A large international genome-wide association study identified five new genetic variants and 22 high-probability risk genes linked to irritable bowel syndrome (IBS), narrowing the biological pathways and highlighting three potential drug targets. The analysis, presented at United European Gastroenterology Week 2025, provides the most detailed genetic map of the disorder to date and may guide future precision therapy.

Using data from more than 80,000 cases and over one million control individuals, the investigators combined five major cohorts using transcriptome and Mendelian randomization analyses.

This study improves statistical power beyond that of all previous studies, identifies subtype-specific signals, and highlights pathways that could support personalized treatment strategies.

IBS is the most common digestive disorder worldwide, affecting an estimated 10%-15 % of adults, with higher prevalence in women. It is classified as a disorder of gut-brain interaction, and its underlying biology remains poorly defined despite known predisposing factors.

Investigators conducted a genome-wide association study using the All of Us Research Program from the US National Institutes of Health, adjusting for age, sex, and other covariates. Two independent susceptibility loci reached genome-wide significance in the All of Us cohort (14,897 cases and 245,388 control individuals; P < 5 × 10^-8).

A subsequent meta-analysis combined data from All of Us, UK Biobank, FinnGen, UKB/Bellygenes, and the Resource for Genetic Epidemiology Research on Aging, including 80,737 IBS cases and over one million control individuals. Twelve additional independent signals were identified, and five previously unreported loci were identified: rs143348218, rs3748618, rs6432674, rs9536395, and rs976714.

Subtype analyses revealed three loci specific to the constipation-predominant subtype and 44 loci specific to the mixed subtype, including two new signals. Functional annotation links each region to the nearby genes or biological mechanisms.

Transcriptome-wide association, colocalization, and Mendelian randomization analyses prioritized genes with plausible causal roles, resulting in 22 risk genes with a high causality probability, 12 of which were novel genes.

Several genes, including CADM2, PCLO, PHF2, and SHISA6, have emerged as compelling candidates. Two of these, PCLO (previously linked to bipolar disorder and major depressive disorder) and SHISA6 (noted for increased expression in platelets and T lymphocytes), have not been associated with IBS.

Cross-referencing genes strongly associated with IBS with major pharmacological databases, such as DGIdb, DrugBank, and Open Targets, revealed three potential therapeutic targets that could support new drug development and repositioning.

“Genes with a high probability of causality were compared with major drug databases to assess therapeutic potential,” said Yajie Zhang, MD, from the Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, in Guangzhou, China. “This integrated approach identified three priority targets that could lead to new treatment strategies for irritable bowel syndrome.”

This landmark study, the largest genetic investigation of IBS to date, identified 12 genetic loci associated with IBS risk, five of which were novel. It also pinpointed twenty-two high-confidence causal genes, 12 of which were new, thereby strengthening the genetic foundation of the disorder.

“This study maps the genetic makeup of IBS, linking new biological mechanisms to targets already exploitable for personalized treatments,” Zhang said.

“It highlights mechanisms involving calcium signaling, epithelial barrier, and neuronal plasticity. Three newly identified genes are already associated with approved or developing drugs, opening immediate prospects for therapeutic repurposing.”

“Previous genetic studies have left gaps in our understanding. Their sample sizes were often < 53,000 cases, which is insufficient for detecting subtle genetic effects. Most studies have focused on European populations, and none have identified loci specific to the clinical subtypes IBS-C, IBS-D, and IBS-M. Our study relies on unprecedented statistical power, broader population diversity, and a thorough analytical approach,” said Zhang.

By providing a detailed genetic map of IBS, this study paves the way for new precision medicine approaches for treatment.

Zhang reported having no relevant conflicts of interest.

This story was translated and adapted from Medscape’s French edition.