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

Abstract

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 and Results 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. Combining gene expression data with genome-wide single nucleotide polymorphism (SNP) data, we found that approximately two-thirds of the expressed genes were regulated in cis by common genetic variants at a false discovery rate of <0.05, defined as cis-expression quantitative trait loci (cis-eQTLs). 12 of 23 reported AF genome wide association loci displayed genome-wide significant cis-eQTLs, at PRRX1 (chromosome 1q24), SNRNP27 (1q24), CEP68 (2p14), FKBP7 (2q31), KCNN2 (5q22), FAM13B (5q31), CAV1 (7q31), ASAH1 (8p22), MYOZ1 (10q22), C11ORF45 (11q24), TBX5 (12q24), and SYNE2 (14q23), suggesting that altered expression of these genes plays a role in AF susceptibility. Allelic expression imbalance was employed as an independent method to characterize the cis-control of gene expression. 1248 of 5153 queried genes had cis-SNPs 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.

Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness

“…Our previous eQTL analysis indicated that rs1152591, the top AF GWAS SNP at this locus, was a strong eQTL for SYNE2 expression at the gene level (p=6.13E-17) 4 . Here we performed transcript-level analysis, and we found that the linked SNPs rs1152595 and rs1152591 were the top two significant eQTLs for the SYNE21 isoform, and our reporter gene transfection showed that the risk alleles of both SNPs decreased enhancer and/or promoter activities, suggesting that these two eQTL SNPs regulate SYNE21 expression, and thereby play a role in the AF susceptibility.…”

“…AF associated rs1152591 and rs1152595 are eQTLs for SYNE21, a short mRNA isoform 235 LAA tissues were obtained during cardiac surgery from subjects of European ancestry and 30 self-reported African Americans, the clinical characteristics were reported in our previous study 4 . In that study, we performed a gene-level transcriptome analysis and we found that the AF GWAS SNP rs1152591 was a strong cis-eQTL for SYNE2 gene expression (q=6.7E-17) 4 .…”

“…Sample handling, the demographics of these subjects, RNAseq by paired-end 150bp sequencing, and gene-based eQTL analyses were as previously described in Hsu et al 4 .…”

Causal SNP regulating FAM13B expression identified for the Chr. 5q31 atrial fibrillation susceptibility locus

“…Demographics of this population were previously published. 4 Total RNA was isolated for subsequent sequencing analysis. These methods are detailed in our prior publication.…”

“…Our prior expression quantitative trait locus (eQTL) study utilized next generation RNA sequencing (RNAseq) and single nucleotide polymorphism (SNP) genotyping in human left atrial appendages to identify the cis genes whose expression are associated with the top SNP at the AF GWAS loci. 4 We identified FAM13B as the gene whose expression is associated with the top GWAS SNP at chr. 5q31.…”