Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.

Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
PLoS Genetics (Impact Factor: 8.17). 06/2011; 7(6):e1002138. DOI: 10.1371/journal.pgen.1002138
Source: PubMed

ABSTRACT For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

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    ABSTRACT: We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999-2000, and 2001-2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.
    PLoS Genetics 12/2014; 10(12):e1004678. DOI:10.1371/journal.pgen.1004678 · 8.17 Impact Factor
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    ABSTRACT: Purpose:Substantial progress has been made in identifying susceptibility variants for age-related macular degeneration (AMD) in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci. Methods:Targeted genotyping was performed across study sites for AMD and lipid trait-associated SNPs. Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity to determine risk of any AMD. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study. Results:AMD index variants rs1061170 (CFH) and rs10490924 (ARMS2) were associated with AMD at p=3.05x10-8 and p=6.36x10-6, respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans (p<0.05). Four lipid-associated SNPs (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans at a liberal significance threshold (p<0.05). Conclusions:While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14246 · 3.66 Impact Factor
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    ABSTRACT: Background-A founder mutation was recently discovered and described as conferring favorable lipid profiles and reduced subclinical atherosclerotic disease in a Pennsylvania Amish population. Preliminary data have suggested that this null mutation APOC3 R19X (rs76353203) is rare in the general population. Methods and Results-To better describe the frequency and lipid profile in the general population, we as part of the Population Architecture using Genomics and Epidemiology I Study and the Epidemiological Architecture for Genes Linked to Environment Study genotyped rs76353203 in 1113 Amish participants from Ohio and Indiana and 19 613 participants from the National Health and Nutrition Examination Surveys (NHANES III, 1999 to 2002, and 2007 to 2008). We found no carriers among the Ohio and Indiana Amish. Of the 19 613 NHANES participants, we identified 31 participants carrying the 19X allele, for an overall allele frequency of 0.08%. Among fasting adults, the 19X allele was associated with lower triglycerides (n=7603; beta=-71.20; P=0.007) and higher high-density lipoprotein cholesterol (n=8891; beta=15.65; P=0.0002) and, although not significant, lower low-density lipoprotein cholesterol (n=6502; beta=-4.85; P=0.68) after adjustment for age, sex, and race/ethnicity. On average, 19X allele participants had approximately half the triglyceride levels (geometric means, 51.3 to 69.7 versus 134.6 to 141.3 mg/dL), >20% higher high-density lipoprotein cholesterol levels (geometric means, 56.8 to 74.4 versus 50.38 to 53.36 mg/dL), and lower low-density lipoprotein cholesterol levels (geometric means, 104.5 to 128.6 versus 116.1 to 125.7 mg/dL) compared with noncarrier participants. Conclusions-These data demonstrate that APOC3 19X exists in the general US population in multiple racial/ethnic groups and is associated with cardio-protective lipid profiles.
    Circulation Cardiovascular Genetics 11/2014; 7(6). DOI:10.1161/CIRCGENETICS.113.000369 · 6.73 Impact Factor

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