and higher if both methods are used together.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Female, Heart Failure, Humans, Incidence, Male, Patient Discharge, Prognosis}, issn = {1047-2797}, doi = {10.1016/j.annepidem.2005.02.012}, author = {Schellenbaum, Gina D and Heckbert, Susan R and Smith, Nicholas L and Rea, Thomas D and Lumley, Thomas and Kitzman, Dalane W and Roger, Veronique L and Taylor, Herman A and Psaty, Bruce M} } @article {914, title = {New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {29}, year = {2006}, month = {2006 Sep}, pages = {2012-7}, abstract = {

OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes.

RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality.

RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41\% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95\% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95\% CI 1.7-10.8]), and did not increase over time.

CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Blood Glucose, Cardiovascular Diseases, Diabetes Complications, Diabetes Mellitus, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Risk Factors, Survival Rate, Time Factors}, issn = {0149-5992}, doi = {10.2337/dc06-0574}, author = {Smith, Nicholas L and Barzilay, Joshua I and Kronmal, Richard and Lumley, Thomas and Enquobahrie, Daniel and Psaty, Bruce M} } @article {849, title = {The sensitivity and specificity of markers for event times.}, journal = {Biostatistics}, volume = {7}, year = {2006}, month = {2006 Apr}, pages = {182-97}, abstract = {

The statistical literature on assessing the accuracy of risk factors or disease markers as diagnostic tests deals almost exclusively with settings where the test, Y, is measured concurrently with disease status D. In practice, however, disease status may vary over time and there is often a time lag between when the marker is measured and the occurrence of disease. One example concerns the Framingham risk score (FR-score) as a marker for the future risk of cardiovascular events, events that occur after the score is ascertained. To evaluate such a marker, one needs to take the time lag into account since the predictive accuracy may be higher when the marker is measured closer to the time of disease occurrence. We therefore consider inference for sensitivity and specificity functions that are defined as functions of time. Semiparametric regression models are proposed. Data from a cohort study are used to estimate model parameters. One issue that arises in practice is that event times may be censored. In this research, we extend in several respects the work by Leisenring et al. (1997) that dealt only with parametric models for binary tests and uncensored data. We propose semiparametric models that accommodate continuous tests and censoring. Asymptotic distribution theory for parameter estimates is developed and procedures for making statistical inference are evaluated with simulation studies. We illustrate our methods with data from the Cardiovascular Health Study, relating the FR-score measured at enrollment to subsequent risk of cardiovascular events.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Biometry, Cardiovascular Diseases, Female, Humans, Male, Models, Statistical, Risk Factors, ROC Curve, Sensitivity and Specificity, Time Factors}, issn = {1465-4644}, doi = {10.1093/biostatistics/kxi047}, author = {Cai, Tianxi and Pepe, Margaret Sullivan and Zheng, Yingye and Lumley, Thomas and Jenny, Nancy Swords} } @article {995, title = {Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {28}, year = {2008}, month = {2008 Jan}, pages = {173-9}, abstract = {

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.

}, keywords = {African Americans, Aged, Aged, 80 and over, Coronary Disease, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Male, Myocardial Infarction, National Heart, Lung, and Blood Institute (U.S.), Polymorphism, Single Nucleotide, Proportional Hazards Models, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.107.153981}, author = {Shiffman, Dov and O{\textquoteright}Meara, Ellen S and Bare, Lance A and Rowland, Charles M and Louie, Judy Z and Arellano, Andre R and Lumley, Thomas and Rice, Kenneth and Iakoubova, Olga and Luke, May M and Young, Bradford A and Malloy, Mary J and Kane, John P and Ellis, Stephen G and Tracy, Russell P and Devlin, James J and Psaty, Bruce M} } @article {1007, title = {The relationship between exercise and risk of venous thrombosis in elderly people.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Mar}, pages = {517-22}, abstract = {

OBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.

DESIGN: Observational study with a median follow-up of 11.6 years.

SETTING: The Cardiovascular Health Study in four U.S. communities.

PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).

MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.

RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95\% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95\% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95\% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95\% CI=1.08-2.83) than no exercise at all.

CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.

}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Energy Metabolism, Exercise, Female, Humans, Male, Prevalence, Risk Factors, United States, Venous Thrombosis}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01588.x}, author = {van Stralen, Karlijn J and Doggen, Carine J M and Lumley, Thomas and Cushman, Mary and Folsom, Aaron R and Psaty, Bruce M and Siscovick, David and Rosendaal, Frits R and Heckbert, Susan R} } @article {1153, title = {Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {2}, year = {2009}, month = {2009 Apr}, pages = {125-33}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.108.825224}, author = {Dehghan, Abbas and Yang, Qiong and Peters, Annette and Basu, Saonli and Bis, Joshua C and Rudnicka, Alicja R and Kavousi, Maryam and Chen, Ming-Huei and Baumert, Jens and Lowe, Gordon D O and McKnight, Barbara and Tang, Weihong and de Maat, Moniek and Larson, Martin G and Eyhermendy, Susana and McArdle, Wendy L and Lumley, Thomas and Pankow, James S and Hofman, Albert and Massaro, Joseph M and Rivadeneira, Fernando and Kolz, Melanie and Taylor, Kent D and van Duijn, Cornelia M and Kathiresan, Sekar and Illig, Thomas and Aulchenko, Yurii S and Volcik, Kelly A and Johnson, Andrew D and Uitterlinden, Andr{\'e} G and Tofler, Geoffrey H and Gieger, Christian and Psaty, Bruce M and Couper, David J and Boerwinkle, Eric and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C and Strachan, David P and Smith, Nicholas L and Folsom, Aaron R} } @article {1087, title = {Common variants at ten loci influence QT interval duration in the QTGEN Study.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Apr}, pages = {399-406}, abstract = {

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.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Arrhythmias, Cardiac, Chromosome Mapping, Death, Sudden, Cardiac, Electroencephalography, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, KCNQ1 Potassium Channel, Meta-Analysis as Topic, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Risk Factors, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.364}, author = {Newton-Cheh, Christopher and Eijgelsheim, Mark and Rice, Kenneth M and de Bakker, Paul I W and Yin, Xiaoyan and Estrada, Karol and Bis, Joshua C and Marciante, Kristin and Rivadeneira, Fernando and Noseworthy, Peter A and Sotoodehnia, Nona and Smith, Nicholas L and Rotter, Jerome I and Kors, Jan A and Witteman, Jacqueline C M and Hofman, Albert and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Lumley, Thomas and Larson, Martin G and Stricker, Bruno H Ch} } @article {1064, title = {Gene variants associated with ischemic stroke: the cardiovascular health study.}, journal = {Stroke}, volume = {40}, year = {2009}, month = {2009 Feb}, pages = {363-8}, abstract = {

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.

METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).

RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90\% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90\% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10\% versus 6\%) and black (12\% versus 3\%) participants of CHS.

CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Coronary Disease, Ethnic Groups, European Continental Ancestry Group, Female, Gene Frequency, Genetic Variation, Humans, Kaplan-Meier Estimate, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.108.521328}, author = {Luke, May M and O{\textquoteright}Meara, Ellen S and Rowland, Charles M and Shiffman, Dov and Bare, Lance A and Arellano, Andre R and Longstreth, W T and Lumley, Thomas and Rice, Kenneth and Tracy, Russell P and Devlin, James J and Psaty, Bruce M} } @article {1108, title = {Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.}, journal = {JAMA}, volume = {302}, year = {2009}, month = {2009 Jul 08}, pages = {168-78}, abstract = {

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55\% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1\% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1\%-3\% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

}, keywords = {Adult, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Atria, Heart Ventricles, Humans, Male, Middle Aged, Organ Size, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1538-3598}, doi = {10.1001/jama.2009.978-a}, author = {Vasan, Ramachandran S and Glazer, Nicole L and Felix, Janine F and Lieb, Wolfgang and Wild, Philipp S and Felix, Stephan B and Watzinger, Norbert and Larson, Martin G and Smith, Nicholas L and Dehghan, Abbas and Grosshennig, Anika and Schillert, Arne and Teumer, Alexander and Schmidt, Reinhold and Kathiresan, Sekar and Lumley, Thomas and Aulchenko, Yurii S and K{\"o}nig, Inke R and Zeller, Tanja and Homuth, Georg and Struchalin, Maksim and Aragam, Jayashri and Bis, Joshua C and Rivadeneira, Fernando and Erdmann, Jeanette and Schnabel, Renate B and D{\"o}rr, Marcus and Zweiker, Robert and Lind, Lars and Rodeheffer, Richard J and Greiser, Karin Halina and Levy, Daniel and Haritunians, Talin and Deckers, Jaap W and Stritzke, Jan and Lackner, Karl J and V{\"o}lker, Uwe and Ingelsson, Erik and Kullo, Iftikhar and Haerting, Johannes and O{\textquoteright}Donnell, Christopher J and Heckbert, Susan R and Stricker, Bruno H and Ziegler, Andreas and Reffelmann, Thorsten and Redfield, Margaret M and Werdan, Karl and Mitchell, Gary F and Rice, Kenneth and Arnett, Donna K and Hofman, Albert and Gottdiener, John S and Uitterlinden, Andr{\'e} G and Meitinger, Thomas and Blettner, Maria and Friedrich, Nele and Wang, Thomas J and Psaty, Bruce M and van Duijn, Cornelia M and Wichmann, H-Erich and Munzel, Thomas F and Kroemer, Heyo K and Benjamin, Emelia J and Rotter, Jerome I and Witteman, Jacqueline C and Schunkert, Heribert and Schmidt, Helena and V{\"o}lzke, Henry and Blankenberg, Stefan} } @article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

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.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1098, title = {Genome-wide association study of blood pressure and hypertension.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {677-87}, abstract = {

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 {\texttimes} 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 {\texttimes} 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

}, keywords = {Blood Pressure, Cell Line, Chromosome Mapping, Chromosomes, Human, Diastole, Gene Expression Regulation, Genetic Association Studies, Genome-Wide Association Study, Humans, Hypertension, Liver, Lymphocytes, Meta-Analysis as Topic, Odds Ratio, Phenotype, Prevalence, Risk Assessment, Systole}, issn = {1546-1718}, doi = {10.1038/ng.384}, author = {Levy, Daniel and Ehret, Georg B and Rice, Kenneth and Verwoert, Germaine C and Launer, Lenore J and Dehghan, Abbas and Glazer, Nicole L and Morrison, Alanna C and Johnson, Andrew D and Aspelund, Thor and Aulchenko, Yurii and Lumley, Thomas and K{\"o}ttgen, Anna and Vasan, Ramachandran S and Rivadeneira, Fernando and Eiriksdottir, Gudny and Guo, Xiuqing and Arking, Dan E and Mitchell, Gary F and Mattace-Raso, Francesco U S and Smith, Albert V and Taylor, Kent and Scharpf, Robert B and Hwang, Shih-Jen and Sijbrands, Eric J G and Bis, Joshua and Harris, Tamara B and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Hofman, Albert and Rotter, Jerome I and Coresh, Josef and Benjamin, Emelia J and Uitterlinden, Andr{\'e} G and Heiss, Gerardo and Fox, Caroline S and Witteman, Jacqueline C M and Boerwinkle, Eric and Wang, Thomas J and Gudnason, Vilmundur and Larson, Martin G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M} } @article {1099, title = {Multiple loci associated with indices of renal function and chronic kidney disease.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {712-7}, abstract = {

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 {\texttimes} 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.

