@article {1456, title = {White blood cell counts in persons aged 65 years or more from the Cardiovascular Health Study. Correlations with baseline clinical and demographic characteristics.}, journal = {Am J Epidemiol}, volume = {143}, year = {1996}, month = {1996 Jun 01}, pages = {1107-15}, abstract = {

A higher white blood cell (WBC) count has been shown to be a risk factor for myocardial infarction and stroke in middle-aged populations. This study evaluated the relation between baseline WBC count and other risk factors, as well as subclinical and prevalent disease, in the Cardiovascular Health Study, an epidemiologic study of coronary heart disease and stroke in 5,201 persons aged 65 years or older. Baseline data were collected over a 12-month period in 1989-1990. WBC counts were statistically significantly higher in people with prevalent and subclinical atherosclerotic cardiovascular disease than in those who were free of disease. WBC counts correlated (p < 0.01) positively with coagulation factors, measures of glucose metabolism, creatinine, smoking, and triglycerides. In contrast, WBC counts correlated negatively with high density lipoprotein cholesterol, forced expiratory volume, forced vital capacity, and height. The correlations between WBC counts and risk factors were similar in both the entire cohort and the subgroup of persons who had never smoked. The authors conclude that WBC counts in the elderly are associated with prevalent and subclinical atherosclerotic cardiovascular disease, as well as its risk factors.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Cerebrovascular Disorders, Female, Humans, Leukocyte Count, Leukocytosis, Longitudinal Studies, Male, Myocardial Infarction, Prevalence, Reference Values, Risk Factors, United States}, issn = {0002-9262}, author = {Bovill, E G and Bild, D E and Heiss, G and Kuller, L H and Lee, M H and Rock, R and Wahl, P W} } @article {683, title = {Weight change in old age and its association with mortality.}, journal = {J Am Geriatr Soc}, volume = {49}, year = {2001}, month = {2001 Oct}, pages = {1309-18}, abstract = {

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

DESIGN: Longitudinal observational cohort study.

SETTING: Four U.S. communities.

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

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

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

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

}, keywords = {Aged, Analysis of Variance, Body Weight, Chi-Square Distribution, Female, Health Status, Humans, Longitudinal Studies, Male, Mortality, Proportional Hazards Models, Risk Factors, United States, Weight Gain, Weight Loss}, issn = {0002-8614}, doi = {10.1046/j.1532-5415.2001.49258.x}, author = {Newman, A B and Yanez, D and Harris, T and Duxbury, A and Enright, P L and Fried, L P} } @article {687, title = {Weight-modification trials in older adults: what should the outcome measure be?}, journal = {Curr Control Trials Cardiovasc Med}, volume = {3}, year = {2002}, month = {2002 Jan 07}, pages = {1}, abstract = {

BACKGROUND: Overweight older adults are often counseled to lose weight, even though there is little evidence of excess mortality in that age group. Overweight and underweight may be more associated with health status than with mortality, but few clinical trials of any kind have been based on maximizing years of healthy life (YHL), as opposed to years of life (YOL). OBJECTIVE: This paper examines the relationship of body mass index (BMI) to both YHL and YOL. Results were used to determine whether clinical trials of weight-modification based on improving YHL would be more powerful than studies based on survival. DESIGN: We used data from a cohort of 4,878 non-smoking men and women aged 65-100 at baseline (mean age 73) and followed 7 years. We estimated mean YHL and YOL in four categories of BMI: underweight, normal, overweight, and obese. RESULTS: Subjects averaged 6.3 YOL and 4.6 YHL of a possible 7 years. Both measures were higher for women and whites. For men, none of the BMI groups was significantly different from the normal group on either YOL or YHL. For women, the obese had significantly lower YHL (but not YOL) than the normals, and the underweight had significantly lower YOL and YHL. The overweight group was not significantly different from the normal group on either measure. CONCLUSIONS: Clinical trials of weight loss interventions for obese older women would require fewer participants if YHL rather than YOL was the outcome measure. Interventions for obese men or for the merely overweight are not likely to achieve differences in either YOL or YHL. Evaluations of interventions for the underweight (which would presumably address the causes of their low weight) may be conducted efficiently using either outcome measure.

}, issn = {1468-6708}, doi = {10.1186/1468-6708-3-1}, author = {Diehr, Paula and Newman, Anne B and Jackson, Sharon A and Kuller, Lewis and Powe, Neil} } @article {788, title = {White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke.}, journal = {Stroke}, volume = {35}, year = {2004}, month = {2004 Aug}, pages = {1821-5}, abstract = {

BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors.

METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8\% per year for participants with high WMG (grades > or =5), compared with only 0.6\% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

}, keywords = {Aged, Brain, Female, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Radiography, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000132193.35955.69}, author = {Kuller, Lewis H and Longstreth, W T and Arnold, Alice M and Bernick, Charles and Bryan, R Nick and Beauchamp, Norman J} } @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 {907, title = {White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Sep}, pages = {1307-15}, abstract = {

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50\% black and 40\% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Biomarkers, Brain, Cardiovascular Diseases, Cerebral Ventricles, European Continental Ancestry Group, Female, Geriatric Assessment, Health Status, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Retrospective Studies, Risk Factors, Sex Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.06.010}, author = {Kuller, Lewis H and Arnold, Alice M and Longstreth, W T and Manolio, Teri A and O{\textquoteright}Leary, Daniel H and Burke, Gregory L and Fried, Linda P and Newman, Anne B} } @article {1000, title = {Weight, mortality, years of healthy life, and active life expectancy in older adults.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Jan}, pages = {76-83}, abstract = {

OBJECTIVES: To determine whether weight categories predict subsequent mortality and morbidity in older adults.

DESIGN: Multistate life tables, using data from the Cardiovascular Health Study, a longitudinal population-based cohort of older adults.

SETTING: Data were provided by community-dwelling seniors in four U.S. counties: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Five thousand eight hundred eighty-eight adults aged 65 and older at baseline.

MEASUREMENTS: The age- and sex-specific probabilities of transition from one health state to another and from one weight category to another were estimated. From these probabilities, future life expectancy, years of healthy life, active life expectancy, and the number of years spent in each weight and health category after age 65 were estimated.

RESULTS: Women who are healthy and of normal weight at age 65 have a life expectancy of 22.1 years. Of that, they spend, on average, 9.6 years as overweight or obese and 5.3 years in fair or poor health. For both men and women, being underweight at age 65 was associated with worse outcomes than being normal weight, whereas being overweight or obese was rarely associated with worse outcomes than being normal weight and was sometimes associated with significantly better outcomes.

CONCLUSION: Similar to middle-aged populations, older adults are likely to be or to become overweight or obese, but higher weight is not associated with worse health in this age group. Thus, the number of older adults at a "healthy" weight may be much higher than currently believed.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Body Mass Index, Body Weight, Female, Health Status Indicators, Humans, Life Expectancy, Life Style, Male, Prognosis, Risk Factors, Sex Factors, Survival Rate, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01500.x}, author = {Diehr, Paula and O{\textquoteright}Meara, Ellen S and Fitzpatrick, Annette and Newman, Anne B and Kuller, Lewis and Burke, Gregory} } @article {1333, title = {White matter lesions and brain gray matter volume in cognitively normal elders.}, journal = {Neurobiol Aging}, volume = {33}, year = {2012}, month = {2012 Apr}, pages = {834.e7-16}, abstract = {

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Brain, Cognition Disorders, Female, Humans, Imaging, Three-Dimensional, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory Disorders, Mental Status Schedule, Neuropsychological Tests, Regression Analysis, Retrospective Studies}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2011.08.010}, author = {Raji, Cyrus A and Lopez, Oscar L and Kuller, Lewis H and Carmichael, Owen T and Longstreth, William T and Gach, H Michael and Boardman, John and Bernick, Charles B and Thompson, Paul M and Becker, James T} } @article {6283, title = {Whole-genome sequence-based analysis of high-density lipoprotein cholesterol.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Aug}, pages = {899-901}, abstract = {

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

}, keywords = {Cholesterol, HDL, Computational Biology, Databases, Genetic, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genomics, Heterozygote, Humans, Open Reading Frames}, issn = {1546-1718}, doi = {10.1038/ng.2671}, author = {Morrison, Alanna C and Voorman, Arend and Johnson, Andrew D and Liu, Xiaoming and Yu, Jin and Li, Alexander and Muzny, Donna and Yu, Fuli and Rice, Kenneth and Zhu, Chengsong and Bis, Joshua and Heiss, Gerardo and O{\textquoteright}Donnell, Christopher J and Psaty, Bruce M and Cupples, L Adrienne and Gibbs, Richard and Boerwinkle, Eric} } @article {6564, title = {What do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study.}, journal = {J Am Soc Echocardiogr}, volume = {27}, year = {2014}, month = {2014 Sep}, pages = {998-1005.e2}, abstract = {

BACKGROUND: The aim of this study was to evaluate whether the addition of ultrasound carotid intima-media thickness (CIMT) measurements and risk categories of plaque help predict incident stroke and cardiovascular disease (CVD) in older adults.

METHODS: Carotid ultrasound studies were recorded in the multicenter Cardiovascular Health Study. CVD was defined as coronary heart disease plus heart failure plus stroke. Ten-year risk prediction Cox proportional-hazards models for stroke and CVD were calculated using Cardiovascular Health Study-specific coefficients for Framingham risk score factors. Categories of CIMT and CIMT plus plaque were added to Framingham risk score prediction models, and categorical net reclassification improvement (NRI) and Harrell{\textquoteright}s c-statistic were calculated.

