Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
Bibliographical noteFunding Information:
P.T.E is the PI on a grant from Bayer to the Broad Institute focused on the genetics and therapeutics of AF. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.K. receives research support from the European Union, the British Heart Foundation, the Leducq Foundation, the Medical Research Council (UK) and the German Centre for Cardiovascular Research, and from several drug and device companies active in AF, and has received honoraria from several such companies. P.K. is also listed as an inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). K.L. is an employee of Bayer. The genotyping of participants in the Broad AF study and the expression analysis of LA tissue samples were supported by a grant from Bayer to the Broad Institute. S.N. is a consultant to Biosense Webster, Siemens and Cardiosolv. S.N. also receives research grants from NIH/NHLBI, Siemens, Biosense Webster and Imricor. S. Kathiresan has received grant support from Bayer and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Corvidia Therapeutics and Novo Ventures. S. Kathiresan also received personal fees for consulting services from Novartis, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Merck, Noble Insights, Bayer, Ionis Pharmaceuticals, Novo Ventures, Haug Partners LLC and Genetic Modifiers Newco, Inc. S.A.L. receives sponsored research support from Bristol Myers Squibb, Bayer, Biotronik and Boehringer Ingelheim, and has consulted for St. Jude Medical/Abbott and Quest Diagnostics. The remaining authors have no disclosures.