}, keywords = {Chromosome Mapping, Cohort Studies, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Meta-Analysis as Topic, Mucoproteins, Netherlands, Polymorphism, Single Nucleotide, Prevalence, Uromodulin}, issn = {1546-1718}, doi = {10.1038/ng.377}, author = {K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Hwang, Shih-Jen and Katz, Ronit and Li, Man and Yang, Qiong and Gudnason, Vilmundur and Launer, Lenore J and Harris, Tamara B and Smith, Albert V and Arking, Dan E and Astor, Brad C and Boerwinkle, Eric and Ehret, Georg B and Ruczinski, Ingo and Scharpf, Robert B and Chen, Yii-Der Ida and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Sarnak, Mark and Siscovick, David and Benjamin, Emelia J and Levy, Daniel and Upadhyay, Ashish and Aulchenko, Yurii S and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Chasman, Daniel I and Par{\'e}, Guillaume and Ridker, Paul M and Kao, W H Linda and Witteman, Jacqueline C and Coresh, Josef and Shlipak, Michael G and Fox, Caroline S} } @article {1141, title = {Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Nov}, pages = {1191-8}, abstract = {

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.

}, keywords = {Blood Pressure, Cell Line, Cohort Studies, Endothelial Cells, Erythrocytes, Gene Expression, Genome, Human, Genome-Wide Association Study, Humans, Hypertension, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.466}, author = {Ganesh, Santhi K and Zakai, Neil A and van Rooij, Frank J A and Soranzo, Nicole and Smith, Albert V and Nalls, Michael A and Chen, Ming-Huei and K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Kuhnel, Brigitte and Aspelund, Thor and Yang, Qiong and Tanaka, Toshiko and Jaffe, Andrew and Bis, Joshua C M and Verwoert, Germaine C and Teumer, Alexander and Fox, Caroline S and Guralnik, Jack M and Ehret, Georg B and Rice, Kenneth and Felix, Janine F and Rendon, Augusto and Eiriksdottir, Gudny and Levy, Daniel and Patel, Kushang V and Boerwinkle, Eric and Rotter, Jerome I and Hofman, Albert and Sambrook, Jennifer G and Hernandez, Dena G and Zheng, Gang and Bandinelli, Stefania and Singleton, Andrew B and Coresh, Josef and Lumley, Thomas and Uitterlinden, Andr{\'e} G and Vangils, Janine M and Launer, Lenore J and Cupples, L Adrienne and Oostra, Ben A and Zwaginga, Jaap-Jan and Ouwehand, Willem H and Thein, Swee-Lay and Meisinger, Christa and Deloukas, Panos and Nauck, Matthias and Spector, Tim D and Gieger, Christian and Gudnason, Vilmundur and van Duijn, Cornelia M and Psaty, Bruce M and Ferrucci, Luigi and Chakravarti, Aravinda and Greinacher, Andreas and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Furth, Susan and Cushman, Mary and Harris, Tamara B and Lin, Jing-Ping} } @article {1124, title = {Total and cause-specific mortality in the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1251-61}, abstract = {

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cause of Death, Chronic Disease, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Kaplan-Meier Estimate, Male, Probability, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp127}, author = {Newman, Anne B and Sachs, Michael C and Arnold, Alice M and Fried, Linda P and Kronmal, Richard and Cushman, Mary and Psaty, Bruce M and Harris, Tamara B and Robbins, John A and Burke, Gregory L and Kuller, Lewis H and Lumley, Thomas} } @article {1114, title = {Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Aug}, pages = {879-81}, abstract = {

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

}, keywords = {Atrial Fibrillation, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Meta-Analysis as Topic, Mutation, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.416}, author = {Benjamin, Emelia J and Rice, Kenneth M and Arking, Dan E and Pfeufer, Arne and van Noord, Charlotte and Smith, Albert V and Schnabel, Renate B and Bis, Joshua C and Boerwinkle, Eric and Sinner, Moritz F and Dehghan, Abbas and Lubitz, Steven A and D{\textquoteright}Agostino, Ralph B and Lumley, Thomas and Ehret, Georg B and Heeringa, Jan and Aspelund, Thor and Newton-Cheh, Christopher and Larson, Martin G and Marciante, Kristin D and Soliman, Elsayed Z and Rivadeneira, Fernando and Wang, Thomas J and Eiriksdottir, Gudny and Levy, Daniel and Psaty, Bruce M and Li, Man and Chamberlain, Alanna M and Hofman, Albert and Vasan, Ramachandran S and Harris, Tamara B and Rotter, Jerome I and Kao, W H Linda and Agarwal, Sunil K and Stricker, Bruno H Ch and Wang, Ke and Launer, Lenore J and Smith, Nicholas L and Chakravarti, Aravinda and Uitterlinden, Andr{\'e} G and Wolf, Philip A and Sotoodehnia, Nona and K{\"o}ttgen, Anna and van Duijn, Cornelia M and Meitinger, Thomas and Mueller, Martina and Perz, Siegfried and Steinbeck, Gerhard and Wichmann, H-Erich and Lunetta, Kathryn L and Heckbert, Susan R and Gudnason, Vilmundur and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Witteman, Jacqueline C M} } @article {1197, title = {Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {256-66}, abstract = {

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12\%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16\%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cohort Studies, Endopeptidases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heart Failure, Humans, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, Ubiquitin-Specific Proteases}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.895763}, author = {Smith, Nicholas L and Felix, Janine F and Morrison, Alanna C and Demissie, Serkalem and Glazer, Nicole L and Loehr, Laura R and Cupples, L Adrienne and Dehghan, Abbas and Lumley, Thomas and Rosamond, Wayne D and Lieb, Wolfgang and Rivadeneira, Fernando and Bis, Joshua C and Folsom, Aaron R and Benjamin, Emelia and Aulchenko, Yurii S and Haritunians, Talin and Couper, David and Murabito, Joanne and Wang, Ying A and Stricker, Bruno H and Gottdiener, John S and Chang, Patricia P and Wang, Thomas J and Rice, Kenneth M and Hofman, Albert and Heckbert, Susan R and Fox, Ervin R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Willerson, James T and Levy, Daniel and van Duijn, Cornelia M and Psaty, Bruce M and Witteman, Jacqueline C M and Boerwinkle, Eric and Vasan, Ramachandran S} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

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{\texttimes}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{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1199, title = {Genome-wide analysis of genetic loci associated with Alzheimer disease.}, journal = {JAMA}, volume = {303}, year = {2010}, month = {2010 May 12}, pages = {1832-40}, abstract = {

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.

}, keywords = {Age of Onset, Aged, Alzheimer Disease, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1538-3598}, doi = {10.1001/jama.2010.574}, author = {Seshadri, Sudha and Fitzpatrick, Annette L and Ikram, M Arfan and DeStefano, Anita L and Gudnason, Vilmundur and Boada, Merce and Bis, Joshua C and Smith, Albert V and Carassquillo, Minerva M and Lambert, Jean Charles and Harold, Denise and Schrijvers, Elisabeth M C and Ramirez-Lorca, Reposo and Debette, Stephanie and Longstreth, W T and Janssens, A Cecile J W and Pankratz, V Shane and Dartigues, Jean Fran{\c c}ois and Hollingworth, Paul and Aspelund, Thor and Hernandez, Isabel and Beiser, Alexa and Kuller, Lewis H and Koudstaal, Peter J and Dickson, Dennis W and Tzourio, Christophe and Abraham, Richard and Antunez, Carmen and Du, Yangchun and Rotter, Jerome I and Aulchenko, Yurii S and Harris, Tamara B and Petersen, Ronald C and Berr, Claudine and Owen, Michael J and Lopez-Arrieta, Jesus and Varadarajan, Badri N and Becker, James T and Rivadeneira, Fernando and Nalls, Michael A and Graff-Radford, Neill R and Campion, Dominique and Auerbach, Sanford and Rice, Kenneth and Hofman, Albert and Jonsson, Palmi V and Schmidt, Helena and Lathrop, Mark and Mosley, Thomas H and Au, Rhoda and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and Farrer, Lindsay A and Lumley, Thomas and Ruiz, Agustin and Williams, Julie and Amouyel, Philippe and Younkin, Steve G and Wolf, Philip A and Launer, Lenore J and Lopez, Oscar L and van Duijn, Cornelia M and Breteler, Monique M B} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1187, title = {Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {248-55}, abstract = {

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

}, keywords = {African Americans, Aged, Aged, 80 and over, Chemokines, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Failure, Humans, Introns, Male, MARVEL Domain-Containing Proteins, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.895995}, author = {Morrison, Alanna C and Felix, Janine F and Cupples, L Adrienne and Glazer, Nicole L and Loehr, Laura R and Dehghan, Abbas and Demissie, Serkalem and Bis, Joshua C and Rosamond, Wayne D and Aulchenko, Yurii S and Wang, Ying A and Haritunians, Talin and Folsom, Aaron R and Rivadeneira, Fernando and Benjamin, Emelia J and Lumley, Thomas and Couper, David and Stricker, Bruno H and O{\textquoteright}Donnell, Christopher J and Rice, Kenneth M and Chang, Patricia P and Hofman, Albert and Levy, Daniel and Rotter, Jerome I and Fox, Ervin R and Uitterlinden, Andr{\'e} G and Wang, Thomas J and Psaty, Bruce M and Willerson, James T and van Duijn, Cornelia M and Boerwinkle, Eric and Witteman, Jacqueline C M and Vasan, Ramachandran S and Smith, Nicholas L} } @article {1150, title = {Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Jan}, pages = {45-52}, abstract = {

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

}, keywords = {Databases, Genetic, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung, Lung Diseases, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.500}, author = {Hancock, Dana B and Eijgelsheim, Mark and Wilk, Jemma B and Gharib, Sina A and Loehr, Laura R and Marciante, Kristin D and Franceschini, Nora and van Durme, Yannick M T A and Chen, Ting-Hsu and Barr, R Graham and Schabath, Matthew B and Couper, David J and Brusselle, Guy G and Psaty, Bruce M and van Duijn, Cornelia M and Rotter, Jerome I and Uitterlinden, Andr{\'e} G and Hofman, Albert and Punjabi, Naresh M and Rivadeneira, Fernando and Morrison, Alanna C and Enright, Paul L and North, Kari E and Heckbert, Susan R and Lumley, Thomas and Stricker, Bruno H C and O{\textquoteright}Connor, George T and London, Stephanie J} } @article {1179, title = {A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 May}, pages = {478-87}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Cohort Studies, Confidence Intervals, Female, Genome-Wide Association Study, Genotype, Humans, Longevity, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1758-535X}, doi = {10.1093/gerona/glq028}, author = {Newman, Anne B and Walter, Stefan and Lunetta, Kathryn L and Garcia, Melissa E and Slagboom, P Eline and Christensen, Kaare and Arnold, Alice M and Aspelund, Thor and Aulchenko, Yurii S and Benjamin, Emelia J and Christiansen, Lene and D{\textquoteright}Agostino, Ralph B and Fitzpatrick, Annette L and Franceschini, Nora and Glazer, Nicole L and Gudnason, Vilmundur and Hofman, Albert and Kaplan, Robert and Karasik, David and Kelly-Hayes, Margaret and Kiel, Douglas P and Launer, Lenore J and Marciante, Kristin D and Massaro, Joseph M and Miljkovic, Iva and Nalls, Michael A and Hernandez, Dena and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome and Seshadri, Sudha and Smith, Albert V and Taylor, Kent D and Tiemeier, Henning and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vaupel, James W and Walston, Jeremy and Westendorp, Rudi G J and Harris, Tamara B and Lumley, Thomas and van Duijn, Cornelia M and Murabito, Joanne M} } @article {1235, title = {Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Dec}, pages = {523-30}, abstract = {

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{\textquoteright}s Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4{\texttimes}10(-8) to 2{\texttimes}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{\texttimes}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{\textquoteright}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.

