Journal Article

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

Zalloua, Pierre, Wolford, Brooke N., Thorleifsson, Gudmar, Ma, Lijiang, Helgadottir, Anna, Ishigaki, Kazuyoshi, Costanzo, Maria C., Watkins, Hugh, Kyriakou, Theodosios, Kamatani, Yoichiro, Komuro, Issei, Atri, Deepak S., Jang, Dong-Keun, Aragam, Krishna G., Sabatine, Marc S., Koyama, Satoshi, Jiang, Tao, Farrall, Martin, Erdmann, Jeanette, Wang, Minxian, Kamanu, Frederick K., Hveem, Kristian, Giardoglou, Panagiota, Melander, Olle, Gupta, Rajat M., Marston, Nicholas A., de Vries, Paul S., Li, Ling, Burtt, Noël P., Deloukas, Panos, Pang, Shichao, Morrison, Alanna C., Stefansson, Kari, Murgia, Federico, Schunkert, Heribert, Brown, Michael R., Baras, Aris, Sherliker, Paul, Weeks, Elle M., Webb, Thomas R., Clarke, Robert, Kathiresan, Sekar, Venegas, Loreto Muñoz, Ellinor, Patrick T., Munz, Matthias, Dedoussis, George, Flannick, Jason, Kessler, Thorsten, Samani, Nilesh J., Finucane, Hilary K., Smedley, Damian, Thorgeirsson, Gudmundur, Brumpton, Ben, Güldener, Ulrich, Reinberger, Tobias, Schnitzler, Gavin, Khera, Amit V., Haider, Syed M. Ijlal, Orho-Melander, Marju, Giannakopoulou, Olga, Kastrati, Adnan, Hopewel

2022

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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