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

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 Europea...

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Published in:	Nature genetics Vol. 54; no. 12; pp. 1803 - 1815
Main 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., 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.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.12.2022 Nature Publishing Group
Subjects:	631/208/205/2138 692/699/75/2 Agriculture Animal Genetics and Genomics Basic Medicine Biobanks Biomedical and Life Sciences Biomedicine Blood pressure Cancer Research Cardiovascular disease Cell cycle Cell migration Clustering Coronary artery disease Coronary Artery Disease - genetics Coronary vessels Gene Function Gene loci Gene mapping Genes Genome-wide association studies Genome-Wide Association Study Genomes Heart diseases Human Genetics Humans Interrogation Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Meta-analysis Pathogenesis Risk Risk factors Vein & artery diseases United Kingdom > UK
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	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. Genome-wide association analyses, functionally informed fine-mapping and complementary gene prioritization approaches identify new risk loci and candidate effector genes for CAD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-022-01233-6