Schizophrenia Genetic Liability Drives Chronic Disease Risk in Unaffected Individuals Through Immune and Metabolic Pathways

Background Comorbidity between schizophrenia (SCZ) and chronic diseases is well documented. However, it remains unknown whether unaffected individuals with elevated SCZ genetic liability also face increased risk, and what biological pathways may underlie these associations. Methods We analyzed 426,237 UK Biobank participants without SCZ to test associations between SCZ polygenic risk score (SCZ-PRS) and 24 chronic diseases using logistic regression. Multi-omics mediation analysis incorporated seven inflammatory markers, 1,463 plasma proteins, and 250 circulating metabolites to delineate intermediate pathways linking genetic liability to disease outcomes. Genetic colocalization analyses were further conducted to determine whether SCZ genetic liability and chronic diseases share common association signals at the locus level. Results Higher SCZ-PRS was associated with increased risk of asthma (OR=1.018, 95% CI 1.008-1.029), COPD (1.033, 1.017-1.050), liver disease (1.033, 1.015-1.051), peptic ulcer (1.032, 1.013-1.051), and fluid/electrolyte disorders (1.027, 1.014-1.040), while conferring reduced risk of diabetes (0.979, 0.968-0.991) and renal disease (0.978, 0.964-0.992). Multi-omics mediation revealed that these bidirectional associations were linked to immune cell activity (notably eosinophils, neutrophils, and monocytes), lipid and energy metabolism (lipoprotein composition, fatty-acid unsaturation, creatinine, lactate), and immune-regulatory proteins (e.g., HLA-E, CD1C, SPINT1). Shared genetic signals, notably at HLA and SLC39A8, reinforced these immune-metabolic pathways. Conclusions SCZ-PRS is associated with multiple chronic diseases among unaffected individuals, and these associations suggest shared biological pathways. These findings support a psycho-neuro-immune-metabolic interpretation of SCZ-related chronic physical comorbidity and a more integrated psychosomatic understanding of the shared biology linking psychiatric vulnerability with chronic physical disease.