Background

Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

Objective

To study the association of genetic variants with AF at GWAS top loci.

Methods

In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

Results

One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

Conclusions

We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.