RESULTS: In 4,384 Cardiovascular Health Study participants (61\% women, 14\% black; mean baseline age, 72~{\textpm}~5 years) without CVD at baseline, higher CIMT category and the presence of plaque were both associated with higher incidence rates for stroke and CVD. The addition of CIMT improved the ability of Framingham risk score-type risk models to discriminate cases from noncases of incident stroke and CVD (NRI~= 0.062, P~=~.015, and NRI~= 0.027, P < .001, respectively), with no further improvement by adding plaque. For both outcomes, NRI was driven by down-classifying those without incident disease. Although the addition of plaque to CIMT~did not result in a significant NRI for either outcome, it was significant among those without incident disease.

CONCLUSIONS: In older adults, the addition of CIMT modestly improves 10-year risk prediction for stroke and CVD beyond a traditional risk factor model, mainly by down-classifying risk in those without stroke or CVD; the addition of plaque to CIMT adds no statistical benefit in the overall cohort, although there is evidence of down-classification in those without events.

}, keywords = {Aged, Cardiovascular Diseases, Carotid Intima-Media Thickness, Carotid Stenosis, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Male, Reproducibility of Results, Risk Factors, Sensitivity and Specificity, Stroke, Survival Rate}, issn = {1097-6795}, doi = {10.1016/j.echo.2014.06.013}, author = {Gardin, Julius M and Bartz, Traci M and Polak, Joseph F and O{\textquoteright}Leary, Daniel H and Wong, Nathan D} } @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 {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 {7250, title = {Whole Exome Sequencing in Atrial Fibrillation.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Sep}, pages = {e1006284}, abstract = {

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78\%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86\%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95\% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006284}, author = {Lubitz, Steven A and Brody, Jennifer A and Bihlmeyer, Nathan A and Roselli, Carolina and Weng, Lu-Chen and Christophersen, Ingrid E and Alonso, Alvaro and Boerwinkle, Eric and Gibbs, Richard A and Bis, Joshua C and Cupples, L Adrienne and Mohler, Peter J and Nickerson, Deborah A and Muzny, Donna and Perez, Marco V and Psaty, Bruce M and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Benjamin, Emelia J and Heckbert, Susan R and Arking, Dan E and Ellinor, Patrick T and Lin, Honghuang} } @article {7263, title = {Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {785}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.002}, author = {Polfus, Linda M and Khajuria, Rajiv K and Schick, Ursula M and Pankratz, Nathan and Pazoki, Raha and Brody, Jennifer A and Chen, Ming-Huei and Auer, Paul L and Floyd, James S and Huang, Jie and Lange, Leslie and van Rooij, Frank J A and Gibbs, Richard A and Metcalf, Ginger and Muzny, Donna and Veeraraghavan, Narayanan and Walter, Klaudia and Chen, Lu and Yanek, Lisa and Becker, Lewis C and Peloso, Gina M and Wakabayashi, Aoi and Kals, Mart and Metspalu, Andres and Esko, T{\~o}nu and Fox, Keolu and Wallace, Robert and Franceschini, Nora and Matijevic, Nena and Rice, Kenneth M and Bartz, Traci M and Lyytik{\"a}inen, Leo-Pekka and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Li-Gao, Ruifang and Mook-Kanamori, Dennis O and Lettre, Guillaume and van Duijn, Cornelia M and Franco, Oscar H and Rich, Stephen S and Rivadeneira, Fernando and Hofman, Albert and Uitterlinden, Andr{\'e} G and Wilson, James G and Psaty, Bruce M and Soranzo, Nicole and Dehghan, Abbas and Boerwinkle, Eric and Zhang, Xiaoling and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Johnsen, Jill M and Reiner, Alexander P and Ganesh, Santhi K and Sankaran, Vijay G} } @article {7785, title = {Whole exome sequencing study identifies novel rare and common Alzheimer{\textquoteright}s-Associated variants involved in immune response and transcriptional regulation.}, journal = {Mol Psychiatry}, year = {2018}, month = {2018 Aug 14}, abstract = {

The Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 {\texttimes} 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 {\texttimes} 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 {\texttimes} 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

