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Circ Res. 2019 Nov 6. doi: 10.1161/CIRCRESAHA.119.315686. [Epub ahead of print]

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

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Medical and Population Genetics, Broad Institute of MIT and Harvard, UNITED STATES.
Cardiovascular Research Center, Massachusetts General Hospital, UNITED STATES.
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, UNITED STATES.
Center for Genomic Medicine, Massachusetts General Hospital, UNITED STATES.
Biostatistics, Boston University School of Public Health, UNITED STATES.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, UNITED STATES.


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 TTN 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 and Results: 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 {greater than or equal to} 10 LOF carriers. A polygenic risk score (PRS) for AF was estimated using the LDpred algorithm. We then compared the contribution of AF PRS and LOF variants to AF risk. The study included 1,546 AF cases and 41,593 controls. In an analysis of 9,099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (OR 2.71, P=2.50x10-8). The association with AF was more significant (OR 6.15, P=3.26x10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF PRS, only 9.3% had AF. In contrast, an AF PRS explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%. Conclusions: Both monogenic and polygenic factors contribute to AF risk in the general population. While monogenic TTNLOF variants confer a substantial AF penetrance, polygenic risk explains a larger proportion of genetic susceptibility to AF.


polygenic risk score

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