Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank.

Abstract

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 <i>TTN</i> and early-onset AF. We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. 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. 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, <i>TTN</i> (odds ratio, 2.71, <i>P</i>=2.50×10^-8). The association with AF was more significant (odds ratio, 6.15, <i>P</i>=3.26×10^-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (<i>TTN</i>_LOF). Overall, 0.44% of individuals carried <i>TTN</i>_LOF 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 <i>TTN</i>_LOF variants only accounted for 0.2%. Both monogenic and polygenic factors contribute to AF risk in the general population. While rare <i>TTN</i>_LOF variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.