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Roselli, C.* ; Surakka, I.* ; Olesen, M.S.* ; Sveinbjornsson, G.* ; Marston, N.A.* ; Choi, S.H.* ; Holm, H.* ; Chaffin, M.* ; Gudbjartsson, D.* ; Hill, M.C.* ; Aegisdottir, H.* ; Albert, C.M.* ; Alonso, A.* ; Anderson, C.D.* ; Arking, D.E.* ; Arnar, D.O.* ; Barnard, J.* ; Benjamin, E.J.* ; Braunwald, E.* ; Brumpton, B.* ; Campbell, A.* ; Chami, N.* ; Chasman, D.I.* ; Cho, K.* ; Choi, E.K.* ; Christophersen, I.E.* ; Chung, M.K.* ; Conen, D.* ; Crijns, H.J.* ; Cutler, M.J.* ; Czuba, T.* ; Damrauer, S.M.* ; Dichgans, M.* ; Dörr, M.* ; Dudink, E.A.* ; Duong, T.* ; Erikstrup, C.* ; Esko, T.* ; Fatkin, D.* ; Faul, J.D.* ; Ferreira, M.* ; Freitag, D.F.* ; Ganesh, S.K.* ; Gaziano, J.M.* ; Geelhoed, B.* ; Ghouse, J.* ; Gieger, C. ; Giulianini, F.* ; Graham, S.E.* ; Gudnason, V.* ; Guo, X.* ; Haggerty, C.* ; Hayward, C.* ; Heckbert, S.R.* ; Hveem, K.* ; Ito, K.* ; Johnson, R.* ; Jukema, J.W.* ; Jurgens, S.J.* ; Kääb, S.* ; Kane, J.P.* ; Kany, S.* ; Kardia, S.L.R.* ; Kavousi, M.* ; Khurshid, S.* ; Kamanu, F.K.* ; Kirchhof, P.* ; Kleber, M.E.* ; Knight, S.* ; Komuro, I.* ; Krieger, J.E.* ; Launer, L.J.* ; Li, D.* ; Lin, H.* ; Lin, H.J.* ; Loos, R.J.F.* ; Lotta, L.A.* ; Lubitz, S.A.* ; Lunetta, K.L.* ; Macfarlane, P.W.* ; Magnusson, P.K.E.* ; Malik, R.* ; Mantineo, H.* ; Marcus, G.M.* ; März, W.* ; McManus, D.D.* ; Melander, O.* ; Melloni, G.E.M.* ; Meyre, P.B.* ; Miyazawa, K.* ; Mohanty, S.* ; Monfort, L.M.* ; Müller-Nurasyid, M.* ; Nafissi, N.A.* ; Natale, A.* ; Nazarian, S.* ; Ostrowski, S.R.* ; Pak, H.N.* ; Pang, S.* ; Pedersen, O.B.* ; Pedersen, N.L.* ; Pereira, A.C.* ; Pirruccello, J.P.* ; Preuss, M.* ; Psaty, B.M.* ; Pullinger, C.R.* ; Rader, D.J.* ; Rämö, J.T.* ; Ridker, P.M.* ; Rienstra, M.* ; Risch, L.* ; Roden, D.M.* ; Rotter, J.I.* ; Sabatine, M.S.* ; Schunkert, H.* ; Shah, S.H.* ; Shim, J.* ; Shoemaker, M.B.* ; Simonson, B.* ; Sinner, M.F.* ; Smit, R.A.J.* ; Smith, J.A.* ; Smith, N.L.* ; Smith, J.G.* ; Soliman, E.Z.* ; Sørensen, E.* ; Sotoodehnia, N.* ; Strbian, D.* ; Stricker, B.H.* ; Teder-Laving, M.* ; Sun, Y.V.* ; Thériault, S.* ; Thorolfsdottir, R.B.* ; Thorsteinsdottir, U.* ; Tveit, A.* ; van der Harst, P.* ; van Meurs, J.* ; Wang, B.* ; Weiss, S.* ; Wells, Q.S.* ; Weng, L.C.* ; Wilson, P.W.* ; Xiao, L.* ; Yang, P.S.* ; Yao, J.* ; Yoneda, Z.T.* ; Zeller, T.* ; Zeng, L.* ; Zhao, W.* ; Zhou, X.* ; Zöllner, S.* ; Ruff, C.T.* ; Bundgaard, H.* ; Willer, C.* ; Stefansson, K.* ; Ellinor, P.T.*

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.

Nat. Genet. 57, 539-547 (2025)

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Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Variants; Loci; Mutation; Cohort; Common; Zfhx3

ISSN (print) / ISBN 1061-4036

e-ISSN 1546-1718

Journal Nature Genetics

Quellenangaben Volume: 57, Issue: 3, Pages: 539-547

Publisher Nature Publishing Group

Publishing Place New York, NY

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology (EPI)

Grants Office of Research and Development, Veterans Health Administration
NINDS
NIMH
NIDA
NHLBI
NHGRI
NCI
Common Fund of the Office of the Director of the National Institutes of Health