In EDS ansehen

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

Gespeichert in:
Bibliographische Detailangaben
Titel: Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
Autoren: 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., Åsvold, B.O., Brown, M.R., Brumpton, B., 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., Munz, 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., Björkegren, 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., 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., Biobank Japan, EPIC-CVD, The CARDIoGRAMplusC4D Consortium
Verlagsinformationen: 2022.
Publikationsjahr: 2022
Schlagwörter: 16. Peace & justice, 3. Good health
Beschreibung: 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. © 2022, The Author(s).
Publikationsart: Article
Sprache: Greek
Zugangs-URL: https://pergamos.lib.uoa.gr/uoa/dl/object/3345712
Dokumentencode: edsair.od......2127..8e02d934aebbe19c1eb9b059c20addb8
Datenbank: OpenAIRE
Beschreibung
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. © 2022, The Author(s).