Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation.

Background: Genome-wide association studies have identified 23 loci for atrial fibrillation (AF), but the mechanisms responsible for these associations, as well as the causal genes and genetic variants, remain undefined.

Methods: To identify the effect of common genetic variants on gene expression that might explain the mechanisms linking genome-wide association loci with AF risk, we performed RNA sequencing of left atrial appendages from a biracial cohort of 265 subjects.

Results: Combining gene expression data with genome-wide single nucleotide polymorphism data, we found that approximately two-thirds of the expressed genes were regulated in by common genetic variants at a false discovery rate of <0.05, defined as cis-expression quantitative trait loci. Twelve of 23 reported AF genome-wide association loci displayed genome-wide significant -expression quantitative trait loci, at (chromosome 1q24), (1q24), (2p14), (2q31), (5q22), (5q31), (7q31), (8p22), (10q22), (11q24), (12q24), and (14q23), suggesting that altered expression of these genes plays a role in AF susceptibility. Allelic expression imbalance was used as an independent method to characterize the cis-control of gene expression. One thousand two hundred forty-eight of 5153 queried genes had -single nucleotide polymorphisms that significantly regulated allelic expression at a false discovery rate of <0.05.

Conclusions: We provide a genome-wide catalog of the genetic control of gene expression in human left atrial appendage. These data can be used to confirm the relevance of genome-wide association loci and to direct future functional studies to identify the genes and genetic variants responsible for complex diseases such as AF.