Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.Authorship note: Reza Wakili and Niels Voigt contributed equally to this work.

CHF causes profound changes in Ca(2+)-handling and -regulatory proteins that produce atrial fibrillation-promoting atrial cardiomyocyte Ca(2+)-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.