Functional relevance for multiple sclerosis-associated genetic variants

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system. Many genetic variants associated with MS have been identified by genome-wide association studies, but functional mechanism underlying the associations is largely unclear. Utilizing the publically available datasets, we carried out gene relationships among implicated loci (GRAIL) analyses to search for MS-associated SNPs/genes. Expression quantitative trait loci (eQTLs) analyses were conducted to identify eQTL SNPs/target genes. Further, functional prediction for SNP, differential gene expression, and functional annotation clustering analyses for gene were conducted to explore their functional relevance to MS. Among the 284 identified MS-associated SNPs (P < 10−4), eQTL analysis showed that 45 SNPs act as cis-effect regulators on 19 MS-associated genes. Among the 19 eQTL target genes, 14 showed significantly differential expressions in MS-related cells. Among the 45 SNPs, 15 were predicted most likely located in transcription factor (TF) binding sites, and five predicted SNPs (rs3095329 of TUBB, rs9469220/rs2647046 of HLA-DQB1, rs11154801 of AHI1, and rs1062158 of NDFIP1) have corresponding target genes with significantly differential expressions in multiple cell groups, while rs7194 of HLA-DRA was predicted in the has-miR-6507-3p binding site. The functional evidence, taken together, highlighted the functional relevance of the six SNPs to MS. The present findings provide novel insights into the functional mechanisms underlying the MS-associated genetic variants, which improve our understanding of the genetic association for MS.