Common variants in KCNN3 are associated with lone atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Figure 1. Manhattan plot of meta-analysis results for genome-wide association of lone AF

The -log₁₀(p value) is plotted against the physical positions of each SNP on each chromosome. The threshold for genome-wide significance, P <5×10⁻⁸, is indicated by the dashed line.

Figure 2. Regional plot for locus on chromosome 1 associated with lone atrial fibrillation

Figures prepared using SNAP. SNPs are plotted with the meta-analysis P-value and genomic position (NCBI Build 36). The SNP of interest is labeled. The strength of the linkage disequilibrium (LD) is indicated by gradient of red. Estimated recombination rates are shown by the blue line and gene annotations are indicated by dark green arrows. LD and recombination rates are based on the CEU HapMap release 22.