Glucagon-like peptide-1 receptor activation and mental health: a drug-target Mendelian randomization study

Concerns have been raised about the psychiatric safety of glucagon-like peptide-1 receptor (GLP-1R) agonists, but trial evidence suggests that they ameliorate depressive symptoms. We aimed to assess the associations of GLP-1R activation with mental health well-being and the risk of mental health disorders and substance use disorders. We performed drug-target Mendelian randomization and colocalization analyses using the largest relevant publicly available genome-wide association studies in European ancestry individuals. After correcting for multiple comparisons, genetically predicted lower body mass index (BMI) via GLP-1R activation was associated with a better well-being spectrum (0.06 standard deviation [95% confidence interval 0.03-0.08]) and lower risk of depression (odds ratio 0.83 [0.74-0.94]) and bipolar disorder (odds ratio 0.61 [0.47-0.79]) per 1-kg/m ² decrease in BMI. There was also suggestive evidence that genetically predicted lower BMI via GLP-1R activation was associated with lower risk of post-partum depression, attention deficit hyperactivity disorder, and substance use disorders, and that genetically predicted lower glycated hemoglobin (HbA1c) via GLP-1R activation was associated with higher risk of anorexia nervosa but lower risk of Tourette syndrome. These associations were stronger than the associations for genetically predicted lower BMI and lower HbA1c based on genome-wide variants. The posterior probabilities of a shared causal variant affecting both BMI and the outcome at the GLP1R gene were 59.3% for the well-being spectrum, 3.8% for depression, and 45.9% for bipolar disorder. GLP-1R activation was associated with better mental health well-being and lower risk of depression and bipolar disorder beyond that expected from the reduction in BMI and HbA1c.