TY - JOUR T1 - Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. JF - Nat Med Y1 - 2022 A1 - Tcheandjieu, Catherine A1 - Zhu, Xiang A1 - Hilliard, Austin T A1 - Clarke, Shoa L A1 - Napolioni, Valerio A1 - Ma, Shining A1 - Lee, Kyung Min A1 - Fang, Huaying A1 - Chen, Fei A1 - Lu, Yingchang A1 - Tsao, Noah L A1 - Raghavan, Sridharan A1 - Koyama, Satoshi A1 - Gorman, Bryan R A1 - Vujkovic, Marijana A1 - Klarin, Derek A1 - Levin, Michael G A1 - Sinnott-Armstrong, Nasa A1 - Wojcik, Genevieve L A1 - Plomondon, Mary E A1 - Maddox, Thomas M A1 - Waldo, Stephen W A1 - Bick, Alexander G A1 - Pyarajan, Saiju A1 - Huang, Jie A1 - Song, Rebecca A1 - Ho, Yuk-Lam A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - Haessler, Jeffrey A1 - Loos, Ruth J F A1 - Do, Ron A1 - Verbanck, Marie A1 - Chaudhary, Kumardeep A1 - North, Kari E A1 - Avery, Christy L A1 - Graff, Mariaelisa A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Wilkens, Lynne R A1 - Bis, Joshua C A1 - Leonard, Hampton A1 - Shen, Botong A1 - Lange, Leslie A A1 - Giri, Ayush A1 - Dikilitas, Ozan A1 - Kullo, Iftikhar J A1 - Stanaway, Ian B A1 - Jarvik, Gail P A1 - Gordon, Adam S A1 - Hebbring, Scott A1 - Namjou, Bahram A1 - Kaufman, Kenneth M A1 - Ito, Kaoru A1 - Ishigaki, Kazuyoshi A1 - Kamatani, Yoichiro A1 - Verma, Shefali S A1 - Ritchie, Marylyn D A1 - Kember, Rachel L A1 - Baras, Aris A1 - Lotta, Luca A A1 - Kathiresan, Sekar A1 - Hauser, Elizabeth R A1 - Miller, Donald R A1 - Lee, Jennifer S A1 - Saleheen, Danish A1 - Reaven, Peter D A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Natarajan, Pradeep A1 - Huffman, Jennifer E A1 - Voight, Benjamin F A1 - Rader, Daniel J A1 - Chang, Kyong-Mi A1 - Lynch, Julie A A1 - Damrauer, Scott M A1 - Wilson, Peter W F A1 - Tang, Hua A1 - Sun, Yan V A1 - Tsao, Philip S A1 - O'Donnell, Christopher J A1 - Assimes, Themistocles L KW - Coronary Artery Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

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.

VL - 28 IS - 8 ER -