}, keywords = {Cardiovascular Diseases, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Gout, Humans, Male, Risk Factors, Uric Acid}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.934455}, author = {Yang, Qiong and K{\"o}ttgen, Anna and Dehghan, Abbas and Smith, Albert V and Glazer, Nicole L and Chen, Ming-Huei and Chasman, Daniel I and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore and Nalls, Michael and Hernandez, Dena and Arking, Dan E and Boerwinkle, Eric and Grove, Megan L and Li, Man and Linda Kao, W H and Chonchol, Michel and Haritunians, Talin and Li, Guo and Lumley, Thomas and Psaty, Bruce M and Shlipak, Michael and Hwang, Shih-Jen and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Upadhyay, Ashish and van Duijn, Cornelia M and Hofman, Albert and Rivadeneira, Fernando and Stricker, Bruno and Uitterlinden, Andr{\'e} G and Par{\'e}, Guillaume and Parker, Alex N and Ridker, Paul M and Siscovick, David S and Gudnason, Vilmundur and Witteman, Jacqueline C and Fox, Caroline S and Coresh, Josef} } @article {1183, title = {New loci associated with kidney function and chronic kidney disease.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 May}, pages = {376-84}, abstract = {

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.

}, keywords = {Cohort Studies, Creatinine, Cystatin C, Diet, Europe, Genetic Markers, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Models, Genetic, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.568}, author = {K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Glazer, Nicole L and Parsa, Afshin and Gao, Xiaoyi and Yang, Qiong and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Li, Man and Schmidt, Helena and Tanaka, Toshiko and Isaacs, Aaron and Ketkar, Shamika and Hwang, Shih-Jen and Johnson, Andrew D and Dehghan, Abbas and Teumer, Alexander and Par{\'e}, Guillaume and Atkinson, Elizabeth J and Zeller, Tanja and Lohman, Kurt and Cornelis, Marilyn C and Probst-Hensch, Nicole M and Kronenberg, Florian and T{\"o}njes, Anke and Hayward, Caroline and Aspelund, Thor and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Rampersaud, Evadnie and Mitchell, Braxton D and Arking, Dan E and Boerwinkle, Eric and Struchalin, Maksim and Cavalieri, Margherita and Singleton, Andrew and Giallauria, Francesco and Metter, Jeffrey and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Siscovick, David and Psaty, Bruce M and Zillikens, M Carola and Oostra, Ben A and Feitosa, Mary and Province, Michael and de Andrade, Mariza and Turner, Stephen T and Schillert, Arne and Ziegler, Andreas and Wild, Philipp S and Schnabel, Renate B and Wilde, Sandra and Munzel, Thomas F and Leak, Tennille S and Illig, Thomas and Klopp, Norman and Meisinger, Christa and Wichmann, H-Erich and Koenig, Wolfgang and Zgaga, Lina and Zemunik, Tatijana and Kolcic, Ivana and Minelli, Cosetta and Hu, Frank B and Johansson, Asa and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and Schreiber, Stefan and Aulchenko, Yurii S and Felix, Janine F and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Imboden, Medea and Nitsch, Dorothea and Brandst{\"a}tter, Anita and Kollerits, Barbara and Kedenko, Lyudmyla and M{\"a}gi, Reedik and Stumvoll, Michael and Kovacs, Peter and Boban, Mladen and Campbell, Susan and Endlich, Karlhans and V{\"o}lzke, Henry and Kroemer, Heyo K and Nauck, Matthias and V{\"o}lker, Uwe and Polasek, Ozren and Vitart, Veronique and Badola, Sunita and Parker, Alexander N and Ridker, Paul M and Kardia, Sharon L R and Blankenberg, Stefan and Liu, Yongmei and Curhan, Gary C and Franke, Andre and Rochat, Thierry and Paulweber, Bernhard and Prokopenko, Inga and Wang, Wei and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Shlipak, Michael G and van Duijn, Cornelia M and Borecki, Ingrid and Kr{\"a}mer, Bernhard K and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Witteman, Jacqueline C and Pramstaller, Peter P and Rettig, Rainer and Hastie, Nick and Chasman, Daniel I and Kao, W H and Heid, Iris M and Fox, Caroline S} } @article {1176, title = {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.}, journal = {Circulation}, volume = {121}, year = {2010}, month = {2010 Mar 30}, pages = {1382-92}, abstract = {

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.

}, keywords = {Adult, Factor VII, Factor VIII, Female, Genome-Wide Association Study, Hemostasis, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Thrombosis, von Willebrand Factor}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.869156}, author = {Smith, Nicholas L and Chen, Ming-Huei and Dehghan, Abbas and Strachan, David P and Basu, Saonli and Soranzo, Nicole and Hayward, Caroline and Rudan, Igor and Sabater-Lleal, Maria and Bis, Joshua C and de Maat, Moniek P M and Rumley, Ann and Kong, Xiaoxiao and Yang, Qiong and Williams, Frances M K and Vitart, Veronique and Campbell, Harry and M{\"a}larstig, Anders and Wiggins, Kerri L and van Duijn, Cornelia M and McArdle, Wendy L and Pankow, James S and Johnson, Andrew D and Silveira, Angela and McKnight, Barbara and Uitterlinden, Andr{\'e} G and Aleksic, Nena and Meigs, James B and Peters, Annette and Koenig, Wolfgang and Cushman, Mary and Kathiresan, Sekar and Rotter, Jerome I and Bovill, Edwin G and Hofman, Albert and Boerwinkle, Eric and Tofler, Geoffrey H and Peden, John F and Psaty, Bruce M and Leebeek, Frank and Folsom, Aaron R and Larson, Martin G and Spector, Timothy D and Wright, Alan F and Wilson, James F and Hamsten, Anders and Lumley, Thomas and Witteman, Jacqueline C M and Tang, Weihong and O{\textquoteright}Donnell, Christopher J} } @article {1275, title = {Cerivastatin, genetic variants, and the risk of rhabdomyolysis.}, journal = {Pharmacogenet Genomics}, volume = {21}, year = {2011}, month = {2011 May}, pages = {280-8}, abstract = {

OBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.

METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.

RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95\% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40\% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95\% confidence interval: 0.36-0.63).

CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

}, keywords = {Adult, Aged, Aged, 80 and over, Aryl Hydrocarbon Hydroxylases, Case-Control Studies, Cytochrome P-450 CYP2C8, Female, Genetic Variation, Genome-Wide Association Study, Glucuronosyltransferase, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Organic Anion Transporters, Polymorphism, Single Nucleotide, Pyridines, Rhabdomyolysis, Risk, Ryanodine Receptor Calcium Release Channel, Solute Carrier Organic Anion Transporter Family Member 1b1}, issn = {1744-6880}, doi = {10.1097/FPC.0b013e328343dd7d}, author = {Marciante, Kristin D and Durda, Jon P and Heckbert, Susan R and Lumley, Thomas and Rice, Ken and McKnight, Barbara and Totah, Rheem A and Tamraz, Bani and Kroetz, Deanna L and Fukushima, Hisayo and Kaspera, R{\"u}diger and Bis, Joshua C and Glazer, Nicole L and Li, Guo and Austin, Thomas R and Taylor, Kent D and Rotter, Jerome I and Jaquish, Cashell E and Kwok, Pui-Yan and Tracy, Russell P and Psaty, Bruce M} } @article {1271, title = {CUBN is a gene locus for albuminuria.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Mar}, pages = {555-70}, abstract = {

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 {\texttimes} 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.

}, keywords = {African Continental Ancestry Group, Albuminuria, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Humans, Mutation, Missense, Receptors, Cell Surface}, issn = {1533-3450}, doi = {10.1681/ASN.2010060598}, author = {B{\"o}ger, Carsten A and Chen, Ming-Huei and Tin, Adrienne and Olden, Matthias and K{\"o}ttgen, Anna and de Boer, Ian H and Fuchsberger, Christian and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and Teumer, Alexander and Liu, Ching-Ti and Glazer, Nicole L and Li, Man and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Peralta, Carmen A and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Zhao, Jing Hua and Hwang, Shih-Jen and Akylbekova, Ermeg and Kramer, Holly and van der Harst, Pim and Smith, Albert V and Lohman, Kurt and de Andrade, Mariza and Hayward, Caroline and Kollerits, Barbara and T{\"o}njes, Anke and Aspelund, Thor and Ingelsson, Erik and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Shuldiner, Alan R and Mitchell, Braxton D and Arking, Dan E and Franceschini, Nora and Boerwinkle, Eric and Egan, Josephine and Hernandez, Dena and Reilly, Muredach and Townsend, Raymond R and Lumley, Thomas and Siscovick, David S and Psaty, Bruce M and Kestenbaum, Bryan and Haritunians, Talin and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Mooser, Vincent and Waterworth, Dawn and Johnson, Andrew D and Florez, Jose C and Meigs, James B and Lu, Xiaoning and Turner, Stephen T and Atkinson, Elizabeth J and Leak, Tennille S and Aasar{\o}d, Knut and Skorpen, Frank and Syv{\"a}nen, Ann-Christine and Illig, Thomas and Baumert, Jens and Koenig, Wolfgang and Kr{\"a}mer, Bernhard K and Devuyst, Olivier and Mychaleckyj, Josyf C and Minelli, Cosetta and Bakker, Stephan J L and Kedenko, Lyudmyla and Paulweber, Bernhard and Coassin, Stefan and Endlich, Karlhans and Kroemer, Heyo K and Biffar, Reiner and Stracke, Sylvia and V{\"o}lzke, Henry and Stumvoll, Michael and M{\"a}gi, Reedik and Campbell, Harry and Vitart, Veronique and Hastie, Nicholas D and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Polasek, Ozren and Curhan, Gary and Kronenberg, Florian and Prokopenko, Inga and Rudan, Igor and Arnl{\"o}v, Johan and Hallan, Stein and Navis, Gerjan and Parsa, Afshin and Ferrucci, Luigi and Coresh, Josef and Shlipak, Michael G and Bull, Shelley B and Paterson, Nicholas J and Wichmann, H-Erich and Wareham, Nicholas J and Loos, Ruth J F and Rotter, Jerome I and Pramstaller, Peter P and Cupples, L Adrienne and Beckmann, Jacques S and Yang, Qiong and Heid, Iris M and Rettig, Rainer and Dreisbach, Albert W and Bochud, Murielle and Fox, Caroline S and Kao, W H L} } @article {1311, title = {Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jul}, pages = {e1002193}, abstract = {

