Identifying Potential Drug Targets for the Treatment of Ulcerative Colitis Using Mendelian Randomization Combined with Co-localization Analysis

Abstract

Abstract Purpose To identify potential therapeutic targets for ulcerative colitis by integrating Mendelian randomization (MR) and Bayesian colocalization analysis to pinpoint gene expression quantitative trait loci (eQTLs) associated with ulcerative colitis risk. Methods Leveraging peripheral blood eQTL data from the eQTLGen Consortium and ulcerative colitis genome-wide association study (GWAS) summary statistics, we performed MR analysis to identify eQTLs significantly associated with ulcerative colitis risk in the discovery and replication datasets. The identified eQTLs were then subjected to Bayesian colocalization to evaluate whether the same single nucleotide polymorphisms (SNPs) influence both gene expression and disease risk. Finally, the Drug Gene Interaction database (DGIdb) was queried for known drugs targeting the associated genes. Results MR analysis identified 15 potentially positive eQTLs, of which 7 (CD300C, GPX1, LAMC3, RORC, SIGLEC6, SLC22A5, and WFIKKN1) were replicated to be associated with ulcerative colitis risk (Correction P-value < 0.005). Colocalization analysis provided strong evidence that the SNPs driving these 7 eQTLs also impact disease susceptibility. While RORC, SLC22A5, and LAMC3 have drugs approved for other indications, CD300C, GPX1, SIGLEC6, and WFIKKN1 represent potential novel drug targets. Conclusions By integrating MR and colocalization, this study pinpointed 7 ulcerative colitis-associated genes from the genome, including 3 with existing drugs and 4 potential new targets (CD300C, GPX1, SIGLEC6, and WFIKKN1), providing important leads for drug development in ulcerative colitis.