Inflammatory bowel disease and psoriasis as causal drivers of psychiatric disorders: A two-stage Mendelian randomization study grounded in the gut-brain-skin axis.

BACKGROUND Psoriasis (PsO), inflammatory bowel disease (IBD), and psychiatric disorders(PDs)often coexist clinically. We hypothesize the gut-brain-skin axis mediates their cross-system interactions, though causal direction remains unclear. Mendelian randomization (MR) resolves confounding and reverse causality.

METHODS We used a two-stage and two-sample MR framework. Stage 1 screened causal associations between PsO and 199 comorbidity datasets across 9 organ systems. Stage 2 conducted bidirectional analyses among PsO, PDs, and IBD. We adopted the inverse-variance weighted (IVW) method as the main analysis approach and pleiotropy testing as core quality control.

RESULTS PsO exhibits significant positive causal relationships with multiple mental disorders, including Depression (broad) (DB) and Bipolar and major depression status: Probable Recurrent major depression (moderate) (BMD). Patients with psoriatic arthritis also demonstrate correlations with Seen doctor (GP) for nerves, anxiety, tension, or depression (SDN). Crohn's disease shows positive causal relationships with BMD. Both inflammatory bowel diseases and Ulcerative colitis present significant causal associations with palmoplantar pustulosis. PDs show no significant causal relationships with either phenotype.

CONCLUSION This large-scale two-sample MR study established causal relationships between PsO, IBD, and PDs. The findings revealed that genetic susceptibility to IBD causally increases the risk of both PsO and PDs, indicating chronic intestinal inflammation as the upstream driver; PsO occupies an intermediate position, exerting causal effects on PDs while demonstrating a protective association with IBD; PDs serve as downstream outcomes. This population genetics-based causal hierarchy provides empirical support for the gut-skin-brain axis hypothesis and offers a theoretical framework for multi-system disease management.