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10$^{-}$$^{6}$$^{4}$) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10$^{-}$$^{5}$$^{8}$) and docosapentaenoic acid (DPA, p = 4 x 10$^{-}${\textonesuperior}$^{5}$$^{4}$). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10$^{-}${\textonesuperior}{\texttwosuperior}) and DPA (p = 1 x 10$^{-}$$^{4}${\textthreesuperior}) and lower docosahexaenoic acid (DHA, p = 1 x 10$^{-}${\textonesuperior}$^{5}$). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10$^{-}$$^{8}$). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

}, keywords = {Alleles, Continental Population Groups, Fatty Acids, Omega-3, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002193}, author = {Lemaitre, Rozenn N and Tanaka, Toshiko and Tang, Weihong and Manichaikul, Ani and Foy, Millennia and Kabagambe, Edmond K and Nettleton, Jennifer A and King, Irena B and Weng, Lu-Chen and Bhattacharya, Sayanti and Bandinelli, Stefania and Bis, Joshua C and Rich, Stephen S and Jacobs, David R and Cherubini, Antonio and McKnight, Barbara and Liang, Shuang and Gu, Xiangjun and Rice, Kenneth and Laurie, Cathy C and Lumley, Thomas and Browning, Brian L and Psaty, Bruce M and Chen, Yii-der I and Friedlander, Yechiel and Djouss{\'e}, Luc and Wu, Jason H Y and Siscovick, David S and Uitterlinden, Andr{\'e} G and Arnett, Donna K and Ferrucci, Luigi and Fornage, Myriam and Tsai, Michael Y and Mozaffarian, Dariush and Steffen, Lyn M} } @article {1284, title = {Genetic predictors of fibrin D-dimer levels in healthy adults.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 May 03}, pages = {1864-72}, abstract = {

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{\textendash}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{\texttimes}10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4{\texttimes}10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9{\texttimes}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{\textendash}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.

}, keywords = {Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.009480}, author = {Smith, Nicholas L and Huffman, Jennifer E and Strachan, David P and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C and Wild, Sarah H and Rumley, Ann and Yang, Qiong and Uitterlinden, Andr{\'e} G and Stott, David J and Davies, Gail and Carter, Angela M and Thorand, Barbara and Polasek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R and Chen, Ming-Huei and Buckley, Brendan M and Harris, Sarah E and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J M and Liewald, David C and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J and Luciano, Michelle and Porteous, David J and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P Eline and Visscher, Peter M and Spector, Tim D and Illig, Thomas and Rudan, Igor and Bovill, Edwin G and Wright, Alan F and McArdle, Wendy L and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G J and Starr, John M and Grant, Peter J and Karakas, Mahir and Hastie, Nicholas D and Psaty, Bruce M and Wilson, James F and Lowe, Gordon D O and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Jukema, J Wouter and Deary, Ian J and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline} } @article {6096, title = {Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 25}, pages = {1082-90}, abstract = {

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 {\texttimes} 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

}, keywords = {Child, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests}, issn = {1546-1718}, doi = {10.1038/ng.941}, author = {Soler Artigas, Maria and Loth, Daan W and Wain, Louise V and Gharib, Sina A and Obeidat, Ma{\textquoteright}en and Tang, Wenbo and Zhai, Guangju and Zhao, Jing Hua and Smith, Albert Vernon and Huffman, Jennifer E and Albrecht, Eva and Jackson, Catherine M and Evans, David M and Cadby, Gemma and Fornage, Myriam and Manichaikul, Ani and Lopez, Lorna M and Johnson, Toby and Aldrich, Melinda C and Aspelund, Thor and Barroso, In{\^e}s and Campbell, Harry and Cassano, Patricia A and Couper, David J and Eiriksdottir, Gudny and Franceschini, Nora and Garcia, Melissa and Gieger, Christian and Gislason, Gauti Kjartan and Grkovic, Ivica and Hammond, Christopher J and Hancock, Dana B and Harris, Tamara B and Ramasamy, Adaikalavan and Heckbert, Susan R and Heli{\"o}vaara, Markku and Homuth, Georg and Hysi, Pirro G and James, Alan L and Jankovic, Stipan and Joubert, Bonnie R and Karrasch, Stefan and Klopp, Norman and Koch, Beate and Kritchevsky, Stephen B and Launer, Lenore J and Liu, Yongmei and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Lumley, Thomas and Al Balushi, Khalid A and Ang, Wei Q and Barr, R Graham and Beilby, John and Blakey, John D and Boban, Mladen and Boraska, Vesna and Brisman, Jonas and Britton, John R and Brusselle, Guy G and Cooper, Cyrus and Curjuric, Ivan and Dahgam, Santosh and Deary, Ian J and Ebrahim, Shah and Eijgelsheim, Mark and Francks, Clyde and Gaysina, Darya and Granell, Raquel and Gu, Xiangjun and Hankinson, John L and Hardy, Rebecca and Harris, Sarah E and Henderson, John and Henry, Amanda and Hingorani, Aroon D and Hofman, Albert and Holt, Patrick G and Hui, Jennie and Hunter, Michael L and Imboden, Medea and Jameson, Karen A and Kerr, Shona M and Kolcic, Ivana and Kronenberg, Florian and Liu, Jason Z and Marchini, Jonathan and McKeever, Tricia and Morris, Andrew D and Olin, Anna-Carin and Porteous, David J and Postma, Dirkje S and Rich, Stephen S and Ring, Susan M and Rivadeneira, Fernando and Rochat, Thierry and Sayer, Avan Aihie and Sayers, Ian and Sly, Peter D and Smith, George Davey and Sood, Akshay and Starr, John M and Uitterlinden, Andr{\'e} G and Vonk, Judith M and Wannamethee, S Goya and Whincup, Peter H and Wijmenga, Cisca and Williams, O Dale and Wong, Andrew and Mangino, Massimo and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and North, Kari E and Omenaas, Ernst and Palmer, Lyle J and Pietil{\"a}inen, Kirsi H and Pin, Isabelle and Pola Sbreve Ek, Ozren and Pouta, Anneli and Psaty, Bruce M and Hartikainen, Anna-Liisa and Rantanen, Taina and Ripatti, Samuli and Rotter, Jerome I and Rudan, Igor and Rudnicka, Alicja R and Schulz, Holger and Shin, So-Youn and Spector, Tim D and Surakka, Ida and Vitart, Veronique and V{\"o}lzke, Henry and Wareham, Nicholas J and Warrington, Nicole M and Wichmann, H-Erich and Wild, Sarah H and Wilk, Jemma B and Wjst, Matthias and Wright, Alan F and Zgaga, Lina and Zemunik, Tatijana and Pennell, Craig E and Nyberg, Fredrik and Kuh, Diana and Holloway, John W and Boezen, H Marike and Lawlor, Debbie A and Morris, Richard W and Probst-Hensch, Nicole and Kaprio, Jaakko and Wilson, James F and Hayward, Caroline and K{\"a}h{\"o}nen, Mika and Heinrich, Joachim and Musk, Arthur W and Jarvis, Deborah L and Gl{\"a}ser, Sven and Jarvelin, Marjo-Riitta and Ch Stricker, Bruno H and Elliott, Paul and O{\textquoteright}Connor, George T and Strachan, David P and London, Stephanie J and Hall, Ian P and Gudnason, Vilmundur and Tobin, Martin D} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

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 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 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.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {1289, title = {Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Jul}, pages = {1851-6}, abstract = {

BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke.

METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95\% confidence intervals (95\% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure.

RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95\% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95\% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95\% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95\% CI, 1.6 to 3.4).

CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.

}, keywords = {Bacterial Infections, Brain Ischemia, Cardiology, Cohort Studies, Cross-Over Studies, Female, Follow-Up Studies, Hospitalization, Humans, Male, Odds Ratio, Proportional Hazards Models, Regression Analysis, Risk, Stroke, Time Factors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.110.608588}, author = {Elkind, Mitchell S V and Carty, Cara L and O{\textquoteright}Meara, Ellen S and Lumley, Thomas and Lefkowitz, David and Kronmal, Richard A and Longstreth, W T} } @article {1355, title = {New gene functions in megakaryopoiesis and platelet formation.}, journal = {Nature}, volume = {480}, year = {2011}, month = {2011 Nov 30}, pages = {201-8}, abstract = {

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.

