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

Roselli, C.; Surakka, I.; Olesen, M.S.; Sveinbjornsson, G.; Marston, N.A.; Choi, S.H.; ... ; Regeneron Genetics Ctr (2025)

Article / Letter to editor

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.

• All authors: 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.; 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.Q.; 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.; 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.; Sorensen, E.; Sotoodehnia, N.; Strbian, D.; Stricker, B.H.; Teder-Laving, M.; Sun, Y.V.; Thériault, S.; Thorolfsdottir, R.B.; Thorsteinsdottir, U.; Tveit, A.; Harst, P. van der; Meurs, J. van; 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.Y.; Zhao, W.; Zhou, X.; Zöllner, S.; Ruff, C.T.; Willer, C.; Ellinor, P.T.; Bundgaard, H.; Stefansson, K.; DBDS Genomic Consortium; BioBank Japan Project; Regeneron Genetics Ctr
• Date: 2025-03-06
• Journal: Nature Genetics
• Volume: 57
• Issue: 3
• Pages: 539 - 547
• DOI: doi:10.1038/s41588-024-02072-3