Dataset Information

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

ABSTRACT: Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

SUBMITTER: Hu Y

PROVIDER: S-EPMC7145272 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Hu Yao Y Graff Mariaelisa M Haessler Jeffrey J Buyske Steven S Bien Stephanie A SA Tao Ran R Highland Heather M HM Nishimura Katherine K KK Zubair Niha N Lu Yingchang Y Verbanck Marie M Hilliard Austin T AT Klarin Derek D Damrauer Scott M SM Ho Yuk-Lam YL Wilson Peter W F PWF Chang Kyong-Mi KM Tsao Philip S PS Cho Kelly K O'Donnell Christopher J CJ Assimes Themistocles L TL Petty Lauren E LE Below Jennifer E JE Dikilitas Ozan O Schaid Daniel J DJ Kosel Matthew L ML Kullo Iftikhar J IJ Rasmussen-Torvik Laura J LJ Jarvik Gail P GP Feng Qiping Q Wei Wei-Qi WQ Larson Eric B EB Mentch Frank D FD Almoguera Berta B Sleiman Patrick M PM Raffield Laura M LM Correa Adolfo A Martin Lisa W LW Daviglus Martha M Matise Tara C TC Ambite Jose Luis JL Carlson Christopher S CS Do Ron R Loos Ruth J F RJF Wilkens Lynne R LR Le Marchand Loic L Haiman Chris C Stram Daniel O DO Hindorff Lucia A LA North Kari E KE Kooperberg Charles C Cheng Iona I Peters Ulrike U

PLoS genetics 20200330 3

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, fol ...[more]

PMID: 32226016

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Project description:By relating hundreds of thousands of genotypes to only a few phenotypes, mostly in individuals of one ancestry, genome-wide association (GWA) studies are identifying a rapidly growing number of associations. The Population Architecture using Genomics and Epidemiology (PAGE) Study is designed to further characterize the most promising variants along an epidemiological dimension that is substantial in its sample size, ethnic diversity, breadth of phenotypes, and exposures. PAGE includes scientists and population samples from large ongoing cohort studies: CALiCo (Causal Variants Across the Life Course, a consortium of ARIC, CARDIA, CHS, HCHS/SOL, Strong Heart Cohort Study, Strong Heart Family Study), EAGLE (Epidemiologic Architecture for Genes Linked to Environment, based on 3 National Health and Nutrition Examination Surveys (NHANES), MEC (Multiethnic Cohort) and WHI (Women's Health Initiative), with logistical and scientific support contributed by a Coordinating Center and the NHGRI Office of Population Genomics. These studies combined include over 270,000 participants, and populations represented include Asian Americans, African Americans, European Americans, Hispanic Americans, Native Hawaiians and American Indians. Health outcomes and traits of interest are prioritized, followed by replication of trait-genotype associations and generalization of their effects across population groups and environmental contexts. The first phase of genotyping focused on 901 high-profile SNPs having replicated associations with phenotypes related to diabetes, obesity, cardiovascular disease, lipids, cancers, menopause/menarche, inflammation and autoimmunity that are being genotyped in over 121,000 participants, as available for trait-specific analyses. SNP genotyping, quality control and population-specific association analyses are performed within each cohort, followed by meta-analyses using harmonized phenotypes and standardized analytic methods. The second phase of genotyping will be done using the Metabochip. The Metabochip is a custom large-scale (~200K SNPs) Illumina chip designed for association testing of several metabolic-related phenotypes. Genotyping will be performed at each study site and centralized analysis will be managed through the coordinating center. PAGE is generating 3 types of data: tier 1 (minimally curated phenotypes and analyses, all SNPs by all available phenotypes, used for Phenome-wide association study (PheWAS analysis)), tier 2 (carefully curated analyses of phenotypes available at only one of the four PAGE sites) and tier 3 (carefully curated phenotypes for multi-site analyses, data specifically generated for manuscripts). All tiers of data are submitted to the CC, where they undergo QC prior to submission to dbGaP.

Dataset Information

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Publications

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Similar Datasets

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