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RATIONALE: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in and early-onset AF.

OBJECTIVE: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.

METHODS: The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk.

RESULTS: The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, (odds ratio, 2.71, =2.50×10). The association with AF was more significant (odds ratio, 6.15, =3.26×10) when restricting to LOF variants located in exons highly expressed in cardiac tissue (). Overall, 0.44% of individuals carried variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while variants only accounted for 0.2%.

CONCLUSIONS: Both monogenic and polygenic factors contribute to AF risk in the general population. While rare variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.