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Aragam, K.G.* ; Jiang, T.* ; Goel, A.* ; Kanoni, S.* ; Wolford, B.N.* ; Atri, D.S.* ; Weeks, E.M.* ; Wang, M.* ; Hindy, G.* ; Zhou, W.* ; Grace, C.* ; Roselli, C.* ; Marston, N.A.* ; Kamanu, F.K.* ; Surakka, I.* ; Venegas, L.M.* ; Sherliker, P.* ; Koyama, S.* ; Ishigaki, K.* ; Asvold, B.O.* ; Brown, M.R.* ; Brumpton, B.M.* ; de Vries, P.S.* ; Giannakopoulou, O.* ; Giardoglou, P.* ; Gudbjartsson, D.F.* ; Güldener, U.* ; Haider, S.M.I.* ; Helgadottir, A.* ; Ibrahim, M.* ; Kastrati, A.* ; Kessler, T.* ; Kyriakou, T.* ; Konopka, T.* ; Li, L.* ; Ma, L.* ; Meitinger, T. ; Mucha, S.* ; Münz, M.* ; Murgia, F.* ; Nielsen, J.B.* ; Nöthen, M.M.* ; Pang, S.* ; Reinberger, T.* ; Schnitzler, G.* ; Smedley, D.* ; Thorleifsson, G.* ; von Scheidt, M.* ; Ulirsch, J.C.* ; Danesh, J.* ; Arnar, D.O.* ; Burtt, N.P.* ; Costanzo, M.C.* ; Flannick, J.* ; Ito, K.* ; Jang, D.K.* ; Kamatani, Y.* ; Khera, A.V.* ; Komuro, I.* ; Kullo, I.J.* ; Lotta, L.A.* ; Nelson, C.P.* ; Roberts, R.* ; Thorgeirsson, G.* ; Thorsteinsdottir, U.* ; Webb, T.R.* ; Baras, A.* ; Bjorkegren, J.L.M.* ; Boerwinkle, E.* ; Dedoussis, G.* ; Holm, H.* ; Hveem, K.* ; Melander, O.* ; Morrison, A.C.* ; Orho-Melander, M.* ; Rallidis, L.S.* ; Ruusalepp, A.* ; Sabatine, M.S.* ; Stefansson, K.* ; Zalloua, P.A.* ; Ellinor, P.T.* ; Farrall, M.* ; Ruff, C.T.* ; Finucane, H.K.* ; Hopewell, J.C.* ; Clarke, R.* ; Gupta, R.M.* ; Erdmann, J.* ; Samani, N.J.* ; Schunkert, H.* ; Watkins, H.* ; Willer, C.J.* ; Deloukas, P.* ; Kathiresan, S.* ; Butterworth, A.S.*

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

Nat. Genet. 54, 1803-1815 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genome-wide Association; Loci; Inhibition; Identification; Metaanalysis; Design
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 54, Issue: 12, Pages: 1803-1815 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Grants National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services
National Human Genome Research Institute
National Institutes of Health
NIH Roadmap for Medical Research
Stiftelsen Kristian Gerhard Jebsen
Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology
Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics)
Bavarian State Ministry of Health and Care
German Federal Ministry of Education and Research (BMBF)
British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)
Sonderforschungsbereich
UK National Institute for Health Research (NIHR)
University of Michigan Medical School
Central Norway Regional Health Authority
German Research Foundation (DFG)
Medical Research Council DTP studentship
British Heart Foundation
Oxford BHF Centre of Research Excellence
British Heart Foundation Centre of Research Excellence
British Heart Foundation (BHF)
American Heart Association
National Heart, Lung, and Blood Institute
AMED
Swedish Research Council
Heart Lung Foundation
Foundation Leducq (PlaqueOmics: New Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture)
American Heart Association Institute for Precision Cardiovascular Medicine
Harvard Catalyst
National Health and Medical Research Council (NHMRC) of Australia
National Institute of Diabetes and Digestive and Kidney Diseases
UK Medical Research Council
European Commission
NIHR Cambridge Biomedical Research Centre
Health Data Research UK - UK Medical Research Council
Engineering and Physical Sciences Research Council
Economic and Social Research Council
Department of Health and Social Care (England)
Chief Scientist Office of the Scottish Government Health and Social Care Directorates
Health and Social Care Research and Development Division (Welsh Government)
Public Health Agency (Northern Ireland)
Wellcome

TriPartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation
VIAgenomics
Wellcome Trust core award
NIHR Oxford Biomedical Research Centre
NIH
Japan Agency for Medical Research and Development, AMED
BHF
Swedish Heart and Lung Foundation
European Research Council
Lund University Infrastructure grant 'Malmo population-based cohorts'
National Science Foundation Graduate Research Program (DGE)