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Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra ( P  = 0.01) and IL-18 ( P  = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 ( P  = 0.02) and PRS of anxiety and IL-18 ( P  = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R ( P  = 0.02) and PRS of educational attainment and sIL-2R ( P  = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE),  P  = 0.002), and nominally for PRS of openness and IL-1Ra (IE,  P  = 0.02) and sTNFR-1 (IE,  P  = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis