Causal association between glucagon-like peptide-1 receptor agonists and mental disorders: insight from genetic and real-world evidence

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), recognized for hypoglycemic and weight reduction efficacy, have been debated regarding potential association with mental disorders. This study sought to elucidate causal relationship between GLP-1RAs and mental disorders. METHOD: Two-sample Mendelian randomization, Linkage Disequilibrium Score Regression (LDSC) and Bayesian co-localization were conducted to assess causal associations between Glucagon-like peptide-1 receptor (GLP-1R) and seven mental disorders: anxiety, bipolar affective disorders, chronic depression, depression, eating disorders, suicide and schizophrenia. A meta-analysis of clinical studies was conducted between GLP-RAs use and mental health. RESULTS: LDSC revealed no genetic associations between GLP-1R and six mental disorders (Eating disorders were excluded from LDSC due to negative SNP-based heritability). GLP-1R were not causally related to mental disorders: anxiety (OR = 0.870, P CONCLUSION: GLP-1R showed no genetic evidence linking anxiety, bipolar affective disorders, chronic depression, depression, eating disorders, suicide, and schizophrenia. The pooled results of real-world evidence showed consistent results.