Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study
Year: 2020
Type: review
Study design: Observational 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.
Source: PLoS Genetics
Authors: Yao Hu, Mariaelisa Graff, Jeffrey Haessler, Steven Buyske, Stephanie A. Bien, Ran Tao, Heather M. Highland, Katherine K. Nishimura, Niha Zubair, Yingchang Lu, Marie Verbanck, Austin T. Hilliard, Derek Klarin, Scott M. Damrauer, Yuk-Lam Ho, the VA Million Veteran Program, Peter W. F. Wilson, Kyong-Mi Chang, Philip S. Tsao, Kelly Cho, Christopher J. O’Donnell, Themistocles L. Assimes, Lauren E. Petty, Jennifer E. Below, Ozan Dikilitas, Daniel J. Schaid, Matthew L. Kosel, Iftikhar J. Kullo, Laura J. Rasmussen-Torvik, Gail P. Jarvik, Qiping Feng, Wei-Qi Wei, Eric B. Larson, Frank D. Mentch, Berta Almoguera, Patrick M. Sleiman, Laura M. Raffield, Adolfo Correa, Lisa W. Martin, Martha Daviglus, Tara C. Matise, Jose Luis Ambite, Christopher S. Carlson, Ron Do, Ruth J. F. Loos, Lynne R. Wilkens, Loic Le Marchand, Chris Haiman, Daniel O. Stram, Lucia A. Hindorff, Kari E. North, Charles Kooperberg, Iona Cheng, Ulrike Peters
Institutions: Fred Hutch Cancer Center, University of North Carolina at Chapel Hill, Rutgers, The State University of New Jersey, Vanderbilt University, Vanderbilt University Medical Center, Icahn School of Medicine at Mount Sinai, VA Palo Alto Health Care System, Palo Alto Veterans Institute for Research, Broad Institute, Harvard University, VA Boston Healthcare System, Massachusetts General Hospital, Emory Clinic, Philadelphia VA Medical Center, University of Pennsylvania, Atlanta VA Medical Center, Stanford Medicine, Stanford University, The University of Texas Health Science Center at Houston, Mayo Clinic, Northwestern University, University of Washington Medical Center, Kaiser Permanente Washington Health Research Institute, Children's Hospital of Philadelphia, University of Mississippi Medical Center, George Washington University, University of Illinois Chicago, University of Southern California, University of Hawaii Cancer Center, National Institutes of Health, National Human Genome Research Institute, Cancer Prevention Institute of California
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: U.S. Department of Health and Human Services, Office of Dietary Supplements, U.S. Department of Veterans Affairs, American Heart Association, Andrea and Charles Bronfman Philanthropies, Brigham and Women's Hospital, Children's Hospital of Philadelphia, Vanderbilt University, University of Miami, Jackson State University, Northwestern University, San Diego State University, Cincinnati Children's Hospital Medical Center, Icahn School of Medicine at Mount Sinai, University of Washington, Johns Hopkins University, Vanderbilt University Medical Center, Broad Institute, Mississippi State Department of Health, Ministerio de Economía y Competitividad, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Institute on Minority Health and Health Disparities
Awards: G1004541261, G10106230, G1042216835, G1081972346, FHCRC High-Performance Computing Cluster, G1085576015, G1093951984, G1114307781, eMERGE Coordinating Center, G1220445869, Using genetic variation to study biology of blood lipids & coronary heart disease, G1295889178, G1301356587, G1312369436, EHR-based Genomic Discovery and Implementation, Hispanic Community Health Study, G1455175283, G1522370804, G1540916838, G1563316267, G1587824183, G1634877266, G1666450717, G1678063915, G1711244518, G1730507467, G1766209448, EHR-based Genomic Risk Assessment and Management for Diverse Populations, G190379715, G1917633662, G1947136479, G2012024608, G2079069761, G2135211244, G2135293100, Harvard Longwood Research Training in Vascular Surgery, G2221742881, G2262505034, G2273349799, G228913406, G2316258288, G2412562481, G2415573643, G2464355595, G2466919156, Institute for Clinical and Translational Research (UL1), HISPANIC COMMUNITY HEALTH STUDY - FIELD