Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 126 (2), 200-209

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

Affiliations

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

Seung Hoan Choi et al. Circ Res.

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.

Similar articles

  • Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.
    Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM, Shoemaker MB, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, Redline S, Vasan RS, Burchard EG, Gogarten SM, Laurie C, Blackwell TW, Abecasis G, Carey DJ, Fornwalt BK, Smelser DT, Baras A, Dewey FE, Jaquish CE, Papanicolaou GJ, Sotoodehnia N, Van Wagoner DR, Psaty BM, Kathiresan S, Darbar D, Alonso A, Heckbert SR, Chung MK, Roden DM, Benjamin EJ, Murray MF, Lunetta KL, Lubitz SA, Ellinor PT; DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. Choi SH, et al. JAMA. 2018 Dec 11;320(22):2354-2364. doi: 10.1001/jama.2018.18179. JAMA. 2018. PMID: 30535219 Free PMC article.
  • Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores.
    Homburger JR, Neben CL, Mishne G, Zhou AY, Kathiresan S, Khera AV. Homburger JR, et al. Genome Med. 2019 Nov 26;11(1):74. doi: 10.1186/s13073-019-0682-2. Genome Med. 2019. PMID: 31771638 Free PMC article.
  • Heritability of Atrial Fibrillation.
    Weng LC, Choi SH, Klarin D, Smith JG, Loh PR, Chaffin M, Roselli C, Hulme OL, Lunetta KL, Dupuis J, Benjamin EJ, Newton-Cheh C, Kathiresan S, Ellinor PT, Lubitz SA. Weng LC, et al. Circ Cardiovasc Genet. 2017 Dec;10(6):e001838. doi: 10.1161/CIRCGENETICS.117.001838. Circ Cardiovasc Genet. 2017. PMID: 29237688 Free PMC article.
  • Atrial fibrillation: the role of common and rare genetic variants.
    Olesen MS, Nielsen MW, Haunsø S, Svendsen JH. Olesen MS, et al. Eur J Hum Genet. 2014 Mar;22(3):297-306. doi: 10.1038/ejhg.2013.139. Epub 2013 Jul 10. Eur J Hum Genet. 2014. PMID: 23838598 Free PMC article. Review.
  • Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation.
    Gladding PA, Legget M, Fatkin D, Larsen P, Doughty R. Gladding PA, et al. Heart Lung Circ. 2020 Apr;29(4):634-640. doi: 10.1016/j.hlc.2019.12.004. Epub 2019 Dec 27. Heart Lung Circ. 2020. PMID: 31974023 Review.
See all similar articles

LinkOut - more resources

Feedback