Bidirectional, time-ordered association network linking psychiatric disorders and immune-mediated inflammatory diseases: Inflammation–sleep mediation and genetic modification

BACKGROUND: Marked comorbidity between mental disorders and immune-mediated inflammatory diseases (IMIDs) suggests a bidirectional interplay, yet most prior work has tackled a single analytic direction, leaving the overall structure of time-ordered associations unclear. METHODS: Using the large, longitudinal UK Biobank cohort, we fitted Cox proportional-hazards models to quantify bidirectional, time-ordered associations between eight prototypical mental disorders and eight common IMIDs. Genetic susceptibility was quantified with polygenic risk scores (PRSs), and mediation models incorporated systemic inflammatory markers and sleep-quality scores. RESULTS: Baseline mental disorders significantly increased IMID incidence (comorbid mental disorders [CMB] → IMIDs: HR = 1.84, 95% CI 1.70-1.99). Major depressive disorder showed the widest range of associations, while post-traumatic stress disorder exhibited the strongest single link, notably with sicca syndrome (HR = 5.88, 95% CI 1.47-23.6). Conversely, baseline IMIDs heightened subsequent mental-disorder risk (IMID → CMB: HR = 1.54, 95% CI 1.45-1.63). In PRS-stratified analyses, psychiatric disorders (exposure) were more strongly associated with later IMID risk (outcome) in participants with lower versus higher genetic IMID risk. In PRS-based effect-modification analyses, we observed super-additive interaction on the additive scale for several pairs. Mediation analyses suggested that systemic inflammation and sleep disturbance accounted for roughly 2-10% and 7-16% of the associations, respectively. CONCLUSIONS: This systematic, bidirectional framework maps a complex interaction network linking IMIDs and mental disorders, jointly mediated by genetic vulnerability, systemic inflammation, and sleep dysregulation. The findings furnish a psychoneuroimmunological basis for integrated preventive and therapeutic strategies.