Genome-Wide Identification of N6-Methyladenosine (m6A) SNPs Associated With Rheumatoid Arthritis.

Abstract

Previous large scale genome-wide association studies (GWAS) have identified more than one hundred susceptibility loci for rheumatoid arthritis (RA) (Stahl et al., 2010; Eyre et al., 2012; Okada et al., 2012, 2014b). One major issue in the post GWAS era is to identify functional (causal) variants in the disease-associated loci. Recently, whole-exome sequencing studies have identified several missense mutations for RA (Mitsunaga et al., 2013; Okada et al., 2014a). Nevertheless, few studies have focused on potentially functional variants which could affect N6-methyladenosine (m6A) methylation. N6-methyladenosine (m6A) has been discovered as the first example of reversible RNA methylation and is a pervasive modification in the mRNA of all eukaryotes. It plays critical roles in regulating many fundamental biological processes such as gene expression control (Meyer and Jaffrey, 2014) and regulation of mRNA stability (Wang et al., 2014) and homeostasis (Edupuganti et al., 2017). Evidence has increasingly shown that m6A modification modulates almost all aspects of RNA processing such as nuclear export, translatability, splicing, and miRNA processing (Visvanathan and Somasundaram, 2018). Thus, m6A modification adds a new layer of gene expression regulation, and it has been implicated in T cell differentiation, homeostasis, and response to HIV infection (Li et al., 2018). Moreover, it was found to be involved in the etiology of various diseases (Visvanathan and Somasundaram, 2018). Given the vital function of m6A modification in gene expression regulation and immune response, it is possible that m6A is involved in the etiology of RA. Recent studies have suggested that SNPs would affect m6A by altering the RNA sequences of the target sites or key flanking nucleotides (Zheng et al., 2018). It means that m6A-associated SNPs (m6A-SNPs) may have regulatory potential to affect gene expression and mRNA stability and homeostasis, which may consequently affect disease such as RA. However, what is the relationship between m6A-SNPs and RA is still unclear. Thus, we examined the effect of the m6A-SNPs on RA in a large scale GWAS. Then, to test whether the RA-associated m6A-SNPs have potential regulatory effects on gene expression and whether these disruptions may contribute to RA, we performed eQTL and differential expression analyses using whole genome data of about 10.5 million SNPs and 21,323 mRNAs from 26 RA cases and 17 controls, as well as public data.