Irritable bowel syndrome (IBS) is a prevalent and debilitating gastrointestinal disorder affecting approximately 5%–10% of the global population. Characterised by abdominal pain, bloating, and altered bowel habits, IBS imposes a significant burden on quality of life and health care systems worldwide.

Despite its prevalence, the exact pathogenesis of IBS remains elusive, and effective prevention strategies are lacking. Di Liu and colleagues conducted a comprehensive Mendelian randomisation (MR) study—an approach that uses genetic variants as instrumental variables to infer causality.

The study integrates Mendelian randomisation (MR) and multiresponse MR (MR2) analyses to distinguish genuine causal relationships from shared or spurious associations. The research is published in the journal eGastroenterology.

The study reviewed observational evidence up to May 2024 and analysed GWAS data from more than 50 studies, including 53,400 IBS cases and 433,201 controls, with validation in the FinnGen Biobank. Researchers assessed more than 50 modifiable factors across seven domains and 20 coexisting disorders.

Using genetic correlation and MR methods, they identified causal and shared risk pathways between IBS and related gastrointestinal and psychiatric conditions, enhancing understanding of modifiable contributors to IBS.

The study identified numerous significant genetic correlations between IBS and modifiable factors, with correlation coefficients (rg) ranging from 0.0005 to 0.718 across datasets. Strong correlations were observed for:

Among the evaluated factors, multisite chronic pain emerged as the strongest and most consistent causal factor. Notably, several dietary and behavioural exposures—including tea intake, coffee consumption, and physical activity—showed no consistent causal relationship with IBS, despite previously reported observational associations.

The MR analyses also highlighted several coexisting gastrointestinal and psychiatric disorders with convincing or suggestive causal links to IBS.

The multiresponse MR (MR2) analysis suggested that factors such as lifetime smoking index, intelligence and childhood maltreatment were found to be linked to coexisting disorders rather than being independent risk factors for IBS.

The study provides compelling evidence that certain psychological and somatic factors are not just correlated but causally linked to IBS. The most robust finding is the role of multisite chronic pain, which remains significant even after adjusting for psychiatric and gastrointestinal comorbidities. This supports the theory that central pain sensitisation and brain-gut axis dysregulation are critical mechanisms underlying IBS.

Psychological well-being also emerged as a strong determinant of IBS risk. Traits such as low positive affect, neuroticism, and depression not only co-occur with IBS but are also likely contributors to its pathogenesis. Meanwhile, associations with lifestyle factors such as smoking and alcohol use, though present, were weaker and possibly mediated through comorbid psychiatric disorders.

These findings suggest that preventive strategies for IBS could benefit from targeting chronic pain syndromes and improving psychological well-being. Moreover, recognising and managing psychiatric comorbidities in IBS patients could improve outcomes and reduce the symptom burden.