Polygenic risk score of glycemic homeostasis, Type 2 Diabetes Mellitus and glycemic components in first episode psychosis

Abstract

Objective: First episode of psychosis (FEP) is associated with glucose homeostasis abnormalities even before pharmacological intervention. Given inconclusive GWAS results regarding a direct genetic link between schizophrenia and type 2 diabetes mellitus (T2DM), we hypothesized that FEP patients may exhibit altered genetic risk for glycemic traits. We compared polygenic risk scores (PRS) for T2DM (PRST2DM), fasting glucose (PRSFG), and glycated hemoglobin (HbA1c) (PRSHbA1c) between FEP patients and controls, examining their associations with glycemic measures over 24 months. Methods: We analyzed data from 242 FEP patients and 119 controls, assessing fasting serum glucose and HbA1c at baseline and 24 months. We examined cross-sectional and longitudinal associations between PRS and glycemic measures within each group. Results: FEP patients and controls did not differ significantly in PRS. Significant associations were observed for PRSFG with baseline serum glucose in controls (p = 0.008), PRSFG during follow-up (p = 0.034), PRSHbA1c at 24 months (p = 0.018), and HbA1c longitudinally (p = 0.025). After multiple testing corrections, only the association between PRSFG and baseline serum glucose in controls remained significant (p_adj = 0.023). No associations were found for PRST2DM. Conclusions: Despite the link between FEP and glycemic disturbances, PRST2DM did not differ between FEP patients and controls. However, PRS for glycemic traits showed associations with glycemic measures in both groups before multiple testing correction, suggesting that genetic predisposition may influence glucose homeostasis in early psychosis. The absence of a direct association between common genetic variants underlying T2DM and early glycemic dysregulation in FEP underscores the importance of considering environmental factors and epigenetic mechanisms.