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The aim of this study was to test the hypothesis that alcohol consumption, both observational (self-reported) and estimated by genetic instruments, is associated with a risk of atrial fibrillation and to determine whether people with high cardiovascular risk are more sensitive towards alcohol than people with low risk.We used data for a total of 88,782 men and women from the Copenhagen City Heart Study 1991-1994 and 2001-2003 and the Copenhagen General Population Study 2003-2010. Information on incident cases of atrial fibrillation was obtained from a validated nationwide register. As a measure of alcohol exposure, both self-reported consumption and genetic variations in alcohol metabolizing genes (ADH1B/ADH1C) were used as instrumental variables. The endpoint was admission to hospital for atrial fibrillation as recorded in a validated hospital register.A total of 3493 cases of atrial fibrillation occurred during follow-up. High alcohol consumption was associated with a risk of atrial fibrillation among men, but not among women. Among the men who drank 28-35 and 35+ drinks/week, the hazards ratios were 1.40 (95% confidence interval 1.09-1.80) and 1.62 (95% confidence interval 1.27-2.05) compared with men who drank < 1 drink/week. Using genotypes as instrumental variables did not reveal a higher risk. Associations in those with high cardiovascular risk were similar to those at lower risk.Observational alcohol consumption was associated with a higher risk of atrial fibrillation in men. In women, only a high alcohol intake (28+ drinks/week) was associated with a higher risk. Participants with a high cardiovascular risk were no more sensitive towards alcohol than those at low risk. Genetic analysis did not support a causal relationship of linear association between alcohol intake and atrial fibrillation.