Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.
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Authors
Jiang, Tao
Hindy, George
Grace, Christopher
Marston, Nicholas A
Surakka, Ida
Venegas, Loreto Muñoz
Sherliker, Paul
Brown, Michael R
de Vries, Paul S
Giannakopoulou, Olga
Giardoglou, Panagiota
Haider, Syed M Ijlal
Ibrahim, Maysson
Kastrati, Adnan
Kyriakou, Theodosios
Konopka, Tomasz
Ma, Lijiang
Meitinger, Thomas
Nielsen, Jonas B
Nöthen, Markus M
Reinberger, Tobias
Schnitzler, Gavin
Biobank Japan
EPIC-CVD
Arnar, David O
Burtt, Noël P
Jang, Dong-Keun
Kamatani, Yoichiro
Lotta, Luca A
Nelson, Christopher P
Thorgeirsson, Gudmundur
Thorsteinsdottir, Unnur
Boerwinkle, Eric
Dedoussis, George
Hveem, Kristian
Melander, Olle
Rallidis, Loukianos S
Ruusalepp, Arno
Sabatine, Marc S
Zalloua, Pierre
Ellinor, Patrick T
Danesh, John
Ruff, Christian T
Hopewell, Jemma C
Gupta, Rajat M
Deloukas, Panos
CARDIoGRAMplusC4D Consortium
Publication Date
2022-12Journal Title
Nat Genet
ISSN
1061-4036
Publisher
Nature Research
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Aragam, K. G., Jiang, T., Goel, A., Kanoni, S., Wolford, B. N., Atri, D. S., Weeks, E. M., et al. (2022). Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.. Nat Genet https://doi.org/10.1038/s41588-022-01233-6
Abstract
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.
Sponsorship
Medical Research Council (G0800270)
European Research Council (268834)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
National Institute for Health Research (IS-BRC-1215-20014)
Identifiers
External DOI: https://doi.org/10.1038/s41588-022-01233-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335646
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