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

Aragam, Krishna G ; Hindy, George LU ; Koyama, Satoshi LU orcid ; Melander, Olle LU orcid ; Orho-Melander, Marju LU and Butterworth, Adam S. (2022) In Nature Genetics 54(12). p.1803-1815
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... (More)

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.

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author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Coronary Artery Disease/genetics, Genome-Wide Association Study
in
Nature Genetics
volume
54
issue
12
pages
1803 - 1815
publisher
Nature Publishing Group
external identifiers
  • pmid:36474045
  • scopus:85143409775
ISSN
1546-1718
DOI
10.1038/s41588-022-01233-6
language
English
LU publication?
yes
additional info
© 2022. The Author(s).
id
50f86865-802b-4787-a3f5-a6548a1dfbaa
date added to LUP
2023-01-12 11:37:08
date last changed
2024-06-10 13:48:32
@article{50f86865-802b-4787-a3f5-a6548a1dfbaa,
  abstract     = {{<p>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 &gt;250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.</p>}},
  author       = {{Aragam, Krishna G and Hindy, George and Koyama, Satoshi and Melander, Olle and Orho-Melander, Marju and Butterworth, Adam S.}},
  issn         = {{1546-1718}},
  keywords     = {{Humans; Coronary Artery Disease/genetics; Genome-Wide Association Study}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1803--1815}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants}},
  url          = {{http://dx.doi.org/10.1038/s41588-022-01233-6}},
  doi          = {{10.1038/s41588-022-01233-6}},
  volume       = {{54}},
  year         = {{2022}},
}