Integrative Analysis Predicts m <sup>6</sup>A-SNPs in Type 2 Diabetes Pathogenesis

Abstract

Genome-wide association studies have identified a large number of susceptibility loci for exploring the genetic factors in the pathogenesis of type 2 diabetes (T2D). However, the specific mechanism by which these SNPs (especially in non-coding region) are involved in T2D pathogenesis still remains unclear. Recently, genetic variation is considered to affect the N(6)-methyladenosine (m6A) RNA modification, which is the most prevalent posttranscriptional messenger RNA modification. In this study, we identified a large number of T2D-associated m6A-SNPs from published T2D GWAS summary statistics and explored their potential mechanisms involved in T2D pathogenesis with public databases. In summary, among the 15,124 T2D-associated m6A-SNPs, 71 m6A-SNPs reached the genome-wide suggestive threshold (5.0E-05), while 51 of them showed eQTL signals. The leading SNP rs4993986 (C/G) is located next to the m6A modification site at the 3’ end of the HLA-DQB1 transcript, which is predicted to affect its m6A modification and regulate the expression of the HLA-DQB1 to participate in T2D pathogenesis. This m6A-SNP / gene expression / T2D triplets provides a new annotation for the pathogenic mechanism of T2D susceptibility loci identified by GWAS. Funding Statement: This study is supported by the National Natural Science Foundation of China (document no. 81801018). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Data was publicly available.