}, issn = {1476-5578}, doi = {10.1038/s41380-018-0112-7}, author = {Bis, Joshua C and Jian, Xueqiu and Kunkle, Brian W and Chen, Yuning and Hamilton-Nelson, Kara L and Bush, William S and Salerno, William J and Lancour, Daniel and Ma, Yiyi and Renton, Alan E and Marcora, Edoardo and Farrell, John J and Zhao, Yi and Qu, Liming and Ahmad, Shahzad and Amin, Najaf and Amouyel, Philippe and Beecham, Gary W and Below, Jennifer E and Campion, Dominique and Charbonnier, Camille and Chung, Jaeyoon and Crane, Paul K and Cruchaga, Carlos and Cupples, L Adrienne and Dartigues, Jean-Fran{\c c}ois and Debette, Stephanie and Deleuze, Jean-Francois and Fulton, Lucinda and Gabriel, Stacey B and Genin, Emmanuelle and Gibbs, Richard A and Goate, Alison and Grenier-Boley, Benjamin and Gupta, Namrata and Haines, Jonathan L and Havulinna, Aki S and Helisalmi, Seppo and Hiltunen, Mikko and Howrigan, Daniel P and Ikram, M Arfan and Kaprio, Jaakko and Konrad, Jan and Kuzma, Amanda and Lander, Eric S and Lathrop, Mark and Lehtim{\"a}ki, Terho and Lin, Honghuang and Mattila, Kari and Mayeux, Richard and Muzny, Donna M and Nasser, Waleed and Neale, Benjamin and Nho, Kwangsik and Nicolas, Ga{\"e}l and Patel, Devanshi and Pericak-Vance, Margaret A and Perola, Markus and Psaty, Bruce M and Quenez, Olivier and Rajabli, Farid and Redon, Richard and Reitz, Christiane and Remes, Anne M and Salomaa, Veikko and Sarnowski, Chloe and Schmidt, Helena and Schmidt, Michael and Schmidt, Reinhold and Soininen, Hilkka and Thornton, Timothy A and Tosto, Giuseppe and Tzourio, Christophe and van der Lee, Sven J and van Duijn, Cornelia M and Vardarajan, Badri and Wang, Weixin and Wijsman, Ellen and Wilson, Richard K and Witten, Daniela and Worley, Kim C and Zhang, Xiaoling and Bellenguez, C{\'e}line and Lambert, Jean-Charles and Kurki, Mitja I and Palotie, Aarno and Daly, Mark and Boerwinkle, Eric and Lunetta, Kathryn L and DeStefano, Anita L and Dupuis, Jos{\'e}e and Martin, Eden R and Schellenberg, Gerard D and Seshadri, Sudha and Naj, Adam C and Fornage, Myriam and Farrer, Lindsay A} } @article {7661, title = {Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer{\textquoteright}s disease.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Apr}, pages = {406-417}, abstract = {

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer{\textquoteright}s disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95\% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

}, issn = {2328-9503}, doi = {10.1002/acn3.537}, author = {Vardarajan, Badri N and Barral, Sandra and Jaworski, James and Beecham, Gary W and Blue, Elizabeth and Tosto, Giuseppe and Reyes-Dumeyer, Dolly and Medrano, Martin and Lantigua, Rafael and Naj, Adam and Thornton, Timothy and DeStefano, Anita and Martin, Eden and Wang, Li-San and Brown, Lisa and Bush, William and van Duijn, Cornelia and Goate, Allison and Farrer, Lindsay and Haines, Jonathan L and Boerwinkle, Eric and Schellenberg, Gerard and Wijsman, Ellen and Pericak-Vance, Margaret A and Mayeux, Richard and Wang, Li-San} } @article {7810, title = {Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer{\textquoteright}s disease.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Jul}, pages = {832-842}, abstract = {

Objective: The genetic bases of Alzheimer{\textquoteright}s disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer{\textquoteright}s disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer{\textquoteright}s Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 {\texttimes} 10; OR: 36.2 [95\% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer{\textquoteright}s disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer{\textquoteright}s disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer{\textquoteright}s disease in a large whole-exome study of unrelated cases and controls.

}, issn = {2328-9503}, doi = {10.1002/acn3.582}, author = {Raghavan, Neha S and Brickman, Adam M and Andrews, Howard and Manly, Jennifer J and Schupf, Nicole and Lantigua, Rafael and Wolock, Charles J and Kamalakaran, Sitharthan and Petrovski, Slave and Tosto, Giuseppe and Vardarajan, Badri N and Goldstein, David B and Mayeux, Richard} } @article {8446, title = {Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002766}, abstract = {

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6{\texttimes}10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7{\texttimes}10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5{\texttimes}10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5{\texttimes}10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1{\texttimes}10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002766}, author = {Ma, Jiantao and Rebholz, Casey M and Braun, Kim V E and Reynolds, Lindsay M and Aslibekyan, Stella and Xia, Rui and Biligowda, Niranjan G and Huan, Tianxiao and Liu, Chunyu and Mendelson, Michael M and Joehanes, Roby and Hu, Emily A and Vitolins, Mara Z and Wood, Alexis C and Lohman, Kurt and Ochoa-Rosales, Carolina and van Meurs, Joyce and Uitterlinden, Andre and Liu, Yongmei and Elhadad, Mohamed A and Heier, Margit and Waldenberger, Melanie and Peters, Annette and Colicino, Elena and Whitsel, Eric A and Baldassari, Antoine and Gharib, Sina A and Sotoodehnia, Nona and Brody, Jennifer A and Sitlani, Colleen M and Tanaka, Toshiko and Hill, W David and Corley, Janie and Deary, Ian J and Zhang, Yan and Sch{\"o}ttker, Ben and Brenner, Hermann and Walker, Maura E and Ye, Shumao and Nguyen, Steve and Pankow, Jim and Demerath, Ellen W and Zheng, Yinan and Hou, Lifang and Liang, Liming and Lichtenstein, Alice H and Hu, Frank B and Fornage, Myriam and Voortman, Trudy and Levy, Daniel} } @article {8639, title = {Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 14}, pages = {5182}, abstract = {

