Common Mechanisms for Type 2 Diabetes and Psychosis: Findings from a Prospective Birth Cohort

Background: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation.

Methods: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3,768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses.

Results: Genetic predisposition for T2DM was associated with PEs (adjusted OR=1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR=1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR=1.10; 95% C.I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p=0.040).

Conclusions: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.