Dataset Information

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

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 (TTN_LOF). Overall, 0.44% of individuals carried TTN_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 TTN_LOF variants only accounted for 0.2%.

Conclusions

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

SUBMITTER: Choi SH

PROVIDER: S-EPMC7007701 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Choi Seung Hoan SH Jurgens Sean J SJ Weng Lu-Chen LC Pirruccello James P JP Roselli Carolina C Chaffin Mark M Lee Christina J-Y CJ Hall Amelia W AW Khera Amit V AV Lunetta Kathryn L KL Lubitz Steven A SA Ellinor Patrick T PT

Circulation research 20191106 2

<h4>Rationale</h4>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.<h4>Objective</h4>We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.<h4>Methods</h4>The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome s ...[more]

PMID: 31691645

Similar Datasets

Project description:BackgroundThe relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.MethodsWe performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.ResultsThe mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).ConclusionsBoth familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

Dataset Information

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

Rationale

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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