Integration Analysis of Epigenetic-related m6A-SNPs Associated with Atrial Fibrillation

Objective: Numerous single nucleotide polymorphisms (SNPs) have been identified as genetic contributors to atrial fibrillation (AF). The aim of this study was to investigate the effects of genome-wide N6-methyladenosine (m6A)-SNPs on AF. Method: m6A-SNPs were identified by analysis of raw data from published AF GWAS datasets and the list of m6A-SNPs from the m6AVar database. Expression quantitative trait loci (eQTL) analysis was conducted to evaluate the effects of m6A-SNPs on gene expression. The expression of linked genes was validated in three independent AF-associated gene expression datasets (GSE14975, GSE108660 and GSE2240). Results: A total of 1429 (6.2%) unique m6A-SNPs that were significantly associated with AF were identified. Seventeen m6A-SNPs in 14 genes reached genome-wide significance. Eight m6A-SNPs demonstrated eQTL signals. Four m6A-SNPs (rs383692, rs3211105, rs1061259 and rs1152582) exhibited strong cis-eQTL signals associated with the gene expression levels of SMIM8, JMJD1C and SYNE2. SYNE2 and SMIM8 had differential gene expression levels between the AF and sinus rhythm groups. In addition, SYNE2 expression was uniformly downregulated in AF samples compared with normal control samples in the three datasets. Conclusions: Our results provide the first demonstration that m6A-SNPs are strongly associated with AF, and extend understanding of m6A modification as a potential biological pathway underlying AF.