Multi-omics mendelian randomization integrating GWAS and eQTL data revealed potential drug target for irritable bowel syndrome

IntroductionIrritable bowel syndrome (IBS) is a common gastrointestinal disorder mainly affecting the young and female with limited therapeutic options, necessitating the identification of novel drug targets. This study aimed to identify and prioritize new, genetically validated drug targets for IBS by leveraging large-scale human genetic data.MethodsWe conducted a systematic, druggable genome-wide Mendelian randomization (MR) analysis to evaluate the causal effects of 5,642 potential druggable protein-coding genes on IBS risk. The analysis integrated summary statistics from the largest available IBS genome-wide association study (GWAS), including 53,400 cases and 433,201 controls, with comprehensive blood expression quantitative trait loci (eQTL) data. Significant findings were further validated using colocalization analysis. A phenome-wide association study (PheWAS) was performed to assess the potential for on-target adverse effects. Finally, potential therapeutic compounds were predicted using the Drug Signatures Database (DSigDB) and molecular docking.ResultsThe MR analysis identified eight genes with potential causal associations with IBS. Following rigorous validation with colocalization analysis, EP300 and P2RY14 emerged as the most promising candidate targets. Genetically predicted higher expression of both EP300 (OR: 1.128, 95% CI: 1.079-1.180) and P2RY14 (OR: 1.118, 95% CI: 1.067-1.172) was suggestively causally associated with an increased risk of IBS. The PheWAS analysis indicated that EP300 and P2RY14 did not show genome-wide significant associations with any other phenotypes. Additionally, molecular docking predicted that existing compounds, such as captopril and menadione, could effectively bind to the EP300 protein.ConclusionOur study provides genetic evidence establishing EP300 and P2RY14 as promising drug targets for the treatment of IBS, laying a foundation for future drug development and repurposing efforts.