W63 - GWAS on WHIMS and subsample of HT EA women
Investigator Names and Contact Information
Introduction/Intent
GWAS data exists on ~12,000 WHI African American and Hispanic women from the OS and the CT (in M5-SHARe) and ~5,200 cardiovascular outcome cases and controls from the HT trial (M13-GARNET). The current proposal aims to expand existing WHI GWAS data to European Americans (EA) in the HT, focusing on women in WHIMS. Women’s Health Initiative Memory Study (AS39-WHIMS) is an ancillary study to WHI which was designed to examine the effects of hormone therapy on the development and progression of dementia in women over 65 years of age. The proposed GWAS will include 4,660 WHIMS participants, 279 HT EA participants over 65 years of age, 899 HT EA participants under age 65 who were not previously included in GARNET or WHIMS, and 292 blind samples (150 blind duplicate pairs) for a total of approximately 6,130 DNA samples.
EA GWAS will allow for race-ethnicity comparisons for quantitative traits within WHI. The proposed project will expand the GWAS cohort size for studies within the HT cohort when combined with other GWAS data in GARNET. This GWAS with cognitive outcomes expands core resource for future studies of genomics, candidate genes, whole genome (or exome) sequencing, etc. Participant selection from WHIMS avoids case-control selection bias, expands the ability to looks at aging related phenotypes, and will overlap the Long Life Study cohort. These same participants have been or will be analyzed for CVD and diabetes biomarkers (insulin, glucose, CRP, creatinine, cholesterol, HDL, LDL, triglyceride) and thus the GWAS data will also allow for association studies of genetic variants with key biomarkers.
The study has enormous potential for exploring risk factors and outcomes. The WHI dataset itself has detailed data on nutrition, lifestyle and psychosocial characteristics. It has been linked to national datasets like the Center for Medicare Services (CMS) which can yield procedure, medication and cost data, and the datasets that provide data on environment and neighborhood.
Sample Selection of W63 HT EA cohort
| GWAS | Biomarkers in W581 | |
|---|---|---|
| M13-GARNET | 4,416 | |
| < 65 (in M13, not WHIMS) | 1,101 | |
| >65 (in M13, not WHIMS) | 722 | |
| WHIMS (EA) | 6,061 | |
| WHIMS (EA not in M13)2 | 4,660 | |
| < 65 (not M13, not WHIMS)2 | 899 | 899 |
| > 65 (not M13, not WHIMS)2 | 279 | 279 |
| Remaining M13 (not in WHIMS) | 1,192 | |
| Totals | 10,254 | 10,254 |
1 = insulin, glucose, CRP, creatinine, cholesterol, HDL, LDL, trigylceride
2 = To be completed by 2013
Results/Findings
Illumina Omni Express + Exome Array Phenotype data to be updated on dbGaP annually
W63-WHIMS+ was included in the 2013 GWAS Imputation project (imputed to 1000G data). See the table in Key Genetics and Biomarkers Studies for information about the WHIMS+GWAS included in the imputition data. Baseline clinical biomarker data (glucose, insulin, creatinine, CRP, triglycerides, cholesterol, HDL, and LDL) are also available (see study W58).
Publications:
WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Papers of this website.
Data Dictionaries and Study Documentation
This section displays all study-related data dictionaries and study-related files. The investigators for this study will upload the datasets, data dictionaries, and other study-related files. Study-related files will be made available to the public one year after the completion of the ancillary study, with the exception of the datasets, which will only be available to those with a Data Distribution Agreement. Those will be available to those with permission to download and will appear as a download link next to the data dictionary
Data Dictionaries
Name | Description |
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Study Documents
Name | Description |
|---|---|
| NameW63 selection summary 05032011 (2).doc | Description |
Related Papers
Impact of Type 2 diabetes mellitus and postmenopausal hormone therapy on incidence of cognitive impairment in older women
In older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes.The Women's Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average o...
Related Studies: W63
Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits
Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 1...
Prospective associations of C-reactive protein (CRP) levels and CRP genetic risk scores with risk of total knee and hip replacement for osteoarthritis in a diverse cohort
OBJECTIVE: To examine associations of high-sensitivity C-reactive protein (CRP) levels and polygenic CRP genetic risk scores (GRS) with risk of end-stage hip or knee osteoarthritis (OA), defined as incident total hip (THR) or knee replacement (TKR) for OA. DESIGN: This study included a cohort of postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. Women were followed from baseline to date of THR or TKR, death, or December 31, 2014. Medicare claims data i...
Keywords: C-Reactive Protein; Crp; Genetic Risk Score; Inflammation; Osteoarthritis
Broad clinical manifestations of polygenic risk for coronary artery disease in the Women’s Health Initiative
Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized. Methods: We measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women's Health Initiative and applied a phenome-wide association study framework to assess assoc...