}, keywords = {Animals, Blood Platelets, Cell Size, Drosophila melanogaster, Drosophila Proteins, Europe, Gene Expression Profiling, Gene Silencing, Genome, Human, Genome-Wide Association Study, Hematopoiesis, Humans, Megakaryocytes, Platelet Count, Protein Interaction Maps, Transcription, Genetic, Zebrafish, Zebrafish Proteins}, issn = {1476-4687}, doi = {10.1038/nature10659}, author = {Gieger, Christian and Radhakrishnan, Aparna and Cvejic, Ana and Tang, Weihong and Porcu, Eleonora and Pistis, Giorgio and Serbanovic-Canic, Jovana and Elling, Ulrich and Goodall, Alison H and Labrune, Yann and Lopez, Lorna M and M{\"a}gi, Reedik and Meacham, Stuart and Okada, Yukinori and Pirastu, Nicola and Sorice, Rossella and Teumer, Alexander and Voss, Katrin and Zhang, Weihua and Ramirez-Solis, Ramiro and Bis, Joshua C and Ellinghaus, David and G{\"o}gele, Martin and Hottenga, Jouke-Jan and Langenberg, Claudia and Kovacs, Peter and O{\textquoteright}Reilly, Paul F and Shin, So-Youn and Esko, T{\~o}nu and Hartiala, Jaana and Kanoni, Stavroula and Murgia, Federico and Parsa, Afshin and Stephens, Jonathan and van der Harst, Pim and Ellen van der Schoot, C and Allayee, Hooman and Attwood, Antony and Balkau, Beverley and Bastardot, Fran{\c c}ois and Basu, Saonli and Baumeister, Sebastian E and Biino, Ginevra and Bomba, Lorenzo and Bonnefond, Am{\'e}lie and Cambien, Francois and Chambers, John C and Cucca, Francesco and D{\textquoteright}Adamo, Pio and Davies, Gail and de Boer, Rudolf A and de Geus, Eco J C and D{\"o}ring, Angela and Elliott, Paul and Erdmann, Jeanette and Evans, David M and Falchi, Mario and Feng, Wei and Folsom, Aaron R and Frazer, Ian H and Gibson, Quince D and Glazer, Nicole L and Hammond, Chris and Hartikainen, Anna-Liisa and Heckbert, Susan R and Hengstenberg, Christian and Hersch, Micha and Illig, Thomas and Loos, Ruth J F and Jolley, Jennifer and Khaw, Kay Tee and Kuhnel, Brigitte and Kyrtsonis, Marie-Christine and Lagou, Vasiliki and Lloyd-Jones, Heather and Lumley, Thomas and Mangino, Massimo and Maschio, Andrea and Mateo Leach, Irene and McKnight, Barbara and Memari, Yasin and Mitchell, Braxton D and Montgomery, Grant W and Nakamura, Yusuke and Nauck, Matthias and Navis, Gerjan and N{\"o}thlings, Ute and Nolte, Ilja M and Porteous, David J and Pouta, Anneli and Pramstaller, Peter P and Pullat, Janne and Ring, Susan M and Rotter, Jerome I and Ruggiero, Daniela and Ruokonen, Aimo and Sala, Cinzia and Samani, Nilesh J and Sambrook, Jennifer and Schlessinger, David and Schreiber, Stefan and Schunkert, Heribert and Scott, James and Smith, Nicholas L and Snieder, Harold and Starr, John M and Stumvoll, Michael and Takahashi, Atsushi and Tang, W H Wilson and Taylor, Kent and Tenesa, Albert and Lay Thein, Swee and T{\"o}njes, Anke and Uda, Manuela and Ulivi, Sheila and van Veldhuisen, Dirk J and Visscher, Peter M and V{\"o}lker, Uwe and Wichmann, H-Erich and Wiggins, Kerri L and Willemsen, Gonneke and Yang, Tsun-Po and Hua Zhao, Jing and Zitting, Paavo and Bradley, John R and Dedoussis, George V and Gasparini, Paolo and Hazen, Stanley L and Metspalu, Andres and Pirastu, Mario and Shuldiner, Alan R and Joost van Pelt, L and Zwaginga, Jaap-Jan and Boomsma, Dorret I and Deary, Ian J and Franke, Andre and Froguel, Philippe and Ganesh, Santhi K and Jarvelin, Marjo-Riitta and Martin, Nicholas G and Meisinger, Christa and Psaty, Bruce M and Spector, Timothy D and Wareham, Nicholas J and Akkerman, Jan-Willem N and Ciullo, Marina and Deloukas, Panos and Greinacher, Andreas and Jupe, Steve and Kamatani, Naoyuki and Khadake, Jyoti and Kooner, Jaspal S and Penninger, Josef and Prokopenko, Inga and Stemple, Derek and Toniolo, Daniela and Wernisch, Lorenz and Sanna, Serena and Hicks, Andrew A and Rendon, Augusto and Ferreira, Manuel A and Ouwehand, Willem H and Soranzo, Nicole} } @article {6092, title = {Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.}, journal = {Am J Respir Crit Care Med}, volume = {186}, year = {2012}, month = {2012 Oct 01}, pages = {622-32}, abstract = {

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

}, keywords = {Aged, Female, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Receptors, Nicotinic, Receptors, Serotonin, 5-HT4, Smoking, Vital Capacity}, issn = {1535-4970}, doi = {10.1164/rccm.201202-0366OC}, author = {Wilk, Jemma B and Shrine, Nick R G and Loehr, Laura R and Zhao, Jing Hua and Manichaikul, Ani and Lopez, Lorna M and Smith, Albert Vernon and Heckbert, Susan R and Smolonska, Joanna and Tang, Wenbo and Loth, Daan W and Curjuric, Ivan and Hui, Jennie and Cho, Michael H and Latourelle, Jeanne C and Henry, Amanda P and Aldrich, Melinda and Bakke, Per and Beaty, Terri H and Bentley, Amy R and Borecki, Ingrid B and Brusselle, Guy G and Burkart, Kristin M and Chen, Ting-Hsu and Couper, David and Crapo, James D and Davies, Gail and Dupuis, Jos{\'e}e and Franceschini, Nora and Gulsvik, Amund and Hancock, Dana B and Harris, Tamara B and Hofman, Albert and Imboden, Medea and James, Alan L and Khaw, Kay-Tee and Lahousse, Lies and Launer, Lenore J and Litonjua, Augusto and Liu, Yongmei and Lohman, Kurt K and Lomas, David A and Lumley, Thomas and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and Musk, Arthur W and Myers, Richard H and North, Kari E and Postma, Dirkje S and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Rochat, Thierry and Rotter, Jerome I and Soler Artigas, Maria and Starr, John M and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Wijmenga, Cisca and Zanen, Pieter and Province, Michael A and Silverman, Edwin K and Deary, Ian J and Palmer, Lyle J and Cassano, Patricia A and Gudnason, Vilmundur and Barr, R Graham and Loos, Ruth J F and Strachan, David P and London, Stephanie J and Boezen, H Marike and Probst-Hensch, Nicole and Gharib, Sina A and Hall, Ian P and O{\textquoteright}Connor, George T and Tobin, Martin D and Stricker, Bruno H} } @article {6088, title = {Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003098}, abstract = {

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00{\texttimes}10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35{\texttimes}10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28{\texttimes}10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

}, keywords = {Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, Smoking, SOX9 Transcription Factor, Vital Capacity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003098}, author = {Hancock, Dana B and Soler Artigas, Maria and Gharib, Sina A and Henry, Amanda and Manichaikul, Ani and Ramasamy, Adaikalavan and Loth, Daan W and Imboden, Medea and Koch, Beate and McArdle, Wendy L and Smith, Albert V and Smolonska, Joanna and Sood, Akshay and Tang, Wenbo and Wilk, Jemma B and Zhai, Guangju and Zhao, Jing Hua and Aschard, Hugues and Burkart, Kristin M and Curjuric, Ivan and Eijgelsheim, Mark and Elliott, Paul and Gu, Xiangjun and Harris, Tamara B and Janson, Christer and Homuth, Georg and Hysi, Pirro G and Liu, Jason Z and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Manning, Alisa K and Marciante, Kristin D and Obeidat, Ma{\textquoteright}en and Postma, Dirkje S and Aldrich, Melinda C and Brusselle, Guy G and Chen, Ting-Hsu and Eiriksdottir, Gudny and Franceschini, Nora and Heinrich, Joachim and Rotter, Jerome I and Wijmenga, Cisca and Williams, O Dale and Bentley, Amy R and Hofman, Albert and Laurie, Cathy C and Lumley, Thomas and Morrison, Alanna C and Joubert, Bonnie R and Rivadeneira, Fernando and Couper, David J and Kritchevsky, Stephen B and Liu, Yongmei and Wjst, Matthias and Wain, Louise V and Vonk, Judith M and Uitterlinden, Andr{\'e} G and Rochat, Thierry and Rich, Stephen S and Psaty, Bruce M and O{\textquoteright}Connor, George T and North, Kari E and Mirel, Daniel B and Meibohm, Bernd and Launer, Lenore J and Khaw, Kay-Tee and Hartikainen, Anna-Liisa and Hammond, Christopher J and Gl{\"a}ser, Sven and Marchini, Jonathan and Kraft, Peter and Wareham, Nicholas J and V{\"o}lzke, Henry and Stricker, Bruno H C and Spector, Timothy D and Probst-Hensch, Nicole M and Jarvis, Deborah and Jarvelin, Marjo-Riitta and Heckbert, Susan R and Gudnason, Vilmundur and Boezen, H Marike and Barr, R Graham and Cassano, Patricia A and Strachan, David P and Fornage, Myriam and Hall, Ian P and Dupuis, Jos{\'e}e and Tobin, Martin D and London, Stephanie J} } @article {1403, title = {Transforming growth factor beta-1 and incidence of heart failure in older adults: the Cardiovascular Health Study.}, journal = {Cytokine}, volume = {60}, year = {2012}, month = {2012 Nov}, pages = {341-5}, abstract = {

CONTEXT: Transforming growth factor-beta1 (TGF-B1) is a highly pleiotropic cytokine whose functions include a central role in the induction of fibrosis.

OBJECTIVE: To investigate the hypothesis that elevated plasma levels of TGF-B1 are positively associated with incident heart failure (HF).

PARTICIPANTS AND METHODS: The hypotheses were tested using a two-phase case-control study design, ancillary to the Cardiovascular Health Study - a longitudinal, population-based cohort study. Cases were defined as having an incident HF event after their 1992-1993 exam and controls were free of HF at follow-up. TGF-B1 was measured using plasma collected in 1992-1993 and data from 89 cases and 128 controls were used for analysis. The association between TGF-B1 and risk of HF was evaluated using the weighted likelihood method, and odds ratios (OR) for risk of HF were calculated for TGF-B1 as a continuous linear variable and across quartiles of TGF-B1.

RESULTS: The OR for HF was 1.88 (95\% confidence intervals [CI] 1.26-2.81) for each nanogram increase in TGF-B1, and the OR for the highest quartile (compared to the lowest) of TGF-B1 was 5.79 (95\% CI 1.65-20.34), after adjustment for age, sex, C-reactive protein, platelet count and digoxin use. Further adjustment with other covariates did not change the results.

CONCLUSIONS: Higher levels of plasma TGF-B1 were associated with an increased risk of incident heart failure among older adults. However, further study is needed in larger samples to confirm these findings.

}, keywords = {Aged, Case-Control Studies, Health, Heart Failure, Humans, Incidence, Transforming Growth Factor beta1, United States}, issn = {1096-0023}, doi = {10.1016/j.cyto.2012.07.013}, author = {Glazer, Nicole L and Macy, Elizabeth M and Lumley, Thomas and Smith, Nicholas L and Reiner, Alex P and Psaty, Bruce M and King, George L and Tracy, Russell P and Siscovick, David S} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

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{\texttimes}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{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6029, title = {A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.}, journal = {Genet Epidemiol}, volume = {37}, year = {2013}, month = {2013 Jul}, pages = {512-521}, abstract = {

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P <= 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 {\texttimes} 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 {\texttimes} 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

}, keywords = {Aged, Aging, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, Venous Thromboembolism}, issn = {1098-2272}, doi = {10.1002/gepi.21731}, author = {Tang, Weihong and Teichert, Martina and Chasman, Daniel I and Heit, John A and Morange, Pierre-Emmanuel and Li, Guo and Pankratz, Nathan and Leebeek, Frank W and Par{\'e}, Guillaume and de Andrade, Mariza and Tzourio, Christophe and Psaty, Bruce M and Basu, Saonli and Ruiter, Rikje and Rose, Lynda and Armasu, Sebastian M and Lumley, Thomas and Heckbert, Susan R and Uitterlinden, Andr{\'e} G and Lathrop, Mark and Rice, Kenneth M and Cushman, Mary and Hofman, Albert and Lambert, Jean-Charles and Glazer, Nicole L and Pankow, James S and Witteman, Jacqueline C and Amouyel, Philippe and Bis, Joshua C and Bovill, Edwin G and Kong, Xiaoxiao and Tracy, Russell P and Boerwinkle, Eric and Rotter, Jerome I and Tr{\'e}gou{\"e}t, David-Alexandre and Loth, Daan W and Stricker, Bruno H Ch and Ridker, Paul M and Folsom, Aaron R and Smith, Nicholas L} } @article {6072, title = {Genome-wide association study of retinopathy in individuals without diabetes.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e54232}, abstract = {