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Calcium-Binding Proteins, Feasibility Studies, Female, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Inhibitors of Activated STAT, Pulmonary Disease, Chronic Obstructive, Respiratory Physiological Phenomena, Small Ubiquitin-Related Modifier Proteins, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-020-18334-7}, author = {Zhao, Xutong and Qiao, Dandi and Yang, Chaojie and Kasela, Silva and Kim, Wonji and Ma, Yanlin and Shrine, Nick and Batini, Chiara and Sofer, Tamar and Taliun, Sarah A Gagliano and Sakornsakolpat, Phuwanat and Balte, Pallavi P and Prokopenko, Dmitry and Yu, Bing and Lange, Leslie A and Dupuis, Jos{\'e}e and Cade, Brian E and Lee, Jiwon and Gharib, Sina A and Daya, Michelle and Laurie, Cecelia A and Ruczinski, Ingo and Cupples, L Adrienne and Loehr, Laura R and Bartz, Traci M and Morrison, Alanna C and Psaty, Bruce M and Vasan, Ramachandran S and Wilson, James G and Taylor, Kent D and Durda, Peter and Johnson, W Craig and Cornell, Elaine and Guo, Xiuqing and Liu, Yongmei and Tracy, Russell P and Ardlie, Kristin G and Aguet, Francois and VanDenBerg, David J and Papanicolaou, George J and Rotter, Jerome I and Barnes, Kathleen C and Jain, Deepti and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Dugan-Perez, Shannon and Gupta, Namrata and Gabriel, Stacey and Rich, Stephen S and O{\textquoteright}Connor, George T and Redline, Susan and Reed, Robert M and Laurie, Cathy C and Daviglus, Martha L and Preudhomme, Liana K and Burkart, Kristin M and Kaplan, Robert C and Wain, Louise V and Tobin, Martin D and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Abecasis, Goncalo R and Silverman, Edwin K and Barr, R Graham and Cho, Michael H and Manichaikul, Ani} } @article {8989, title = {What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {76}, year = {2021}, month = {2021 09 13}, pages = {e321-e327}, abstract = {

BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion.

METHODS: Study participants (13 589 men and 5043 women aged >=65years) had walking speed (m/s) measured over 4-6 m (mean {\textpm} SD: 1.20 {\textpm} 0.27 m/s in men and 0.94 {\textpm} 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6\% men, 26.4\% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2\%) with walking speed >=0.75 m/s, which we labeled as "fast"; 478 (9.5\%) as "intermediate" (walking speed >=0.62 m/s but <0.75 m/s); and 421 (8.3\%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6\%) with walking speed >=1.00 m/s ("very fast"); 2901 (21.3\%) as "fast" (walking speed >=0.74 m/s but <1.00 m/s); 497 (3.7\%) as "intermediate" (walking speed >=0.57 m/s but <0.74 m/s); and 190 (1.4\%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11\% for men and 19\% for women) and highest in the "slow" (60.5\% in men and 71.0\% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

}, keywords = {Aged, Female, Gait, Humans, Independent Living, Male, Mobility Limitation, Sarcopenia, Walking, Walking Speed}, issn = {1758-535X}, doi = {10.1093/gerona/glab183}, author = {Cawthon, Peggy M and Patel, Sheena M and Kritchevsky, Stephen B and Newman, Anne B and Santanasto, Adam and Kiel, Douglas P and Travison, Thomas G and Lane, Nancy and Cummings, Steven R and Orwoll, Eric S and Duchowny, Kate A and Kwok, Timothy and Hirani, Vasant and Schousboe, John and Karlsson, Magnus K and Mellstr{\"o}m, Dan and Ohlsson, Claes and Ljunggren, Osten and Xue, Qian-Li and Shardell, Michelle and Jordan, Joanne M and Pencina, Karol M and Fielding, Roger A and Magaziner, Jay and Correa-de-Araujo, Rosaly and Bhasin, Shalender and Manini, Todd M} } @article {8664, title = {Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.}, journal = {EBioMedicine}, volume = {63}, year = {2021}, month = {2021 Jan}, pages = {103157}, abstract = {

