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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

2022; Nature Portfolio; Volume: 54; Issue: 12 Linguagem: Inglês

10.1038/s41588-022-01233-6

1546-1718

Krishna G. Aragam, Tao Jiang, Anuj Goel, Stavroula Kanoni, Brooke N. Wolford, Deepak Atri, E. Weeks, Minxian Wang, George Hindy, Wei Zhou, Christopher Grace, Carolina Roselli, Nicholas Marston, Frederick Kamanu, Ida Surakka, Loreto Muñoz Venegas, Paul Sherliker, Satoshi Koyama, Kazuyoshi Ishigaki, Bjørn Olav Åsvold, Michael R. Brown, Ben Brumpton, Paul S. de Vries, Olga Giannakopoulou, Tota Giardoglou, Daníel F. Guðbjartsson, Ulrich Güldener, Syed M. Ijlal Haider, Anna Helgadóttir, M Ibrahim, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Tomasz Konopka, Ling Li, Lijiang Ma, Thomas Meitinger, Sören Mucha, Matthias Munz, Federico Murgia, Jonas B. Nielsen, Markus M. Nöthen, Shichao Pang, Tobias Reinberger, Gavin R. Schnitzler, Damian Smedley, Guðmar Þorleifsson, Moritz von Scheidt, Jacob C. Ulirsch, John Danesh, Davíð O. Arnar, Noël P. Burtt, Maria C. Costanzo, Jason Flannick, Kaoru Ito, Dongkeun Jang, Yoichiro Kamatani, Amit V. Khera, Issei Komuro, Iftikhar J. Kullo, Luca A. Lotta, Christopher P. Nelson, Robert Roberts, Guðmundur Þorgeirsson, Unnur Þorsteinsdóttir, Tom R. Webb, Aris Baras, Johan Björkegren, Eric Boerwinkle, George Dedoussis, Hilma Hólm, Kristian Hveem, Olle Melander, Alanna C. Morrison, Marju Orho‐Melander, Lοukianos S. Rallidis, Arno Ruusalepp, Marc S. Sabatine, Kāri Stefánsson, Pierre Zalloua, Patrick T. Ellinor, Martin Farrall, John Danesh, Christian T. Ruff, Hilary K. Finucane, Jemma C. Hopewell, Robert Clarke, Rajat M. Gupta, Jeanette Erdmann, Nilesh J. Samani, Heribert Schunkert, Hugh Watkins, Cristen J. Willer, Panos Deloukas, Sekar Kathiresan, Adam S. Butterworth, Paul S. de Vries, Moritz von Scheidt,

Congenital heart defects research

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.