A large-scale multi-ethnic genome-wide association study of coronary artery disease
Authors: Assimes Themistocles , Tcheandjieu Catherine , Zhu Xiang , Hilliard Austin , Clarke Shoa , Napolioni Valerio , Ma Shining , Fang Huaying , Gorman Bryan R , Lee Kyung Min , Chen Fei , Pyarajan Saiju , Song Rebecca , Plomondon Mary , Maddox Thomas , Waldo Stephen , Sinnott-Armstrong Nasa , Ho Yuk-Lam , Wojcik Genevieve , Buyske Steven , Kooperberg Charles , Haessler Jeffrey , Loos Ruth , Do Ron , Verbanck Marie , Chaudhary Kumardeep , North Kari , Avery Christy , Haiman Christopher , Marchand Loic Le , Wilkens Lynne , Bis Joshua , Leonard Hampton , Shen Botong , Lange Leslie , Giri Ayush , Lu Yingchang , Dikilitas Ozan , Kullo Iftikhar , Stanaway Ian , Jarvik Gail , Gordon Adam , Hebbring Scott , Namjou Bahram , Kaufman Kenneth , Koyama Satoshi , Ito Kaoru , Ishigaki Kazuyoshi , Kamatani Yoichiro , Tsao Noah , Verma Shefali , Ritchie Marylyn , Kember Rachel , Baras Aris , Lotta Luca , Natarajan Pradeep , Levin Michael , Hauser Elizabeth , Miller Donald , Vujkovic Marijana , Huffman Jennifer , Raghavan Sridharan , Klarin Derek , Lee Jennifer , Voight Benjamin , Rader Daniel , Chang Kyong-Mi , Damrauer Scott , Lynch Julie , Wilson Peter , Tang Hua , Sun Yan , Tsao Phil , O'Donnell Christopher , Kathiresan Sekar , Saleheen Danish , Gaziano J. Michael , Reaven Peter , Cho Kelly , Bick Alexander , Graff Mariaelisa , Huang Jie 
Published: March 2021

Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.