Abstract
Objective: To highlight potential functional variants and causal genes for ischemic stroke (IS) in genomic loci identified by genome-wide association studies (GWAS).Methods: We examined the association between m6A-SNPs and IS in large scale GWAS. Furthermore, eQTL analysis was performed to evaluate the effect of m6A-SNPs on gene expression. The top associations between m6A-SNPs and gene expressions were validated in 40 individuals from the Chinese Han population. Besides, we applied differential expression analysis and Mendelian randomization (MR) analysis to detect potential causal genes for IS.Results: We found 310 (7.39%) m6A-SNPs which were nominally associated with IS. The proportion of m6A-SNPs with P < 0.05 for IS was significantly higher than the non-m6A-SNPs (95%CI: [5.84%, 7.36%], P = 0.02). We found that the IS-associated m6A-SNP rs2013162 was associated with IRF6 expression (P = 6.30 × 10−23), meanwhile IRF6 was differentially expressed between IS cases and controls (P = 6.15 × 10−3) and showed a causal association with IS (P = 3.64 × 10−4). Similar results were found for m6A-SNP rs2273235 in the NDST1 gene which was associated with cardioembolic stroke (P = 8.47 × 10−3). The associations of rs2013162 and rs2273235 with the expression of IRF6 and NDST1 were validated in blood cells (P = 0.0247 and 0.0007), respectively.Conclusions: This study showed that m6A-SNPs may affect IS risk through altering gene expressions. The results suggested that m6A might play a role in IS etiology and gene expressions that affected by m6A may be causal factors for IS.
Highlights
Ischemic stroke (IS) is the second leading cause of death worldwide [1]
In this study we investigated the effect of the m6A-SNPs on IS and showed that by using the genome-wide association studies (GWAS) identified IS-associated m6A-SNPs as a bridge we can assess the relationship between m6A and IS indirectly
We found about 4,000 m6A-SNPs in each the GWAS datasets for AIS, large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS)
Summary
Genetic and epigenetic factors play important roles in IS etiology. Several genome-wide association studies (GWAS) have successfully identified many loci for IS and specific subtypes, including large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS). A recent large-scale meta-analysis of GWAS in 521,612 individuals confirmed 32 IS-associated loci which offering mechanisms not previously implicated in stroke pathophysiology [2]. N6-methyladenosine (m6A) is a pervasive RNA modification that plays critical roles in mRNA stability, protein expression and several other cellular processes [3]. I.e., the m6A-associated SNPs (m6A-SNPs), can influence m6A by changing the RNA sequences of the target sites [8]. If m6A modification was affected by this kind of variants, the biological process would likely be modified, leading to under-
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