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

TitleDiscovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.
Publication TypeJournal Article
Year of Publication2022
AuthorsAragam, KG, Jiang, T, Goel, A, Kanoni, S, Wolford, BN, Atri, DS, Weeks, EM, Wang, M, Hindy, G, Zhou, W, Grace, C, Roselli, C, Marston, NA, Kamanu, FK, Surakka, I, Venegas, LMuñoz, Sherliker, P, Koyama, S, Ishigaki, K, Åsvold, BO, Brown, MR, Brumpton, B, de Vries, PS, Giannakopoulou, O, Giardoglou, P, Gudbjartsson, DF, Güldener, U, Haider, SMIjlal, Helgadottir, A, Ibrahim, M, Kastrati, A, Kessler, T, Kyriakou, T, Konopka, T, Li, L, Ma, L, Meitinger, T, Mucha, S, Munz, M, Murgia, F, Nielsen, JB, Nöthen, MM, Pang, S, Reinberger, T, Schnitzler, G, Smedley, D, Thorleifsson, G, von Scheidt, M, Ulirsch, JC, Arnar, DO, Burtt, NP, Costanzo, MC, Flannick, J, Ito, K, Jang, D-K, Kamatani, Y, Khera, AV, Komuro, I, Kullo, IJ, Lotta, LA, Nelson, CP, Roberts, R, Thorgeirsson, G, Thorsteinsdottir, U, Webb, TR, Baras, A, Björkegren, JLM, Boerwinkle, E, Dedoussis, G, Holm, H, Hveem, K, Melander, O, Morrison, AC, Orho-Melander, M, Rallidis, LS, Ruusalepp, A, Sabatine, MS, Stefansson, K, Zalloua, P, Ellinor, PT, Farrall, M, Danesh, J, Ruff, CT, Finucane, HK, Hopewell, JC, Clarke, R, Gupta, RM, Erdmann, J, Samani, NJ, Schunkert, H, Watkins, H, Willer, CJ, Deloukas, P, Kathiresan, S, Butterworth, AS
Corporate AuthorsBiobank Japan, EPIC-CVD, CARDIoGRAMplusC4D Consortium
JournalNat Genet
Volume54
Issue12
Pagination1803-1815
Date Published2022 Dec
ISSN1546-1718
KeywordsCoronary Artery Disease, Genome-Wide Association Study, Humans
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.

DOI10.1038/s41588-022-01233-6
Alternate JournalNat Genet
PubMed ID36474045
PubMed Central IDPMC9729111
Grant ListBRC-1215-20014 / DH_ / Department of Health / United Kingdom
R01 HL086694 / HL / NHLBI NIH HHS / United States
UM1 DK105554 / DK / NIDDK NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
K08 HL153950 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R35 HL135824 / HL / NHLBI NIH HHS / United States
R01 HL125863 / HL / NHLBI NIH HHS / United States
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
MR/S502443/1 / MRC_ / Medical Research Council / United Kingdom
K08 HG010155 / HG / NHGRI NIH HHS / United States
K08 HL153937 / HL / NHLBI NIH HHS / United States
203141/Z/16/Z / WT_ / Wellcome Trust / United Kingdom
/ DH_ / Department of Health / United Kingdom
FS/14/66/3129 / BHF_ / British Heart Foundation / United Kingdom
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
T32 HG000040 / HG / NHGRI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
SP/13/2/30111 / BHF_ / British Heart Foundation / United Kingdom
SP/16/4/32697 / BHF_ / British Heart Foundation / United Kingdom
T32 HL007604 / HL / NHLBI NIH HHS / United States
R01 HL146860 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
SP/19/2/34462 / BHF_ / British Heart Foundation / United Kingdom
RE/13/1/30181 / BHF_ / British Heart Foundation / United Kingdom
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
HHSN268201700003I / HL / NHLBI NIH HHS / United States
SP/09/002 / BHF_ / British Heart Foundation / United Kingdom
G0800270 / MRC_ / Medical Research Council / United Kingdom

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