A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis

Abstract

AbstractMultiple sclerosis (MS) is a complex dysimmune disorder of the central nervous system. Genome-wide association studies (GWAS) have identified 233 genetic variations associated with MS at the genome-wide significant level. Epigenetic studies have pinpointed differentially methylated CpG sites in MS patients. However, the interplay between genetic risk factors and epigenetic regulation remains elusive. Here, we employed a network model to integrate GWAS summary statistics of 14 802 MS cases and 26 703 controls with DNA methylation profiles from 140 MS cases and 139 controls and the human interactome. We identified differentially methylated genes by aggregating additive effects of differentially methylated CpG sites within promoter regions. We reconstructed a gene regulatory network (GRN) using literature-curated transcription factor knowledge. Colocalization of the MS GWAS and methylation quantitative trait loci (mQTL) was performed to assess the GRN. The resultant MS-associated GRN highlighted several single nucleotide polymorphisms with GWAS-mQTL colocalization: rs6032663, rs6065926 and rs2024568 of CD40 locus, rs9913597 of STAT3 locus, and rs887864 and rs741175 of CIITA locus. Moreover, synergistic mQTL and expression QTL signals were identified in CD40, suggesting gene expression alteration was likely induced by epigenetic changes. Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA) indicated that the GRN was enriched in T follicular helper cells (P-value = 0.0016). Drug target enrichment analysis of annotations from the Therapeutic Target Database revealed the GRN was also enriched with drug target genes (P-value = 3.89 × 10−4), revealing repurposable candidates for MS treatment. These candidates included vorinostat (HDAC1 inhibitor) and sivelestat (ELANE inhibitor), which warrant further investigation.