Mood instability and 22 gastrointestinal disorders: investigating the causal relationships and the mediating factors by Mendelian randomization analysis.

BACKGROUND: Observational studies have suggested correlations between mood instability and gastrointestinal (GI) disorders, however, the causal relationships remain unclear.

METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between mood instability and 22 GI disorders using genome-wide association study (GWAS) data from disease-relevant GWAS studies, the UK Biobank, and the FinnGen project. To ensure the robustness of causal estimates, we applied multiple MR methods and extensive sensitivity analyses. Additionally, multivariable MR (MVMR) and two-step mediation analyses were performed to explore direct causal effects and potential mediating factors.

RESULTS: After multiple-testing correction, genetic liability to mood instability was significantly associated with an increased risk of four GI disorders: gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), diverticular disease, and cholelithiasis. Reverse MR analysis further suggested that genetically predicted GERD and IBS also increased the risk of mood instability. These findings were consistent across sensitivity analyses and were validated in independent datasets. Moreover, MVMR and mediation analyses indicated that smoking and depression may partially mediate the causal effects on GERD.

CONCLUSIONS: Mood instability, as a personality trait, may play a causal role in the development of multiple GI disorders. Our findings suggest that behavioral interventions, such as smoking cessation, may help reduce GI risk among individuals prone to mood instability. This highlights the potential for integrated behavioral-gastrointestinal risk stratification, where psychological profiling could help to identify individuals at high-risk and inform targeted prevention and intervention strategies.