Genetic Evidence for Opposing Associations of Psoriasis and Type 2 Diabetes with Inflammatory Bowel Disease: A Mendelian Randomization Study

Abstract Inflammatory bowel disease (IBD) frequently co-occurs with immune-mediated and metabolic disorders, but whether these associations reflect shared genetics or causal effects remains unclear. We performed two-sample Mendelian randomization (MR) using large-scale genome-wide association study (GWAS) summary statistics to investigate potential causal effects of immune-mediated diseases and lifestyle traits on IBD, Crohn’s disease (CD), and ulcerative colitis (UC). SNP-based heritability and genetic correlations were estimated to contextualize findings. Following false discovery rate correction, genetically predicted psoriasis was positively associated with IBD (OR 1.15), CD (OR 1.23), and UC (OR 1.10), with the strongest effect observed for CD. Genetically predicted type 2 diabetes mellitus (T2DM) showed a modest inverse association with UC (OR 0.88). No lifestyle-related traits remained significant after correction. Sensitivity analyses indicated heterogeneity across instruments and evidence of directional pleiotropy in selected models, whereas no pleiotropy was detected for the T2DM–UC association. These findings support a role of psoriasis-related immune pathways in IBD susceptibility and suggest a potential inverse association between genetic liability to T2DM and UC.