| Title: | Monogenic and Polygenic Contributions to Atrial Fibrillation Risk |
| Journal: | Circulation Research |
| Published: | 6 Nov 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31691645/ |
| DOI: | https://doi.org/10.1161/circresaha.119.315686 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.119.315686 |
Publication 5413
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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.</p>
OBJECTIVE: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.</p>
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.</p>
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%.</p>
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.</p>
13 Keywords
- Aged
- Atrial Fibrillation
- Connectin
- Databases, Genetic
- Exome
- Female
- Humans
- Loss of Function Mutation
- Male
- Middle Aged
- Multifactorial Inheritance
- Penetrance
- Polymorphism, Single Nucleotide
12 Authors
- Seung Hoan Choi
- Sean J Jurgens
- Lu-Chen Weng
- James P Pirruccello
- Carolina Roselli
- Mark Chaffin
- Christina J-Y Lee
- Amelia W Hall
- Amit V Khera
- Kathryn L Lunetta
- Steven A Lubitz
- Patrick T Ellinor
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