3005-LB: A Cross Function of the TAAR1 and Orphan Receptor on Metabolic Dysregulation in Schizophrenia Patients

Introduction and Objective: Although schizophrenia is often accompanied by metabolic disorders, the biological mechanism is yet unknown. This study focused to examine the gene-gene interaction of rare mutations in Trace Amine-Associated Receptor 1 (TAAR1) and Glucagon-Like Peptide 1 Receptor (GLP1R) and their contribution to metabolic disturbances in schizophrenia individuals. Methods: 434 patients meeting DSM-5 criteria for schizophrenia with genotype and metabolic data were retained. Rare protein-truncating and deleterious missense variants were identified in TAAR1 and GLP1R, and gene-gene interaction analyses were performed for BMI, waist circumference, fasting glucose, lipid profiles, and HbA1c while controlling for demographic factors and antipsychotic exposure. Results: Significant gene-gene interaction effects between TAAR1 and GLP1R mutations were found for metabolic phenotypes. The TAAR1 exon2:c.A936G variant had interaction effects with several GLP1R mutations, leading to increased BMI, greater central adiposity, and elevated fasting glucose. Other such interactions involving TAAR1 exon2:c.A864G and TAAR1 exon2:c.T900A affected disturbed lipid profiles, indicating converging effects on pathways regulating energy balance and glucose-lipid homeostasis. Conclusion: TAAR1-GLP1R genetic interactions contribute to metabolic vulnerability especially glucose-lipid metabolic disease in schizophrenia patients. Disclosure Y. Lu: None. Funding National Natural Science Foundation of China (82170870, 82470901)