Heritability of Atrial Fibrillation

Abstract

Background: Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified.

Methods and results: We assessed the contribution of genome-wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, h²_g ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated h²_g using a variance components method with variants having a minor allele frequency ≥1%. We evaluated h²_g in age, sex, and genomic strata of interest. The h²_g for AF was 22.1% (95% confidence interval, 15.6%-28.5%) and was similar for early- versus older-onset AF (≤65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, ≥5%) variants (20.4%; 95% confidence interval, 15.1%-25.6%). Only 6.4% (95% confidence interval, 5.1%-7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions.

Conclusions: Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.

Keywords: atrial fibrillation; epidemiology; genome-wide association study; genomics; medical records.

Figure 1

Manhattan plot demonstrating associations between tested variants and AF. Known AF loci are shown in blue, and loci uniquely associated with AF in the UK Biobank are shown in red.

Figure 2

Regional association plots for loci uniquely associated with AF in the UK Biobank. Panel A displays associations at chromosome 5q31, and panel B at 12p12.

Figure 3

SNP-heritability of AF in clinical and genomic strata.Error bars represent the 95% confidence intervals for the h²_g estimates. Early-onset AF was defined as that occurring prior to age 65, and older-onset AF as occurring after age 65. Low frequency variants were SNPs with minor allele frequencies between 1%–5%, and common variants with frequencies ≥ 5%. GWAS loci were comprised of the 23 top SNPs from a prior independent association study ± 500 kilobases (kb). AF genes included 37 putative AF susceptibility genes ± 5 kb. AF, cardiac arrhythmia, and cardiomyopathy genes included 82 putative susceptibility genes ± 5 kb. The numbers of individuals and variants included in each stratum are provided in Supplemental Table 7.