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Circ Res. 2020 Jan 17;126(2):200-209. doi: 10.1161/CIRCRESAHA.119.315686. Epub 2019 Nov 6.

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

Author information

1
From the Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., L.-C.W., J.P.P., C.R., M.C., C.J.-Y.L., A.W.H., A.V.K., S.A.L., P.T.E.).
2
Cardiovascular Research Center, Massachusetts General Hospital, Boston (L.-C.W., A.W.H., S.A.L., P.T.E.).
3
NHLBI and Boston University's Framingham Heart Study, Framingham, MA (K.L.L.).
4
Department of Biostatistics, Boston University School of Public Health, MA (K.L.L.).

Abstract

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:

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, TTN (odds ratio, 2.71, P=2.50×10-8). The association with AF was more significant (odds ratio, 6.15, P=3.26×10-14) 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 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 TTNLOF variants only accounted for 0.2%.

CONCLUSIONS:

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

KEYWORDS:

atrial fibrillation; exome; genetics; population; risk

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