TY - JOUR
T1 - Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases
AU - The Biobank Japan Project
AU - Regeneron Genetics Center
AU - DBDS Genomic Consortium
AU - Roselli, Carolina
AU - Surakka, Ida
AU - Olesen, Morten S.
AU - Sveinbjornsson, Gardar
AU - Marston, Nicholas A.
AU - Choi, Seung Hoan
AU - Holm, Hilma
AU - Chaffin, Mark
AU - Gudbjartsson, Daniel
AU - Hill, Matthew C.
AU - Aegisdottir, Hildur
AU - Albert, Christine M.
AU - Alonso, Alvaro
AU - Anderson, Christopher D.
AU - Arking, Dan E.
AU - Arnar, David O.
AU - Barnard, John
AU - Benjamin, Emelia J.
AU - Braunwald, Eugene
AU - Brumpton, Ben
AU - Campbell, Archie
AU - Chami, Nathalie
AU - Chasman, Daniel I.
AU - Cho, Kelly
AU - Choi, Eue Keun
AU - Christophersen, Ingrid E.
AU - Chung, Mina K.
AU - Conen, David
AU - Crijns, Harry J.
AU - Cutler, Michael J.
AU - Czuba, Tomasz
AU - Damrauer, Scott M.
AU - Dichgans, Martin
AU - Dörr, Marcus
AU - Dudink, Elton
AU - Duong, Thuy Vy
AU - Erikstrup, Christian
AU - Esko, Tõnu
AU - Fatkin, Diane
AU - Faul, Jessica D.
AU - Ferreira, Manuel
AU - Freitag, Daniel F.
AU - Ganesh, Santhi K.
AU - Gaziano, J. Michael
AU - Geelhoed, Bastiaan
AU - Ghouse, Jonas
AU - Gieger, Christian
AU - Giulianini, Franco
AU - Graham, Sarah E.
AU - Schunkert, Heribert
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=105001208957&partnerID=8YFLogxK
U2 - 10.1038/s41588-024-02072-3
DO - 10.1038/s41588-024-02072-3
M3 - Article
C2 - 40050429
AN - SCOPUS:105001208957
SN - 1061-4036
VL - 57
SP - 539
EP - 547
JO - Nature Genetics
JF - Nature Genetics
IS - 3
M1 - 11303
ER -