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3{\textpm}0.23 (beta {\textpm} standard error), p = 6.6{\texttimes}10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (\~{}2\%), the quality of the imputation was moderate (r(2) \~{}0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

}, keywords = {Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0054232}, author = {Jensen, Richard A and Sim, Xueling and Li, Xiaohui and Cotch, Mary Frances and Ikram, M Kamran and Holliday, Elizabeth G and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore J and Smith, Albert Vernon and Boerwinkle, Eric and Cheung, Ning and Hewitt, Alex W and Liew, Gerald and Mitchell, Paul and Wang, Jie Jin and Attia, John and Scott, Rodney and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Taylor, Kent and Hofman, Albert and de Jong, Paulus T V M and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Tay, Wan-Ting and Teo, Yik Ying and Seielstad, Mark and Liu, Jianjun and Cheng, Ching-Yu and Saw, Seang-Mei and Aung, Tin and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Nalls, Mike A and Wiggins, Kerri L and Kuo, Jane Z and van Duijn, Cornelia M and Gudnason, Vilmundur and Klein, Ronald and Siscovick, David S and Rotter, Jerome I and Tai, E Shong and Vingerling, Johannes and Wong, Tien Y} } @article {5875, title = {Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e53830}, abstract = {

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5{\texttimes}10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3{\texttimes}10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1{\texttimes}10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9{\texttimes}10(-6)) and upstream of GLI2 (rs6721654; P = 6.5{\texttimes}10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5{\texttimes}10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

}, keywords = {Apolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3}, issn = {1932-6203}, doi = {10.1371/journal.pone.0053830}, author = {Holliday, Elizabeth G and Smith, Albert V and Cornes, Belinda K and Buitendijk, Gabri{\"e}lle H S and Jensen, Richard A and Sim, Xueling and Aspelund, Thor and Aung, Tin and Baird, Paul N and Boerwinkle, Eric and Cheng, Ching Yu and van Duijn, Cornelia M and Eiriksdottir, Gudny and Gudnason, Vilmundur and Harris, Tamara and Hewitt, Alex W and Inouye, Michael and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore and Li, Xiaohui and Liew, Gerald and Lumley, Thomas and McElduff, Patrick and McKnight, Barbara and Mitchell, Paul and Psaty, Bruce M and Rochtchina, Elena and Rotter, Jerome I and Scott, Rodney J and Tay, Wanting and Taylor, Kent and Teo, Yik Ying and Uitterlinden, Andr{\'e} G and Viswanathan, Ananth and Xie, Sophia and Vingerling, Johannes R and Klaver, Caroline C W and Tai, E Shyong and Siscovick, David and Klein, Ronald and Cotch, Mary Frances and Wong, Tien Y and Attia, John and Wang, Jie Jin} } @article {6155, title = {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.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

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{\texttimes}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.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @article {6580, title = {ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {350-8}, abstract = {

BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.

METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58{\texttimes}10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56{\texttimes}10(-4)). Analysis of rare variants (minor allele frequency <1\%) using sequence kernel association test did not identify associations with either region.

CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.

}, keywords = {ADAM Proteins, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000066}, author = {London, Stephanie J and Gao, Wei and Gharib, Sina A and Hancock, Dana B and Wilk, Jemma B and House, John S and Gibbs, Richard A and Muzny, Donna M and Lumley, Thomas and Franceschini, Nora and North, Kari E and Psaty, Bruce M and Kovar, Christie L and Coresh, Josef and Zhou, Yanhua and Heckbert, Susan R and Brody, Jennifer A and Morrison, Alanna C and Dupuis, Jos{\'e}e} } @article {6548, title = {Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e99798}, abstract = {

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.

METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] >= 1\%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF<= 1\% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).

CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

}, keywords = {Cell Adhesion Molecules, Neuronal, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Heterogeneity, Humans, Introns, Ischemia, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099798}, author = {Bis, Joshua C and DeStefano, Anita and Liu, Xiaoming and Brody, Jennifer A and Choi, Seung Hoan and Verhaaren, Benjamin F J and Debette, Stephanie and Ikram, M Arfan and Shahar, Eyal and Butler, Kenneth R and Gottesman, Rebecca F and Muzny, Donna and Kovar, Christie L and Psaty, Bruce M and Hofman, Albert and Lumley, Thomas and Gupta, Mayetri and Wolf, Philip A and van Duijn, Cornelia and Gibbs, Richard A and Mosley, Thomas H and Longstreth, W T and Boerwinkle, Eric and Seshadri, Sudha and Fornage, Myriam} } @article {6690, title = {Genetic diversity is a predictor of mortality in humans.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014}, pages = {159}, abstract = {

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{\textquoteright}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.

}, keywords = {Genome-Wide Association Study, Heterozygote, Humans, Mortality, Polymorphism, Single Nucleotide, Proportional Hazards Models}, issn = {1471-2156}, doi = {10.1186/s12863-014-0159-7}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Lunetta, Kathryn L and Nalls, Mike and Smith, Jennifer A and Tanaka, Toshiko and Davies, Gail and Yu, Lei and Mirza, Saira Saeed and Teumer, Alexander and Coresh, Josef and Pankow, James S and Franceschini, Nora and Scaria, Anish and Oshima, Junko and Psaty, Bruce M and Gudnason, Vilmundur and Eiriksdottir, Gudny and Harris, Tamara B and Li, Hanyue and Karasik, David and Kiel, Douglas P and Garcia, Melissa and Liu, Yongmei and Faul, Jessica D and Kardia, Sharon Lr and Zhao, Wei and Ferrucci, Luigi and Allerhand, Michael and Liewald, David C and Redmond, Paul and Starr, John M and De Jager, Philip L and Evans, Denis A and Direk, Nese and Ikram, Mohammed Arfan and Uitterlinden, Andre and Homuth, Georg and Lorbeer, Roberto and Grabe, Hans J and Launer, Lenore and Murabito, Joanne M and Singleton, Andrew B and Weir, David R and Bandinelli, Stefania and Deary, Ian J and Bennett, David A and Tiemeier, Henning and Kocher, Thomas and Lumley, Thomas and Arking, Dan E} } @article {6582, title = {Genome-wide association analysis identifies six new loci associated with forced vital capacity.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jul}, pages = {669-77}, abstract = {

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 {\texttimes} 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

}, keywords = {Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.3011}, author = {Loth, Daan W and Soler Artigas, Maria and Gharib, Sina A and Wain, Louise V and Franceschini, Nora and Koch, Beate and Pottinger, Tess D and Smith, Albert Vernon and Duan, Qing and Oldmeadow, Chris and Lee, Mi Kyeong and Strachan, David P and James, Alan L and Huffman, Jennifer E and Vitart, Veronique and Ramasamy, Adaikalavan and Wareham, Nicholas J and Kaprio, Jaakko and Wang, Xin-Qun and Trochet, Holly and K{\"a}h{\"o}nen, Mika and Flexeder, Claudia and Albrecht, Eva and Lopez, Lorna M and de Jong, Kim and Thyagarajan, Bharat and Alves, Alexessander Couto and Enroth, Stefan and Omenaas, Ernst and Joshi, Peter K and Fall, Tove and Vi{\~n}uela, Ana and Launer, Lenore J and Loehr, Laura R and Fornage, Myriam and Li, Guo and Wilk, Jemma B and Tang, Wenbo and Manichaikul, Ani and Lahousse, Lies and Harris, Tamara B and North, Kari E and Rudnicka, Alicja R and Hui, Jennie and Gu, Xiangjun and Lumley, Thomas and Wright, Alan F and Hastie, Nicholas D and Campbell, Susan and Kumar, Rajesh and Pin, Isabelle and Scott, Robert A and Pietil{\"a}inen, Kirsi H and Surakka, Ida and Liu, Yongmei and Holliday, Elizabeth G and Schulz, Holger and Heinrich, Joachim and Davies, Gail and Vonk, Judith M and Wojczynski, Mary and Pouta, Anneli and Johansson, Asa and Wild, Sarah H and Ingelsson, Erik and Rivadeneira, Fernando and V{\"o}lzke, Henry and Hysi, Pirro G and Eiriksdottir, Gudny and Morrison, Alanna C and Rotter, Jerome I and Gao, Wei and Postma, Dirkje S and White, Wendy B and Rich, Stephen S and Hofman, Albert and Aspelund, Thor and Couper, David and Smith, Lewis J and Psaty, Bruce M and Lohman, Kurt and Burchard, Esteban G and Uitterlinden, Andr{\'e} G and Garcia, Melissa and Joubert, Bonnie R and McArdle, Wendy L and Musk, A Bill and Hansel, Nadia and Heckbert, Susan R and Zgaga, Lina and van Meurs, Joyce B J and Navarro, Pau and Rudan, Igor and Oh, Yeon-Mok and Redline, Susan and Jarvis, Deborah L and Zhao, Jing Hua and Rantanen, Taina and O{\textquoteright}Connor, George T and Ripatti, Samuli and Scott, Rodney J and Karrasch, Stefan and Grallert, Harald and Gaddis, Nathan C and Starr, John M and Wijmenga, Cisca and Minster, Ryan L and Lederer, David J and Pekkanen, Juha and Gyllensten, Ulf and Campbell, Harry and Morris, Andrew P and Gl{\"a}ser, Sven and Hammond, Christopher J and Burkart, Kristin M and Beilby, John and Kritchevsky, Stephen B and Gudnason, Vilmundur and Hancock, Dana B and Williams, O Dale and Polasek, Ozren and Zemunik, Tatijana and Kolcic, Ivana and Petrini, Marcy F and Wjst, Matthias and Kim, Woo Jin and Porteous, David J and Scotland, Generation and Smith, Blair H and Viljanen, Anne and Heli{\"o}vaara, Markku and Attia, John R and Sayers, Ian and Hampel, Regina and Gieger, Christian and Deary, Ian J and Boezen, H Marike and Newman, Anne and Jarvelin, Marjo-Riitta and Wilson, James F and Lind, Lars and Stricker, Bruno H and Teumer, Alexander and Spector, Timothy D and Mel{\'e}n, Erik and Peters, Marjolein J and Lange, Leslie A and Barr, R Graham and Bracke, Ken R and Verhamme, Fien M and Sung, Joohon and Hiemstra, Pieter S and Cassano, Patricia A and Sood, Akshay and Hayward, Caroline and Dupuis, Jos{\'e}e and Hall, Ian P and Brusselle, Guy G and Tobin, Martin D and London, Stephanie J} } @article {6604, title = {Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e100776}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 {\texttimes} 10(-7)). In addition, meta-analysis using the five cohorts with >=3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 {\texttimes} 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

