# Discovering Potential Drug Targets for Irritable Bowel Syndrome Through Genetic Insights: A Mendelian Randomization and Colocalization Study

## TL;DR

This study identifies two potential drug targets for irritable bowel syndrome using genetic analysis and mouse models, which could improve treatment development.

## Contribution

The study proposes P2RY14 and ATRAID as novel therapeutic targets for IBS based on genetic and experimental evidence.

## Key findings

- P2RY14 and ATRAID showed strong genetic and colocalization evidence linking them to IBS.
- Expression of P2RY14 increased and ATRAID decreased in IBS mouse colon tissue.
- Targeting these genes may improve clinical trial success for IBS treatments.

## Abstract

Irritable bowel syndrome (IBS), a gastrointestinal motility disorder affecting millions of patients worldwide, has a substantial impact on healthcare economics and patient quality of life. However, fully satisfactory therapeutic options remain lacking. The identification of pathogenic proteins supported by causal genetic evidence enables the exploration of potential therapeutic targets for IBS.

A Mendelian randomization (MR) study was performed to discover potential treatment targets linked to IBS. Summary data for IBS (outcome) were acquired from the two largest independent cohorts: sample sizes of 486,601 (53,400 cases and 433,201 controls) and 101,884 (24,735 cases and 77,149 controls), respectively. Instrumental variables were derived from cis-expression quantitative trait loci (cis-eQTL) data of druggable genes, obtained through the eQTLGen Consortium database. Colocalization analysis was employed to assess whether IBS risk and gene expression were influenced by shared SNPs. An IBS mouse model was additionally utilized to confirm the therapeutic potential of drug targets.

Four drug targets (P2RY14, SLC5A6, ATRAID, and IL1RL1) displayed notable MR findings in two separate datasets. Purinergic receptor P2Y14 (P2RY14) and all-trans retinoic acid–induced differentiation factor (ATRAID) exhibited robust evidence of colocalization with IBS. We further showed an abnormal increase in expression of P2RY14 and a significant decrease in ATRAID level in the colon tissue of IBS mice.

This study proposes two potential therapeutic targets for IBS: P2RY14 and ATRAID. Drugs aimed at targeting these two genes have a greater chance of success in clinical trials, potentially facilitating the prioritization of IBS drug development and lowering associated costs.