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

By Krishna G. Aragam, Tao Jiang, Anuj Goel, Stavroula Kanoni, Brooke N. Wolford, Elle M. Weeks, Minxian Wang, George Hindy, Wei Zhou, Christopher Grace, Carolina Roselli, Nicholas A Marston, Frederick K Kamanu, Ida Surakka, Loreto Munoz Venegas, Paul Sherliker, Satoshi Koyama, Kazuyoshi Ishigaki, Bjorn O Asvold, Michael R Brown, Ben Brumpton, Paul S. de Vries, Olga Giannakopoulou, Panagiota Giardoglou, Daniel F. Gudbjartsson, Ulrich Guldener, Syed M. Ijlal Haider, Anna Helgadottir, Maysson Ibrahim, Adnan Kastrati, Thorsten Kessler, Ling Li, Lijiang Ma, Thomas Meitinger, Soren Mucha, Matthias Munz, Federico Murgia, Jonas B Nielsen, Markus M Noethen, Shichao Pang, Tobias Reinberger, Gudmar Thorleifsson, Moritz von Scheidt, Jacob K Ulirsch, EPIC-CVD Consortium, Biobank Japan, David O. Arnar, Deepak S. Atri, Noel P Burtt, Maria C Costanzo, Jason Flannick, Rajat M Gupta, Kaoru Ito, Dong-Keun Jang, Yoichiro Kamatani, Amit V. Khera, Issei Komuro, Iftikhar J Kullo, Luca A Lotta, Christopher P Nelson, Robert Roberts, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Thomas R. Webb, Aris Baras, Johan LM Bjorkegren, Eric Boerwinkle, George Dedoussis, Hilma Holm, Kristian Hveem, Olle Melander, Alanna C. Morrison, Marju Orho-Melander, Loukianos S Rallidis, Arno Ruusalepp, Marc S Sabatine, Kari Stefansson, Pierre Zalloua, Patrick T Ellinor, Martin Farrall, John Danesh, Christian T Ruff, Hilary K Finucane, Jemma C. Hopewell, Robert Clarke, Jeanette Erdmann, Nilesh J. Samani, Heribert Schunkert, Hugh Watkins, Cristen Willer, Panos Deloukas, Sekar Kathiresan, Adam S Butterworth, on behalf of the CARDIoGRAMplusC4D Consortium

Posted 02 Jun 2021
medRxiv DOI: 10.1101/2021.05.24.21257377

Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

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