Genome-wide Mendelian randomization and multi-omics integration identify drug targets for irritable bowel syndrome

Abstract

Abstract Introduction: Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder. Despite the intricate and varied range of symptoms, there are now no recognized effective therapeutic methods. Mendelian randomization (MR) is a commonly employed method for repurposing existing licensed medications and identifying novel therapeutic targets. Hence, our objective was to discover new treatment targets for IBS and investigate their pathophysiological mechanisms and potential adverse consequences. Methods A two-sample MR analysis was conducted to determine the causal impact of druggable genes on IBS by merging data from expression quantitative trait loci (eQTLs) and genome-wide association studies (GWAS). Afterward, the colocalization analysis was conducted to identify possible druggable genes associated with the extent of treatment response in IBS patients. Furthermore, the phenome-wide MR approach was utilized to evaluate the potential detrimental impacts of pharmacogenes in treating IBS. In addition, the study conducted multi-omics integration analyses to explore potential pathogenic mechanisms of the druggable genes for IBS. Results 56 potential druggable genes for IBS were discovered by combining IBS GWAS and druggable eQTL data. Following the completion of the colocalization investigation, a total of 8 putative druggable genes for IBS were ultimately discovered. Except for NEU1's association with the quantity of LAMP1, CEACAM6, and DPP4 proteins, further phenome-wide MR analysis revealed that the prospective druggable genes for IBS did not exhibit any potential adverse effects. Eight putative druggable genes for IBS were found to influence IBS from several different angles, including gastrointestinal metabolites, microbiota, and inflammation in the gastrointestinal tract. Conclusions The study employed the MR analysis to identify putative druggable genes for IBS. These discoveries not only offer a new theoretical basis for current approaches but also have the potential to facilitate the creation of more precise treatments and innovative drugs for IBS.