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04\%, P~=~6.1~{\texttimes}~10; METTL8, rs116951054, MAF 0.09\%, P~=~4.5~{\texttimes}~10; and MATK, rs539182790, MAF 0.05\%, P~=~3.4~{\texttimes}~10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P~=~1.2~{\texttimes}~10, nearest gene GATM, and rs71147340, MAF=0.34, P~=~3.3~{\texttimes}~10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2020.103157}, author = {Lin, Bridget M and Grinde, Kelsey E and Brody, Jennifer A and Breeze, Charles E and Raffield, Laura M and Mychaleckyj, Josyf C and Thornton, Timothy A and Perry, James A and Baier, Leslie J and de Las Fuentes, Lisa and Guo, Xiuqing and Heavner, Benjamin D and Hanson, Robert L and Hung, Yi-Jen and Qian, Huijun and Hsiung, Chao A and Hwang, Shih-Jen and Irvin, Margaret R and Jain, Deepti and Kelly, Tanika N and Kobes, Sayuko and Lange, Leslie and Lash, James P and Li, Yun and Liu, Xiaoming and Mi, Xuenan and Musani, Solomon K and Papanicolaou, George J and Parsa, Afshin and Reiner, Alex P and Salimi, Shabnam and Sheu, Wayne H-H and Shuldiner, Alan R and Taylor, Kent D and Smith, Albert V and Smith, Jennifer A and Tin, Adrienne and Vaidya, Dhananjay and Wallace, Robert B and Yamamoto, Kenichi and Sakaue, Saori and Matsuda, Koichi and Kamatani, Yoichiro and Momozawa, Yukihide and Yanek, Lisa R and Young, Betsi A and Zhao, Wei and Okada, Yukinori and Abecasis, Gonzalo and Psaty, Bruce M and Arnett, Donna K and Boerwinkle, Eric and Cai, Jianwen and Yii-Der Chen, Ida and Correa, Adolfo and Cupples, L Adrienne and He, Jiang and Kardia, Sharon Lr and Kooperberg, Charles and Mathias, Rasika A and Mitchell, Braxton D and Nickerson, Deborah A and Turner, Steve T and Vasan, Ramachandran S and Rotter, Jerome I and Levy, Daniel and Kramer, Holly J and K{\"o}ttgen, Anna and Rich, Stephen S and Lin, Dan-Yu and Browning, Sharon R and Franceschini, Nora} } @article {8913, title = {Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.}, journal = {Hum Mol Genet}, year = {2021}, month = {2021 Sep 06}, abstract = {

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI{\textquoteright}s Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddab252}, author = {Little, Amarise and Hu, Yao and Sun, Quan and Jain, Deepti and Broome, Jai and Chen, Ming-Huei and Thibord, Florian and McHugh, Caitlin and Surendran, Praveen and Blackwell, Thomas W and Brody, Jennifer A and Bhan, Arunoday and Chami, Nathalie and Vries, Paul S and Ekunwe, Lynette and Heard-Costa, Nancy and Hobbs, Brian D and Manichaikul, Ani and Moon, Jee-Young and Preuss, Michael H and Ryan, Kathleen and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Abecasis, Goncalo R and Almasy, Laura and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Choquet, Helene and Correa, Adolfo and Curran, Joanne E and Faraday, Nauder and Fornage, Myriam and Glahn, David C and Hou, Lifang and Jorgenson, Eric and Kooperberg, Charles and Lewis, Joshua P and Lloyd-Jones, Donald M and Loos, Ruth J F and Min, Nancy and Mitchell, Braxton D and Morrison, Alanna C and Nickerson, Debbie and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Pankratz, Nathan and Psaty, Bruce M and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Smith, Albert V and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Conomos, Matthew P and Laurie, Cecelia A and Mathias, Rasika A and Li, Yun and Auer, Paul L and Thornton, Timothy and Reiner, Alexander P and Johnson, Andrew D and Raffield, Laura M} } @article {8920, title = {Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 08 26}, pages = {136}, abstract = {

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90\%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 {\texttimes} 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

}, issn = {1756-994X}, doi = {10.1186/s13073-021-00917-8}, author = {Cade, Brian E and Lee, Jiwon and Sofer, Tamar and Wang, Heming and Zhang, Man and Chen, Han and Gharib, Sina A and Gottlieb, Daniel J and Guo, Xiuqing and Lane, Jacqueline M and Liang, Jingjing and Lin, Xihong and Mei, Hao and Patel, Sanjay R and Purcell, Shaun M and Saxena, Richa and Shah, Neomi A and Evans, Daniel S and Hanis, Craig L and Hillman, David R and Mukherjee, Sutapa and Palmer, Lyle J and Stone, Katie L and Tranah, Gregory J and Abecasis, Goncalo R and Boerwinkle, Eric A and Correa, Adolfo and Cupples, L Adrienne and Kaplan, Robert C and Nickerson, Deborah A and North, Kari E and Psaty, Bruce M and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Vasan, Ramachandran S and Wilson, James G and Zhu, Xiaofeng and Redline, Susan} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} } @article {9107, title = {Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 May 12}, abstract = {

