Journal article
Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 7.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41588-022-01233-6
- Publisher:
- Springer Nature
- Journal:
- Nature Genetics More from this journal
- Volume:
- 54
- Issue:
- 12
- Pages:
- 1803-1815
- Publication date:
- 2022-12-06
- Acceptance date:
- 2022-10-17
- DOI:
- EISSN:
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1546-1718
- ISSN:
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1061-4036
- Pmid:
-
36474045
- Language:
-
English
- Keywords:
- Pubs id:
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1312193
- Local pid:
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pubs:1312193
- Deposit date:
-
2023-02-23
Terms of use
- Copyright holder:
- Aragam et al.
- Copyright date:
- 2022
- Rights statement:
- Copyright © 2022, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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