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 = 0.250), bipolar affective disorders (OR = 0.931, P = 1.00), chronic depression (OR = 1.012, P = 0. 878), depression (OR = 0.985, P = 1.00), eating disorders (OR = 0.885, P = 1.00), suicide (OR = 1.040, P = 0.915), schizophrenia (OR = 1.064, P = 1.00). These findings were validated using eQTLGen Consortium or Psychiatric Genomics Consortium (all P > 0.900) and corroborated by Bayesian co-localization. The meta-analysis revealed no significant difference between the GLP-1 RAs exposure group and the control group in suicidal ideation or behavior (OR = 0.92, P = 0.67), anxiety (OR = 1.03, P = 0.93), depressive symptoms (SMD = -0.25, P = 0.39), but showed a significant difference in eating disorders (SMD = -0.71, P = 0.006). FDR FDR FDR FDR FDR FDR FDR FDR OR OR SMD SMD
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.