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute{\textquoteright}s Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5\%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac100}, author = {Pankratz, Nathan and Wei, Peng and Brody, Jennifer A and Chen, Ming-Huei and Vries, Paul S and Huffman, Jennifer E and Stimson, Mary Rachel and Auer, Paul L and Boerwinkle, Eric and Cushman, Mary and Maat, Moniek P M and Folsom, Aaron R and Franco, Oscar H and Gibbs, Richard A and Haagenson, Kelly K and Hofman, Albert and Johnsen, Jill M and Kovar, Christie L and Kraaij, Robert and McKnight, Barbara and Metcalf, Ginger A and Muzny, Donna and Psaty, Bruce M and Tang, Weihong and Uitterlinden, Andr{\'e} G and Rooij, Jeroen G J and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Reiner, Alex P and Morrison, Alanna C and Smith, Nicholas L} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9261, title = {Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Dec 08}, pages = {7592}, abstract = {

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

}, keywords = {Blood Cells, Genome-Wide Association Study, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-022-35354-7}, author = {Wheeler, Marsha M and Stilp, Adrienne M and Rao, Shuquan and Halldorsson, Bjarni V and Beyter, Doruk and Wen, Jia and Mihkaylova, Anna V and McHugh, Caitlin P and Lane, John and Jiang, Min-Zhi and Raffield, Laura M and Jun, Goo and Sedlazeck, Fritz J and Metcalf, Ginger and Yao, Yao and Bis, Joshua B and Chami, Nathalie and de Vries, Paul S and Desai, Pinkal and Floyd, James S and Gao, Yan and Kammers, Kai and Kim, Wonji and Moon, Jee-Young and Ratan, Aakrosh and Yanek, Lisa R and Almasy, Laura and Becker, Lewis C and Blangero, John and Cho, Michael H and Curran, Joanne E and Fornage, Myriam and Kaplan, Robert C and Lewis, Joshua P and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Preuss, Michael and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Tang, Hua and Tracy, Russell P and Boerwinkle, Eric and Abecasis, Goncalo R and Blackwell, Thomas W and Smith, Albert V and Johnson, Andrew D and Mathias, Rasika A and Nickerson, Deborah A and Conomos, Matthew P and Li, Yun and {\TH}orsteinsdottir, Unnur and Magn{\'u}sson, Magn{\'u}s K and Stefansson, Kari and Pankratz, Nathan D and Bauer, Daniel E and Auer, Paul L and Reiner, Alex P} } @article {9258, title = {Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 Nov 29}, abstract = {

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95\% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 {\texttimes} 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95\% confidence interval: 3.06, 9.21) of DKD (P = 2.72 {\texttimes} 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 {\texttimes} 10-8) and NPEPPS (P = 1.51 {\texttimes} 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac290}, author = {Pan, Yang and Sun, Xiao and Mi, Xuenan and Huang, Zhijie and Hsu, Yenchih and Hixson, James E and Munzy, Donna and Metcalf, Ginger and Franceschini, Nora and Tin, Adrienne and K{\"o}ttgen, Anna and Francis, Michael and Brody, Jennifer A and Kestenbaum, Bryan and Sitlani, Colleen M and Mychaleckyj, Josyf C and Kramer, Holly and Lange, Leslie A and Guo, Xiuqing and Hwang, Shih-Jen and Irvin, Marguerite R and Smith, Jennifer A and Yanek, Lisa R and Vaidya, Dhananjay and Chen, Yii-Der Ida and Fornage, Myriam and Lloyd-Jones, Donald M and Hou, Lifang and Mathias, Rasika A and Mitchell, Braxton D and Peyser, Patricia A and Kardia, Sharon L R and Arnett, Donna K and Correa, Adolfo and Raffield, Laura M and Vasan, Ramachandran S and Cupple, L Adrienne and Levy, Daniel and Kaplan, Robert C and North, Kari E and Rotter, Jerome I and Kooperberg, Charles and Reiner, Alexander P and Psaty, Bruce M and Tracy, Russell P and Gibbs, Richard A and Morrison, Alanna C and Feldman, Harold and Boerwinkle, Eric and He, Jiang and Kelly, Tanika N} } @article {8996, title = {{Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project}, journal = {Stroke}, volume = {53}, year = {2022}, month = {Mar}, pages = {875{\textendash}885}, abstract = {Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).\ Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.\ .\ We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.}, author = {Hu, Y. and Haessler, J. W. and Manansala, R. and Wiggins, K. L. and Moscati, A. and Beiser, A. and Heard-Costa, N. L. and Sarnowski, C. and Raffield, L. M. and Chung, J. and Marini, S. and Anderson, C. D. and Rosand, J. and Xu, H. and Sun, X. and Kelly, T. N. and Wong, Q. and Lange, L. A. and Rotter, J. I. and Correa, A. and Vasan, R. S. and Seshadri, S. and Rich, S. S. and Do, R. and Loos, R. J. F. and Longstreth, W. T. and Bis, J. C. and Psaty, B. M. and Tirschwell, D. L. and Assimes, T. L. and Silver, B. and Liu, S. and Jackson, R. and Wassertheil-Smoller, S. and Mitchell, B. D. and Fornage, M. and Auer, P. L. and Reiner, A. P. and Kooperberg, C.} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10\% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9321, title = {Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Mar 24}, pages = {e003532}, abstract = {