Keywords: Polygenic Risk Score; Genetic Risk Score; Phenome-Wide Association Study; Coronary Artery Disease; Cardiovascular Disease; Myocardial Infarction; Coronary Revascularization
Multi-ethnic genome-wide association study of decomposed cardioelectric phenotypes illustrates strategies to identify and characterize evidence of shared genetic effects for complex traits
Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, S...
Keywords: Electrocardiography; Genetics; Pleiotropy; Multivariate; Ion Channels
Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Abstract Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in ...
Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study
Objective: Vasomotor symptoms (VMS, ie, hot flashes or night sweats) are reported by many, but not all, women. The extent to which VMS are genetically determined is unknown. We evaluated the relationship of genetic variation and VMS. Methods: In this observational study, we accessed data from three genome-wide association studies (GWAS) (SNP Health Association Resource cohort [SHARe], WHI Memory Study cohort [WHIMSþ], and Genome-Wide Association Studies of Treatment Response in Randomized Clinic...
Keywords: Gene; Gwas; Genome-Wide Association Study; Menopause; Hot Flashes; Vasomotor Symptoms; Night Sweats
Physical activity modifies genetic susceptibility to obesity in postmenopausal women
OBJECTIVE: We conducted a gene-environment interaction study to evaluate whether the association of body mass index (BMI) associated meta genome-wide association study single-nucleotide polymorphisms (SNPs) (as a genetic risk score) and BMI is modified by physical activity and age. METHODS: In 8,206 women of European ancestry from the Women's Health Initiative (WHI), we used linear regression to examine main effects of the 95 SNP BMI genetic risk score (GRS) and physical activity on BMI, and eva...
Keywords: Obesity; Gene-Environment Interaction; Total Energy Intake; Abdominal Obesity; Insulin Resistance
Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conduct...
Keywords: Pharmacogenomics; Qt Interval; Genetic Epidemiology; Genome-Wide Association Study; Gene-Based Tests
Lipoproteins, triglycerides, and cholesterol in relation to breast cancer risk: a Mendelian randomization analysis
Keywords: N/A
Related Studies: W63
Genome-wide association analyses of pharmacogenomic loci associated with new-onset diabetes after exposure to diabetogenic drug therapy
Keywords: Pharmacogenetics; Diabetes; Thiazide Diuretics; Beta Blockers; Pharmacotherapy
Related Studies: W63
Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions
An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total ...
A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on...
Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. ...
Sleep quality, duration, and breast cancer aggressiveness
PURPOSE: Epidemiological studies suggest that short sleep duration and poor sleep quality may increase breast cancer risk. However, whether sleep is associated with breast tumor aggressiveness characteristics has largely been unexplored. METHODS: The study included 4171 non-Hispanic whites (NHW) and 235 African Americans (AA) diagnosed with incident, primary, invasive breast cancer in the Women's Health Initiative (WHI) Observational Study (1994-2013). We used logistic regression to examine the ...
Keywords: Breast Cancer; Disparities; Race; Sleep Duration; Sleep Quality; Subtype
Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] =0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrati...
Keywords: Hemostasis Traits; Charge Consortium; Exome
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Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We f...
Identification of genetic modifiers of cognitive aging in humans using mouse population genetics
Keywords: Gwas; Cognition; Aging; Modifiers; Translational
Related Studies: W63
Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis
Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting...
Keywords: Breast Cancer; Insulin; Glucose; Obesity; Type 2 Diabetes; Genetics; Mendelian Randomization Analysis
Related Studies: W63
Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucl...
Replication study of genome-wide association study findings of longevity in white, African-American, and Hispanic women: The Women’s Health Initiative
Keywords: Gene; Genome; Healthy Aging; Exceptional Longevity; Snps
Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
Abstract Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four n...
Keywords: Genetic Factors; Exome Chip; Rare Variants; Hemoglobin; Hematocrit
A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs ...
Keywords: Pharmacogenomics; Qt Interval; Genetic Epidemiology; Genome-Wide Association Study; Gene-Based Tests
Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phe...
Discovery of novel heart rate-associated loci using the Exome Chip
Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 Eur...
Keywords: Ecg; Rr Interval; Heart Rate; Exome Chip; Genetic Epidemiology; Arrhythmia
The effect of phenotypic outliers and non-normality on rare-variant association testing
Abstract Rare-variant association studies (RVAS) have made important contributions to human complex trait genetics. These studies rely on specialized statistical methods for analyzing rare-variant associations, both individually and in aggregate. We investigated the impact that phenotypic outliers and non-normality have on the performance of rare-variant association testing procedures. Ignoring outliers or non-normality can significantly inflate Type I error rates. We found that rank-based inver...
Keywords: None Provided
Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-dise...
Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populat...
Genetic analysis of mitochondrial ribosomal proteins and cognitive aging in postemenopausal women
Genes encoding mitochondrial ribosomal proteins (MRPs) have been linked to aging and longevity in model organisms (i.e., mice, Caenorhabditis elegans). Here we evaluated if the MRPs have conserved effects on aging traits in humans. We utilized data from 4,504 participants of the Women's Health Initiative Memory Study (WHIMS) who had both longitudinal cognitive data and genetic data. Two aging phenotypes were considered: (1) gross lifespan (time to all-cause mortality), and (2) cognitive aging (l...