}, keywords = {Adult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration}, issn = {1932-6203}, doi = {10.1371/journal.pone.0100776}, author = {Tang, Wenbo and Kowgier, Matthew and Loth, Daan W and Soler Artigas, Maria and Joubert, Bonnie R and Hodge, Emily and Gharib, Sina A and Smith, Albert V and Ruczinski, Ingo and Gudnason, Vilmundur and Mathias, Rasika A and Harris, Tamara B and Hansel, Nadia N and Launer, Lenore J and Barnes, Kathleen C and Hansen, Joyanna G and Albrecht, Eva and Aldrich, Melinda C and Allerhand, Michael and Barr, R Graham and Brusselle, Guy G and Couper, David J and Curjuric, Ivan and Davies, Gail and Deary, Ian J and Dupuis, Jos{\'e}e and Fall, Tove and Foy, Millennia and Franceschini, Nora and Gao, Wei and Gl{\"a}ser, Sven and Gu, Xiangjun and Hancock, Dana B and Heinrich, Joachim and Hofman, Albert and Imboden, Medea and Ingelsson, Erik and James, Alan and Karrasch, Stefan and Koch, Beate and Kritchevsky, Stephen B and Kumar, Ashish and Lahousse, Lies and Li, Guo and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Lohman, Kurt and Lumley, Thomas and McArdle, Wendy L and Meibohm, Bernd and Morris, Andrew P and Morrison, Alanna C and Musk, Bill and North, Kari E and Palmer, Lyle J and Probst-Hensch, Nicole M and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome I and Schulz, Holger and Smith, Lewis J and Sood, Akshay and Starr, John M and Strachan, David P and Teumer, Alexander and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Voorman, Arend and Wain, Louise V and Wells, Martin T and Wilk, Jemma B and Williams, O Dale and Heckbert, Susan R and Stricker, Bruno H and London, Stephanie J and Fornage, Myriam and Tobin, Martin D and O{\textquoteright}Connor, George T and Hall, Ian P and Cassano, Patricia A} } @article {6667, title = {No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e111156}, abstract = {

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 {\texttimes} 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

}, keywords = {Alcohol Drinking, Body Mass Index, Fibrinogen, Gene-Environment Interaction, Genomics, Humans, Smoking}, issn = {1932-6203}, doi = {10.1371/journal.pone.0111156}, author = {Baumert, Jens and Huang, Jie and McKnight, Barbara and Sabater-Lleal, Maria and Steri, Maristella and Chu, Audrey Y and Trompet, Stella and Lopez, Lorna M and Fornage, Myriam and Teumer, Alexander and Tang, Weihong and Rudnicka, Alicja R and M{\"a}larstig, Anders and Hottenga, Jouke-Jan and Kavousi, Maryam and Lahti, Jari and Tanaka, Toshiko and Hayward, Caroline and Huffman, Jennifer E and Morange, Pierre-Emmanuel and Rose, Lynda M and Basu, Saonli and Rumley, Ann and Stott, David J and Buckley, Brendan M and de Craen, Anton J M and Sanna, Serena and Masala, Marco and Biffar, Reiner and Homuth, Georg and Silveira, Angela and Sennblad, Bengt and Goel, Anuj and Watkins, Hugh and M{\"u}ller-Nurasyid, Martina and R{\"u}ckerl, Regina and Taylor, Kent and Chen, Ming-Huei and de Geus, Eco J C and Hofman, Albert and Witteman, Jacqueline C M and de Maat, Moniek P M and Palotie, Aarno and Davies, Gail and Siscovick, David S and Kolcic, Ivana and Wild, Sarah H and Song, Jaejoon and McArdle, Wendy L and Ford, Ian and Sattar, Naveed and Schlessinger, David and Grotevendt, Anne and Franzosi, Maria Grazia and Illig, Thomas and Waldenberger, Melanie and Lumley, Thomas and Tofler, Geoffrey H and Willemsen, Gonneke and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and R{\"a}ikk{\"o}nen, Katri and Chasman, Daniel I and Folsom, Aaron R and Lowe, Gordon D and Westendorp, Rudi G J and Slagboom, P Eline and Cucca, Francesco and Wallaschofski, Henri and Strawbridge, Rona J and Seedorf, Udo and Koenig, Wolfgang and Bis, Joshua C and Mukamal, Kenneth J and van Dongen, Jenny and Widen, Elisabeth and Franco, Oscar H and Starr, John M and Liu, Kiang and Ferrucci, Luigi and Polasek, Ozren and Wilson, James F and Oudot-Mellakh, Tiphaine and Campbell, Harry and Navarro, Pau and Bandinelli, Stefania and Eriksson, Johan and Boomsma, Dorret I and Dehghan, Abbas and Clarke, Robert and Hamsten, Anders and Boerwinkle, Eric and Jukema, J Wouter and Naitza, Silvia and Ridker, Paul M and V{\"o}lzke, Henry and Deary, Ian J and Reiner, Alexander P and Tr{\'e}gou{\"e}t, David-Alexandre and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Peters, Annette and Smith, Nicholas L} } @article {6591, title = {Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Oct 28}, pages = {5068}, abstract = {

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

}, keywords = {Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6068}, author = {Postmus, Iris and Trompet, Stella and Deshmukh, Harshal A and Barnes, Michael R and Li, Xiaohui and Warren, Helen R and Chasman, Daniel I and Zhou, Kaixin and Arsenault, Benoit J and Donnelly, Louise A and Wiggins, Kerri L and Avery, Christy L and Griffin, Paula and Feng, QiPing and Taylor, Kent D and Li, Guo and Evans, Daniel S and Smith, Albert V and de Keyser, Catherine E and Johnson, Andrew D and de Craen, Anton J M and Stott, David J and Buckley, Brendan M and Ford, Ian and Westendorp, Rudi G J and Slagboom, P Eline and Sattar, Naveed and Munroe, Patricia B and Sever, Peter and Poulter, Neil and Stanton, Alice and Shields, Denis C and O{\textquoteright}Brien, Eoin and Shaw-Hawkins, Sue and Chen, Y-D Ida and Nickerson, Deborah A and Smith, Joshua D and Dub{\'e}, Marie Pierre and Boekholdt, S Matthijs and Hovingh, G Kees and Kastelein, John J P and McKeigue, Paul M and Betteridge, John and Neil, Andrew and Durrington, Paul N and Doney, Alex and Carr, Fiona and Morris, Andrew and McCarthy, Mark I and Groop, Leif and Ahlqvist, Emma and Bis, Joshua C and Rice, Kenneth and Smith, Nicholas L and Lumley, Thomas and Whitsel, Eric A and St{\"u}rmer, Til and Boerwinkle, Eric and Ngwa, Julius S and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and Wei, Wei-Qi and Wilke, Russell A and Liu, Ching-Ti and Sun, Fangui and Guo, Xiuqing and Heckbert, Susan R and Post, Wendy and Sotoodehnia, Nona and Arnold, Alice M and Stafford, Jeanette M and Ding, Jingzhong and Herrington, David M and Kritchevsky, Stephen B and Eiriksdottir, Gudny and Launer, Leonore J and Harris, Tamara B and Chu, Audrey Y and Giulianini, Franco and MacFadyen, Jean G and Barratt, Bryan J and Nyberg, Fredrik and Stricker, Bruno H and Uitterlinden, Andr{\'e} G and Hofman, Albert and Rivadeneira, Fernando and Emilsson, Valur and Franco, Oscar H and Ridker, Paul M and Gudnason, Vilmundur and Liu, Yongmei and Denny, Joshua C and Ballantyne, Christie M and Rotter, Jerome I and Adrienne Cupples, L and Psaty, Bruce M and Palmer, Colin N A and Tardif, Jean-Claude and Colhoun, Helen M and Hitman, Graham and Krauss, Ronald M and Wouter Jukema, J and Caulfield, Mark J} } @article {6220, title = {Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {403-12}, abstract = {

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged >=55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3{\texttimes}10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7{\texttimes}10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, ROC Curve, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.003044}, author = {Ibrahim-Verbaas, Carla A and Fornage, Myriam and Bis, Joshua C and Choi, Seung Hoan and Psaty, Bruce M and Meigs, James B and Rao, Madhu and Nalls, Mike and Fontes, Jo{\~a}o D and O{\textquoteright}Donnell, Christopher J and Kathiresan, Sekar and Ehret, Georg B and Fox, Caroline S and Malik, Rainer and Dichgans, Martin and Schmidt, Helena and Lahti, Jari and Heckbert, Susan R and Lumley, Thomas and Rice, Kenneth and Rotter, Jerome I and Taylor, Kent D and Folsom, Aaron R and Boerwinkle, Eric and Rosamond, Wayne D and Shahar, Eyal and Gottesman, Rebecca F and Koudstaal, Peter J and Amin, Najaf and Wieberdink, Renske G and Dehghan, Abbas and Hofman, Albert and Uitterlinden, Andr{\'e} G and DeStefano, Anita L and Debette, Stephanie and Xue, Luting and Beiser, Alexa and Wolf, Philip A and DeCarli, Charles and Ikram, M Arfan and Seshadri, Sudha and Mosley, Thomas H and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J} } @article {6618, title = {Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e109155}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (>=50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF<=1\%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r{\texttwosuperior} = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r{\texttwosuperior} = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

}, keywords = {Aging, Blood Pressure, Cohort Studies, Heart, Humans, Sequence Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0109155}, author = {Morrison, Alanna C and Bis, Joshua C and Hwang, Shih-Jen and Ehret, Georg B and Lumley, Thomas and Rice, Kenneth and Muzny, Donna and Gibbs, Richard A and Boerwinkle, Eric and Psaty, Bruce M and Chakravarti, Aravinda and Levy, Daniel} } @article {6583, title = {Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {365-73}, abstract = {

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{\textquoteright}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{\texttimes}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{\texttimes}10(-4) and P=5.2{\texttimes}10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82{\texttimes}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{\texttimes}10(-7) and P=2.69{\texttimes}10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67{\texttimes}10(-5)).