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6\% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4{\texttimes}10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6{\texttimes}10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8{\texttimes}10 with the secondary filter), while did not (minimum =4.4{\texttimes}10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4{\texttimes}10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.121.003532}, author = {Seyerle, Amanda A and Laurie, Cecelia A and Coombes, Brandon J and Jain, Deepti and Conomos, Matthew P and Brody, Jennifer and Chen, Ming-Huei and Gogarten, Stephanie M and Beutel, Kathleen M and Gupta, Namrata and Heckbert, Susan R and Jackson, Rebecca D and Johnson, Andrew D and Ko, Darae and Manson, JoAnn E and McKnight, Barbara and Metcalf, Ginger A and Morrison, Alanna C and Reiner, Alexander P and Sofer, Tamar and Tang, Weihong and Wiggins, Kerri L and Boerwinkle, Eric and Andrade, Mariza de and Gabriel, Stacey B and Gibbs, Richard A and Laurie, Cathy C and Psaty, Bruce M and Vasan, Ramachandran S and Rice, Ken and Kooperberg, Charles and Pankow, James S and Smith, Nicholas L and Pankratz, Nathan} } @article {9581, title = {Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1278215}, abstract = {

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP >= 140 or diastolic BP >= 90~mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90~mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90~mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95\% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center{\textquoteright}s DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1278215}, author = {Armstrong, Nicole D and Srinivasasainagendra, Vinodh and Ammous, Farah and Assimes, Themistocles L and Beitelshees, Amber L and Brody, Jennifer and Cade, Brian E and Ida Chen, Yii-Der and Chen, Han and de Vries, Paul S and Floyd, James S and Franceschini, Nora and Guo, Xiuqing and Hellwege, Jacklyn N and House, John S and Hwu, Chii-Min and Kardia, Sharon L R and Lange, Ethan M and Lange, Leslie A and McDonough, Caitrin W and Montasser, May E and O{\textquoteright}Connell, Jeffrey R and Shuey, Megan M and Sun, Xiao and Tanner, Rikki M and Wang, Zhe and Zhao, Wei and Carson, April P and Edwards, Todd L and Kelly, Tanika N and Kenny, Eimear E and Kooperberg, Charles and Loos, Ruth J F and Morrison, Alanna C and Motsinger-Reif, Alison and Psaty, Bruce M and Rao, Dabeeru C and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Smith, Albert V and Irvin, Marguerite R and Arnett, Donna K} } @article {9484, title = {WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 22}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 {\texttimes} 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, doi = {10.1101/2023.08.21.23293271}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra and Chittoor, Geetha and Josyula, Navya S and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Margaret and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Marchand, Loic Le and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Chen, Yii-Der Ida and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Shoemaker, M Benjamin and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Costa, Nancy Heard- and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} } @article {9500, title = {Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.}, journal = {bioRxiv}, year = {2023}, month = {2023 Sep 12}, abstract = {

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

}, doi = {10.1101/2023.09.10.555215}, author = {Jiang, Min-Zhi and Gaynor, Sheila M and Li, Xihao and Van Buren, Eric and Stilp, Adrienne and Buth, Erin and Wang, Fei Fei and Manansala, Regina and Gogarten, Stephanie M and Li, Zilin and Polfus, Linda M and Salimi, Shabnam and Bis, Joshua C and Pankratz, Nathan and Yanek, Lisa R and Durda, Peter and Tracy, Russell P and Rich, Stephen S and Rotter, Jerome I and Mitchell, Braxton D and Lewis, Joshua P and Psaty, Bruce M and Pratte, Katherine A and Silverman, Edwin K and Kaplan, Robert C and Avery, Christy and North, Kari and Mathias, Rasika A and Faraday, Nauder and Lin, Honghuang and Wang, Biqi and Carson, April P and Norwood, Arnita F and Gibbs, Richard A and Kooperberg, Charles and Lundin, Jessica and Peters, Ulrike and Dupuis, Jos{\'e}e and Hou, Lifang and Fornage, Myriam and Benjamin, Emelia J and Reiner, Alexander P and Bowler, Russell P and Lin, Xihong and Auer, Paul L and Raffield, Laura M} } @article {9376, title = {Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 May 30}, pages = {3111}, abstract = {

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

}, keywords = {Ethnicity, Genome-Wide Association Study, Humans, Metabolome, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {2041-1723}, doi = {10.1038/s41467-023-38800-2}, author = {Feofanova, Elena V and Brown, Michael R and Alkis, Taryn and Manuel, Astrid M and Li, Xihao and Tahir, Usman A and Li, Zilin and Mendez, Kevin M and Kelly, Rachel S and Qi, Qibin and Chen, Han and Larson, Martin G and Lemaitre, Rozenn N and Morrison, Alanna C and Grieser, Charles and Wong, Kari E and Gersztern, Robert E and Zhao, Zhongming and Lasky-Su, Jessica and Yu, Bing} }