Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
Authors: Aragam Krishna G. , Jiang Tao , Goel Anuj , Kanoni Stavroula , Wolford Brooke N. , Atri Deepak S. , Weeks Elle M. , Wang Minxian , Hindy George , Zhou Wei , Grace Christopher , Roselli Carolina , Marston Nicholas A. , Kamanu Frederick K. , Surakka Ida , Venegas Loreto Muñoz , Sherliker Paul , Koyama Satoshi , Ishigaki Kazuyoshi , Åsvold Bjørn O. , Brown Michael R. , Brumpton Ben , de Vries Paul S. , Giannakopoulou Olga , Giardoglou Panagiota , Gudbjartsson Daniel F. , Güldener Ulrich , Haider Syed M. Ijlal , Helgadottir Anna , Ibrahim Maysson , Kastrati Adnan , Kessler Thorsten , Kyriakou Theodosios , Konopka Tomasz , Li Ling , Ma Lijiang , Meitinger Thomas , Mucha Sören , Munz Matthias , Murgia Federico , Nielsen Jonas B. , Nöthen Markus M. , Pang Shichao , Reinberger Tobias , Schnitzler Gavin , Smedley Damian , Thorleifsson Gudmar , von Scheidt Moritz , Ulirsch Jacob C. ,   Biobank Japan,   EPIC-CVD, Danesh John , Arnar David O. , Burtt Noël P. , Costanzo Maria C. , Flannick Jason , Ito Kaoru , Jang Dong-Keun , Kamatani Yoichiro , Khera Amit V. , Komuro Issei , Kullo Iftikhar J. , Lotta Luca A. , Nelson Christopher P. , Roberts Robert , Thorgeirsson Gudmundur , Thorsteinsdottir Unnur , Webb Thomas R. , Baras Aris , Björkegren Johan L. M. , Boerwinkle Eric , Dedoussis George , Holm Hilma , Hveem Kristian , Melander Olle , Morrison Alanna C. , Orho-Melander Marju , Rallidis Loukianos S. , Ruusalepp Arno , Sabatine Marc S. , Stefansson Kari , Zalloua Pierre , Ellinor Patrick T. , Farrall Martin , Danesh John , Ruff Christian T. , Finucane Hilary K. , Hopewell Jemma C. , Clarke Robert , Gupta Rajat M. , Erdmann Jeanette , Samani Nilesh J. , Schunkert Heribert , Watkins Hugh , Willer Cristen J. , Deloukas Panos , Kathiresan Sekar , Butterworth Adam S. ,   The CARDIoGRAMplusC4D Consortium, de Vries Paul S. , von Scheidt Moritz 
Published: December 2022

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.