Background <p>Glucagon-like peptide-1 receptor (GLP1R) agonists have gained attention for their role in diabetes treatment along with their diverse effects, such as appetite suppression, suggesting potential psychiatric benefits. This study aimed to assess the effect of GLP1R perturbation on mood disorders based on protein and biomarker levels using Mendelian randomization (MR) approach.</p> Methods <p>We conducted two-sample MR using summary statistics for GLP1R plasma levels (<i>n</i> = 3,301) from the INTERVAL study, glycated hemoglobin (HbA1c) levels (<i>n</i> = 128,610) from the Meta-Analyses of Glucose and Insulin-related traits Consortium, and bipolar disorder (BD: 371 cases/360,823 controls) and major depressive disorder (MDD: 776 cases/360,418 controls) incidences from the UK Biobank. Genetic variants associated with the plasma levels of GLP1R and HbA1c were used as proxies for the variation in GLP1R.</p> Results <p>GLP1R level was significantly associated with a reduced risk of MDD (odds ratio [OR] = 0·9988, 95% confidence interval [CI] = 0·9978-0·9999, <i>P</i> = 0·0291) and of BD (OR = 0·9990, 95% CI = 0·9982-0·9998, <i>P</i> = 0·0182). GLP1R’s HbA1c level-lowering effect was significantly associated with a decreased risk of BD (OR = 0·9786, 95% CI = 0·9613-0·9962, <i>P</i> = 0·0175) but not with MDD.</p> Conclusions <p>GLP1R perturbation may have protective effects on MDD and BD through different mechanisms, although additional clinical trials are required to determine the therapeutic implications.</p> Trial registration <p>Clinical trial number not applicable.</p>