CENTER, G2501967490, G2528054427, G2575730562, G2644289446, G265762973, G2809357584, G2888548701, G2955879720, G2970637568, G2978603772, G303142226, G3057025668, G3062787641, G3112942449, G3165348588, G3204657967, G3226771441, Hispanic Community Health Study, G3398273182, Integrative Analysis of a GWAS Repository with EMRs from over 40,000 Children, eMERGE IV Northwest: A partnership to evaluate the use of genomic information in the health care of diverse participants, G350245564, G3545534745, G3555711967, Genetic Epidemiology of Causal Variants across the Life Course Phase II (CALiCo I, Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy, G3677686024, EMR-Linked Biobank for Translational Genomics, GWA for Gene-Environment Interaction Effects Influencing CHD, G3744596180, The Electronic Medical Records and Genomics (eMERGE) Network Phase III - Coordinating Center (U01), G3838006641, G3853170735, G3856074833, G388572957, G3901643820, G3952816605, G3973572274, G4109850255, G4121762840, G412187901, PAGE III: Population Architecture using Genomics and Epidemiology, Diverse ancestry biobank to map biomedical traits and elucidate health disparitie, G4203491109, G4324164867, Hispanic Community Health Study, G4407350458, G4430667546, G4503763930, G4552920371, Genetic and Environmental Determinants of Obesity and CVD Risk across the Lifecourse: The Santiago Longitudinal Study, G4597579782, G4711807797, G47192932, G4739409156, G4747441672, G4750447874, G4790942633, G4860668542, G4897018079, G4940192625, G4989378220, A Center for GEI Association Studies, G5196702962, G528357465, Discovering lipoprotein lipase pathway variants that protect against CHD, G5365244667, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G543802643, G5478822001, Epidemiologic Studies of Putative Functional Variation in Multiethnic Cohort, G5547620395, G555858244, G5585626916, G5624510383, G5739677117, G5770678025, G579045871, G5878028785, G5906656038, JH/CIDR Genotyping for Genome-Wide Association Studies, G5928944960, G6071621673, G6075306088, G6156511736, G6156766399, PAGE III: Population Architecture using Genomics and Epidemiology, G6182174406, G619791618, Leveraging ancestral diversity to map adiposity loci in Hispanics, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, G635500700, Genomic Medicine at Northwestern: Discovery and Implementation, VGER, the Vanderbilt Genome-Electronic Records Project, G6571475356, G6585687856, G6712854737, G6729976872, G673128162, G6744188800, Biorepository for Genomic Medicine in diverse Communities, G6837735701, G6849114374, G6862617662, G6902273418, G6975713648, Geisinger eGenonic Medicine (GeM) Program, G7032370290, Better Outcomes for Children: GWAS & PheWAS in eMERGEII., G7057037114, G7091571603, G7155745631, G7163342664, G7203655167, G7239480477, NHGRI PAGE Coordinating Center, G7272721675, G7272881256, G7278742613, G7408420985, G7446853542, G7513901258, G7526106616, G7535686976, G7637536449, G7678550560, Vanderbilt Genome Electronic Records Project, The Future of Genomics Medicine in Patient Care: Contributions from CHOP, G8006194172, EMERGE III CENTRAL SEQUENCING, GENOTYPING AND INTERPRETATION FACILITY, eMERGE Phase IV Clinical Center at Mass General Brigham, G8102260223, G814392139, G820454163, A Personalized Genomic Medicine Pilot Program Using the NJgene eMERGE Experience, G833338434, G836417160, G8386326007, G8536616440, G8565821944, IRIS: Incorporating Research Into Sight, Exonic variants and their relation to complex traits in minorities of the WHI, G8618783052, G8637122261, G87163782, G8738262636, HISPANIC COMMUNITY HEALTH STUDY-268065233, G8840902395, DNA Sequencing Support for the eMERGE Network, G8904081916, G89699440, G9000210217, G9000355710, Cardiovascular Epidemiology Training Grant, The Genetic Epidemiology of Heart, Lung, and Blood Traits Training Grant (GenHLB), Hispanic Latino Lipid Consortium, Understanding Population Differences in Cancer: The MEC Study, From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, G942241345
OpenAlex ID: W3013989169