Keywords: Apoe; Cognitive Aging; Gene-Set Analysis; Lifespan; Mitochondrial Ribosomal Proteins
Gene-hormone therapy interaction and fracture risk in postmenopausal women
CONTEXT: Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored. OBJECTIVE: The objective was to test an interaction between genetic susceptibility and HT on fracture risk. DESIGN: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRS) and 50 bone mineral density (BMD) variants (BMD-GRS). We used Cox reg...
Keywords: Bone Mineral Density; Gene-Environment Interaction; Hormone Therapy; Gwas
Related Studies: W63
Epigenome-wide association study of leukocyte telomere length
Abstract
Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Long...
Keywords: Dna Methylation; Leukocyte Telomere Length; Aging; Mortality; Cvd
Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype
Introduction: Whether apolipoprotein E's (APOE's) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. Methods: Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], non-HDL cholesterol, total-to-HDL, LDL-to-HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 po...
Keywords: Probable Dementia; Cholesterol; Statins; Apoe; Global Cognition
Instrumental variable analysis of alcohol use and cardiometabolic risk in the Women's Health Initiative
Keywords: Mendelian Randomization; Instrumental Analysis; Genome-Wide Association Study; Alcohol; Insulin Resistance; Blood Pressure; Dyslipidemia; Cardiovascular Disease.
Genetic analysis of venous thromboembolism highlights the genetic overlap of thrombosis with lipids and arterial vascular disease
Keywords: Venous Thromboembolism; Incident Analysis; Polygenic Risk Score; Genetics; Genomics
Related Studies: W63
Unbiased estimate of heritability of CAD before and after adjustment for risk factors in prospective NHLBI cohorts
Keywords: Genetic Risk Score; Genome-Wide Association Study; Coronary Artery Disease; Death Cause; And Atherosclerotic Cardiovascular Diseases
Related Studies: W63
X-ploring the sex-specific genetic architecture of late-onset Alzheimer’s disease
Related Studies: W63
Rare and low-frequency coding variants alter human adult height
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of...
Keywords: N/A
DNA methylation-based estimator of telomere length
Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p...
Keywords: Dna Methylation; Leukocyte Telomere Length; Aging; Mortality; Cvd
Identification of nine new susceptibility loci for endometrial cancer
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of en...
Keywords: Endometrial Cancer; Genetics; Gwas; Genotype Imputation
A large-scale exome array analysis of venous thromboembolism
Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct sin...
Keywords: Venous Thrombosis; Venous Thromboembolism; Genetics; Exome Array; Meta-Analysis
Interaction of vitamin D status with development of cognitive impairment in participants in the WHIMS Clinical Trial
Related Studies: W63
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals...
Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT...
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (Z...
Genetic determinants of pelvic organ prolapse in women of European American descent: the Women’s Health Initiative
Keywords: Candidate Gene; Urinary Incontinence; Pelvic Organ Prolapse; Pelvic Floor Disorders
Related Studies: W63
Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.
Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5...
Keywords: Genetic Factors; Exome Chip; Rare Variants; Inflammation; Inflammatory Biomarkers; Crp
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tis...
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The influence of genetic susceptibility and calcium plus vitamin D supplementation on fracture risk
BACKGROUND: Fracture is a complex trait, affected by both genetic and environmental factors. A meta-analysis of genome-wide association studies (GWASs) identified multiple bone mineral density (BMD) and fracture-associated loci. OBJECTIVE: We conducted a study to evaluate whether fracture genetic risk score (Fx-GRS) and bone mineral density genetic risk score (BMD-GRS) modify the association between the intake of calcium with vitamin D (CaD) and fracture risk. DESIGN: Data from 5823 white postme...
Keywords: Total Fracture; Genetic Risk Score; Gene-Environmental Interaction; Calcium; Vitamin D
Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure
Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The large...
Keywords: A2bp1; Blood Pressure; Rare Variants
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Polygenic risk scores for prediction of breast cancer and breast cancer subtypes
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided...
Keywords: Breast; Cancer; Epidemiology; Genetic; Polygenic; Prediction; Risk; Score; Screening; Stratification
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New blood pressure-associated loci identified in meta-analyses of 475,000 individuals
BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 sugge...
Keywords: Blood Pressure; Exome; Genetics; Genotype; Sample Size
Genome-wide association of blood pressure traits by Hispanic/Latino background: the Hispanic Community Health Study/Study of Latinos
Hypertension prevalence varies between ethnic groups, possibly due to differences in genetic, environmental, and cultural determinants. Hispanic/Latino Americans are a diverse and understudied population. We performed a genome-wide association study (GWAS) of blood pressure (BP) traits in 12,278 participants from the Hispanics Community Health Study/Study of Latinos (HCHS/SOL). In the discovery phase we identified eight previously unreported BP loci. In the replication stage, we tested these loc...
Keywords: Diverse Populations; Generalization
