Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

• Type of Material: Article
• Authors: Catherine Tcheandjieu, VA Palo Alto Health Care System; Xiang Zhu, VA Palo Alto Health Care System; Austin T Hilliard, VA Palo Alto Health Care System; Shoa L Clarke, VA Palo Alto Health Care System; Valerio Napolioni, University of Camerino; Shining Ma, Stanford University; Kyung Min Lee, VA Salt Lake City Health Care System; Huaying Fang, Stanford University; Fei Chen, University of Southern California; Yingchang Lu, Vanderbilt University; Noah L Tsao, University of Pennsylvania; Sridharan Raghavan, VA Eastern Colorado Health Care System; Satoshi Koyama, RIKEN Center for Integrative Medical Sciences; Bryan R Gorman, VA Boston Healthcare System; Marijana Vujkovic, Corporal Michael J. Crescenz VA Medical Center, Philadelphia; Derek Klarin, VA Palo Alto Health Care System; Michael G Levin, Corporal Michael J. Crescenz VA Medical Center, Philadelphia; Nasa Sinnott-Armstrong, VA Palo Alto Health Care System, Palo Alto; Genevieve L Wojcik, Johns Hopkins University; Mary E Plomondon, Rocky Mountain Regional VA Medical Center; Thomas M Maddox, JC HealthCare Washington Univ Sch Med; Stephen W Waldo, Rocky Mountain Regional VA Medical Center; Alexander G Bick, Vanderbilt University; Saiju Pyarajan, VA Boston Healthcare System; Jie Huang, VA Boston Healthcare System; Rebecca Song, VA Boston Healthcare System; Yuk-Lam Ho, VA Boston Healthcare System; Steven Buyske, Rutgers State Univ; Charles Kooperberg, Fred Hutchinson Cancer Center; Jeffrey Haessler, Fred Hutchinson Cancer Center; Ruth JF Loos, Icahn School of Medicine at Mount Sinai; Ron Do, Icahn School of Medicine at Mount Sinai; Marie Verbanck, Icahn School of Medicine at Mount Sinai; Kumardeep Chaudhary, Icahn School of Medicine at Mount Sinai; Kari E North, University of North Carolina; Christy L Avery, University of North Carolina; Mariaelisa Graff, University of North Carolina; Christopher A Haiman, University of Southern California; Loïc Le Marchand, University of Hawaii Cancer Center; Lynne R Wilkens, University of Hawaii Cancer Center; Joshua C Bis, University of Washington; Hampton Leonard, National Institute on Aging, Bethesda; Botong Shen, National Institute on Aging, Bethesda; Leslie A Lange, Division of Biomedical Informatics and Personalized Medicine, Aurora; Ayush Giri, Vanderbilt University; Ozan Dikilitas, Mayo Clinic, Rochester; Iftikhar J Kullo, Mayo Clinic, Rochester; Ian B Stanaway, University of Washington; Gail P Jarvik, University of Washington; Adam S Gordon, Northwestern University; Scott Hebbring, Marshfield Clinic Research Institute; Bahram Namjou, Cincinnati Children’s Hospital Medical Center; Kenneth M Kaufman, Cincinnati Children’s Hospital Medical Center; Kaoru Ito, RIKEN Center for Integrative Medical Sciences; Kazuyoshi Ishigaki, RIKEN Center for Integrative Medical Sciences; Yoichiro Kamatani, RIKEN Center for Integrative Medical Sciences; Shefali S Verma, University of Pennsylvania; Marylyn D Ritchie, University of Pennsylvania; Rachel L Kember, Corporal Michael J. Crescenz VA Medical Center; Aris Baras, Regeneron Genetics Center, Tarrytown; Luca A Lotta, Regeneron Genetics Center, Tarrytown; Sekar Kathiresan, Broad Institute of MIT and Harvard, Cambridge; Elizabeth R Hauser, Durham VA Health Care System; Donald R Miller, Bedford VA Healthcare System; Jennifer S Lee, VA Palo Alto Health Care System; Danish Saleheen, Corporal Michael J. Crescenz VA Medical Center; Peter D Reaven, Phoenix VA Health Care System; Kelly Cho, VA Boston Healthcare System; Michael J Gaziano, VA Boston Healthcare System; Pradeep Natarajan, Broad Institute of MIT and Harvard; Jennifer E Huffman, VA Boston Healthcare System; Benjamin F Voight, Corporal Michael J. Crescenz VA Medical Center; Daniel J Rader, University of Pennsylvania; Kyong-Mi Chang, Corporal Michael J. Crescenz VA Medical Center; Julie A Lynch, VA Salt Lake City Health Care System; Scott M Damrauer, University of Pennsylvania; Peter Wilson, Emory University; Hua Tang, Stanford University; Yan Sun, Emory University; Philip S Tsao, VA Palo Alto Health Care System; Christopher J O'Donnell, VA Boston Healthcare System; Themistocles L Assimes, VA Palo Alto Health Care System
• Language: English
• Date: 2022-08-01
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply
• Final Published Version (URL): http://dx.doi.org/10.1038/s41591-022-01891-3
• Title of Journal or Parent Work: NATURE MEDICINE
• Volume: 28
• Issue: 8
• Start Page: 1679
• End Page: 1692
• Keywords: Science & Technology; CLINICAL-ASSESSMENT; HEALTH; HERITABILITY; HEART-DISEASE; DATA QUALITY; Medicine, Research & Experimental; METAANALYSIS; PROGRAM; POLYGENIC RISK SCORES; Life Sciences & Biomedicine; Research & Experimental Medicine; Biochemistry & Molecular Biology; REGRESSION; SUSCEPTIBILITY LOCI; Cell Biology
• Research Categories: Statistics

Abstract

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.