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

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000098}, author = {Magnani, Jared W and Brody, Jennifer A and Prins, Bram P and Arking, Dan E and Lin, Honghuang and Yin, Xiaoyan and Liu, Ching-Ti and Morrison, Alanna C and Zhang, Feng and Spector, Tim D and Alonso, Alvaro and Bis, Joshua C and Heckbert, Susan R and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Lubitz, Steven A and Soliman, Elsayed Z and Pulit, Sara L and Newton-Cheh, Christopher and O{\textquoteright}Donnell, Christopher J and Ellinor, Patrick T and Benjamin, Emelia J and Muzny, Donna M and Gibbs, Richard A and Santibanez, Jireh and Taylor, Herman A and Rotter, Jerome I and Lange, Leslie A and Psaty, Bruce M and Jackson, Rebecca and Rich, Stephen S and Boerwinkle, Eric and Jamshidi, Yalda and Sotoodehnia, Nona} } @article {6578, title = {Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {335-43}, abstract = {

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with >=1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency >=1\%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000350}, author = {Lin, Honghuang and Wang, Min and Brody, Jennifer A and Bis, Joshua C and Dupuis, Jos{\'e}e and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Sitlani, Colleen M and Reid, Jeffrey G and Bressler, Jan and Liu, Xiaoming and Davis, Brian C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Kovar, Christie L and Dinh, Huyen and Wu, Yuanqing and Newsham, Irene and Chen, Han and Broka, Andi and DeStefano, Anita L and Gupta, Mayetri and Lunetta, Kathryn L and Liu, Ching-Ti and White, Charles C and Xing, Chuanhua and Zhou, Yanhua and Benjamin, Emelia J and Schnabel, Renate B and Heckbert, Susan R and Psaty, Bruce M and Muzny, Donna M and Cupples, L Adrienne and Morrison, Alanna C and Boerwinkle, Eric} } @article {6577, title = {Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {233-45}, abstract = {

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

}, keywords = {Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.010}, author = {Lange, Leslie A and Hu, Youna and Zhang, He and Xue, Chenyi and Schmidt, Ellen M and Tang, Zheng-Zheng and Bizon, Chris and Lange, Ethan M and Smith, Joshua D and Turner, Emily H and Jun, Goo and Kang, Hyun Min and Peloso, Gina and Auer, Paul and Li, Kuo-Ping and Flannick, Jason and Zhang, Ji and Fuchsberger, Christian and Gaulton, Kyle and Lindgren, Cecilia and Locke, Adam and Manning, Alisa and Sim, Xueling and Rivas, Manuel A and Holmen, Oddgeir L and Gottesman, Omri and Lu, Yingchang and Ruderfer, Douglas and Stahl, Eli A and Duan, Qing and Li, Yun and Durda, Peter and Jiao, Shuo and Isaacs, Aaron and Hofman, Albert and Bis, Joshua C and Correa, Adolfo and Griswold, Michael E and Jakobsdottir, Johanna and Smith, Albert V and Schreiner, Pamela J and Feitosa, Mary F and Zhang, Qunyuan and Huffman, Jennifer E and Crosby, Jacy and Wassel, Christina L and Do, Ron and Franceschini, Nora and Martin, Lisa W and Robinson, Jennifer G and Assimes, Themistocles L and Crosslin, David R and Rosenthal, Elisabeth A and Tsai, Michael and Rieder, Mark J and Farlow, Deborah N and Folsom, Aaron R and Lumley, Thomas and Fox, Ervin R and Carlson, Christopher S and Peters, Ulrike and Jackson, Rebecca D and van Duijn, Cornelia M and Uitterlinden, Andr{\'e} G and Levy, Daniel and Rotter, Jerome I and Taylor, Herman A and Gudnason, Vilmundur and Siscovick, David S and Fornage, Myriam and Borecki, Ingrid B and Hayward, Caroline and Rudan, Igor and Chen, Y Eugene and Bottinger, Erwin P and Loos, Ruth J F and S{\ae}trom, P{\r a}l and Hveem, Kristian and Boehnke, Michael and Groop, Leif and McCarthy, Mark and Meitinger, Thomas and Ballantyne, Christie M and Gabriel, Stacey B and O{\textquoteright}Donnell, Christopher J and Post, Wendy S and North, Kari E and Reiner, Alexander P and Boerwinkle, Eric and Psaty, Bruce M and Altshuler, David and Kathiresan, Sekar and Lin, Dan-Yu and Jarvik, Gail P and Cupples, L Adrienne and Kooperberg, Charles and Wilson, James G and Nickerson, Deborah A and Abecasis, Goncalo R and Rich, Stephen S and Tracy, Russell P and Willer, Cristen J} } @article {6687, title = {Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.}, journal = {Mol Nutr Food Res}, volume = {59}, year = {2015}, month = {2015 Jul}, pages = {1373-83}, abstract = {

SCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.

METHODS AND RESULTS: We conducted meta-analyses (N = 11~668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.

CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.

}, keywords = {Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1613-4133}, doi = {10.1002/mnfr.201400734}, author = {Smith, Caren E and Follis, Jack L and Nettleton, Jennifer A and Foy, Millennia and Wu, Jason H Y and Ma, Yiyi and Tanaka, Toshiko and Manichakul, Ani W and Wu, Hongyu and Chu, Audrey Y and Steffen, Lyn M and Fornage, Myriam and Mozaffarian, Dariush and Kabagambe, Edmond K and Ferruci, Luigi and Chen, Yii-Der Ida and Rich, Stephen S and Djouss{\'e}, Luc and Ridker, Paul M and Tang, Weihong and McKnight, Barbara and Tsai, Michael Y and Bandinelli, Stefania and Rotter, Jerome I and Hu, Frank B and Chasman, Daniel I and Psaty, Bruce M and Arnett, Donna K and King, Irena B and Sun, Qi and Wang, Lu and Lumley, Thomas and Chiuve, Stephanie E and Siscovick, David S and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0{\texttimes}10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} } @article {6602, title = {Generalized estimating equations for genome-wide association studies using longitudinal phenotype data.}, journal = {Stat Med}, volume = {34}, year = {2015}, month = {2015 Jan 15}, pages = {118-30}, abstract = {

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Cohort Studies, Computer Simulation, Cross-Sectional Studies, Epidemiologic Research Design, Gene-Environment Interaction, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Longitudinal Studies, Meta-Analysis as Topic, Models, Genetic, Pharmacogenetics, Risk Assessment, United States}, issn = {1097-0258}, doi = {10.1002/sim.6323}, author = {Sitlani, Colleen M and Rice, Kenneth M and Lumley, Thomas and McKnight, Barbara and Cupples, L Adrienne and Avery, Christy L and Noordam, Raymond and Stricker, Bruno H C and Whitsel, Eric A and Psaty, Bruce M} } @article {6861, title = {White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Nov}, pages = {3048-57}, abstract = {

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{\texttimes}10(-8)). Four loci were suggestive (P<1{\texttimes}10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46{\texttimes}10(-6)); 12q13.13 (rs4761974, P=8.71{\texttimes}10(-7)); 20p12.1 (rs6135309, P=3.69{\texttimes}10(-6)); and 4p15.31 (rs7664442, P=2.26{\texttimes}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.

}, keywords = {Adult, Aged, Cohort Studies, Disease Progression, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Middle Aged, Prospective Studies, White Matter}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.009252}, author = {Hofer, Edith and Cavalieri, Margherita and Bis, Joshua C and DeCarli, Charles and Fornage, Myriam and Sigurdsson, Sigurdur and Srikanth, Velandai and Trompet, Stella and Verhaaren, Benjamin F J and Wolf, Christiane and Yang, Qiong and Adams, Hieab H H and Amouyel, Philippe and Beiser, Alexa and Buckley, Brendan M and Callisaya, Michele and Chauhan, Ganesh and de Craen, Anton J M and Dufouil, Carole and van Duijn, Cornelia M and Ford, Ian and Freudenberger, Paul and Gottesman, Rebecca F and Gudnason, Vilmundur and Heiss, Gerardo and Hofman, Albert and Lumley, Thomas and Martinez, Oliver and Mazoyer, Bernard and Moran, Chris and Niessen, Wiro J and Phan, Thanh and Psaty, Bruce M and Satizabal, Claudia L and Sattar, Naveed and Schilling, Sabrina and Shibata, Dean K and Slagboom, P Eline and Smith, Albert and Stott, David J and Taylor, Kent D and Thomson, Russell and T{\"o}glhofer, Anna M and Tzourio, Christophe and van Buchem, Mark and Wang, Jing and Westendorp, Rudi G J and Windham, B Gwen and Vernooij, Meike W and Zijdenbos, Alex and Beare, Richard and Debette, Stephanie and Ikram, M Arfan and Jukema, J Wouter and Launer, Lenore J and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Schmidt, Helena and Schmidt, Reinhold} } @article {7004, title = {Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0144997}, abstract = {

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5{\texttimes}10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5{\texttimes}10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8{\texttimes}10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2{\texttimes}10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2{\texttimes}10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

}, keywords = {Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0144997}, author = {Dehghan, Abbas and Bis, Joshua C and White, Charles C and Smith, Albert Vernon and Morrison, Alanna C and Cupples, L Adrienne and Trompet, Stella and Chasman, Daniel I and Lumley, Thomas and V{\"o}lker, Uwe and Buckley, Brendan M and Ding, Jingzhong and Jensen, Majken K and Folsom, Aaron R and Kritchevsky, Stephen B and Girman, Cynthia J and Ford, Ian and D{\"o}rr, Marcus and Salomaa, Veikko and Uitterlinden, Andr{\'e} G and Eiriksdottir, Gudny and Vasan, Ramachandran S and Franceschini, Nora and Carty, Cara L and Virtamo, Jarmo and Demissie, Serkalem and Amouyel, Philippe and Arveiler, Dominique and Heckbert, Susan R and Ferrieres, Jean and Ducimetiere, Pierre and Smith, Nicholas L and Wang, Ying A and Siscovick, David S and Rice, Kenneth M and Wiklund, Per-Gunnar and Taylor, Kent D and Evans, Alun and Kee, Frank and Rotter, Jerome I and Karvanen, Juha and Kuulasmaa, Kari and Heiss, Gerardo and Kraft, Peter and Launer, Lenore J and Hofman, Albert and Markus, Marcello R P and Rose, Lynda M and Silander, Kaisa and Wagner, Peter and Benjamin, Emelia J and Lohman, Kurt and Stott, David J and Rivadeneira, Fernando and Harris, Tamara B and Levy, Daniel and Liu, Yongmei and Rimm, Eric B and Jukema, J Wouter and V{\"o}lzke, Henry and Ridker, Paul M and Blankenberg, Stefan and Franco, Oscar H and Gudnason, Vilmundur and Psaty, Bruce M and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {7921, title = {FastSKAT: Sequence kernel association tests for very large sets of markers.}, journal = {Genet Epidemiol}, volume = {42}, year = {2018}, month = {2018 09}, pages = {516-527}, abstract = {

The sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an n{\texttimes}n matrix, for n subjects) has computational complexity proportional to n . As SKAT is often used when n104 , this step becomes a major bottleneck in its use in practice. We therefore propose fastSKAT, a new computationally inexpensive but accurate approximations to the tail probabilities, in which the k largest eigenvalues of a weighted genotype covariance matrix or the largest singular values of a weighted genotype matrix are extracted, and a single term based on the Satterthwaite approximation is used for the remaining eigenvalues. While the method is not particularly sensitive to the choice of k, we also describe how to choose its value, and show how fastSKAT can automatically alert users to the rare cases where the choice may affect results. As well as providing faster implementation of SKAT, the new method also enables entirely new applications of SKAT that were not possible before; we give examples grouping variants by topologically associating domains, and comparing chromosome-wide association by class of histone marker.

}, keywords = {Algorithms, Chromosomes, Human, Genetic Association Studies, Genetic Markers, Histones, Humans, Sequence Analysis, DNA, Statistics as Topic, Time Factors}, issn = {1098-2272}, doi = {10.1002/gepi.22136}, author = {Lumley, Thomas and Brody, Jennifer and Peloso, Gina and Morrison, Alanna and Rice, Kenneth} }