O13.4. GENETIC PREDISPOSITION FOR TYPE 2 DIABETES MELLITUS IS ASSOCIATED WITH ALTERED CHILDHOOD IMMUNE AND METABOLIC FUNCTION WHICH IS LONGITUDINALLY ASSOCIATED WITH RISK OF PSYCHOSIS

Abstract

Background: Subclinical metabolic dysfunction and inflammation have been associated with early psychosis and depression, suggesting the possibility of an intrinsic association. This may be due to shared genetic vulnerability. We aimed to test: 1) whether genetic or environmental predisposition for type 2 diabetes mellitus (T2DM) is longitudinally associated with risk of psychotic disorder and/or depression at age 18 years; 2) whether genetic or environmental predisposition for T2DM is associated with an altered childhood (age 9 years) metabolic or immune function present on the longitudinal pathway leading to risk of psychotic disorder or depression. Method(s): We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We used regression to first test whether polygenic risk scores (PRS) for T2DM (genetic risk) or cardiometabolic family history (environmental risk) were associated with psychosis risk or depression; before and after adjustments. We used logistic and linear regression to test whether genetic or environmental risk for T2DM was associated with a range of biochemical measures of metabolic and immune function at age 9 years, before and after adjustments. We further explored associations by testing mediation by metabolic and immune markers between PRS for T2DM and psychotic disorder/depression, before and after adjustments. We tested for moderation effect of PRS for T2DM on associations between metabolic and immune markers and risk of psychosis. Result(s): We included 4,532 participants. Genetic risk for T2DM was significantly associated with psychotic disorder (adjusted OR=1.62 (95% C.I. 1.10-2.40) but not depression. Environmental risk was not associated with psychotic disorder or depression. After adjustments, genetic risk for T2DM was associated with age 9 levels of fasting plasma glucose, C - reactive protein (CRP) and triglycerides. Age 9 levels of interleukin-6 (IL-6), CRP, and fasting insulin were associated with psychosis risk at age 18 years. Age 9 levels of High Density Lipoprotein (HDL), leptin and IL-6 were associated with depression at age 18 years. We found evidence of an enhancing and association switching interaction effect of PRS for T2DM on the association between IL-6 and psychosis risk. We found evidence that the association between PRS for T2DM and psychosis risk at age 18 years is partially mediated by CRP. Discussion(s): This longitudinal study provides evidence that even before birth, a summation of minor genetic variations may predispose to a course of events through childhood and early adolescence involving minor immune and metabolic alterations, leading over time to risk of psychosis and T2DM. The findings may help to explain known cardiovascular disease associations and decreased life-expectancy borne by patients with psychotic disorders.