Lifelong genetic differences associated with GLP-1 receptor activity indicate potential mental health benefits beyond weight and glycemic control, but clinical evidence remains important.
Study: Glucagon-like peptide-1 receptor activation and mental health: a drug-targeted Mendelian randomized study. Image credit: Bacsica / Shutterstock
In a recent “press article” published in the journal translational psychiatryResearchers evaluated the association between genetically predicted glucagon-like peptide-1 receptor (GLP-1R) activation and mental health outcomes.
GLP-1R agonists (GLP-1RA) can effectively lower blood glucose levels and body weight, with beneficial outcomes on cardiovascular disease and mortality in randomized controlled trials. These drugs act on the vagal afferents, hypothalamus, and hindbrain, suppressing food intake and causing weight loss. However, obesity drugs that act on the central nervous system (CNS) can cause psychological effects.
For example, the combination of phentermine and topiramate increases anxiety and depression. Nevertheless, GLP-1RA was found to moderately reduce depressive symptoms in individuals with type 2 diabetes (T2D), obesity, or overweight. Additionally, animal studies, observational studies, and genetic studies suggest benefits of GLP-1RAs in people with alcohol use disorders, but randomized trials have yielded mixed results, and there are ongoing trials evaluating the efficacy of GLP-1RAs in people with substance use disorders (SUDs) and mental illness.
About research
In this study, researchers examined the association between genetically predicted GLP-1R activation and mental health outcomes. This study used publicly available genome-wide association study (GWAS) data. Genetic tools for GLP-1R activation were selected based on their association with traits associated with drug target effects, such as body mass index (BMI) and glycated hemoglobin (HbA1c).
Genetic associations with HbA1c and BMI were obtained from the UK Biobank (UKB) GWAS and the Genetic Surveillance of Anthropometric Traits (GIANT) study and UKB meta-analysis, respectively. Genetic variants within or near the GLP1R gene associated with BMI or HbA1c with genome-wide significance were used for the primary analysis. A missense GLP1R variant (rs10305492) associated with T2D and fasting blood glucose was used for secondary analysis.
Genetic associations with mental health outcomes were obtained from the largest GWAS. The primary outcomes were SUD, well-being spectrum, and mental health disorders including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), Tourette syndrome, and anorexia nervosa.
Secondary outcomes were SUD subtypes (alcohol dependence and cannabis use disorder), mental health disorder subtypes (BD I, BD II, postpartum depression), and four dimensions of mental well-being (positive affect, depressive symptoms, life satisfaction, and neuroticism). Alcohol Use Disorder Identification Test total, alcohol intake, and alcohol problem scores were also assessed. Additionally, because GLP-1RA has been reported to reduce cardiovascular events and death, the association between GLP-1R activation and parental mortality, a proxy for coronary artery disease and all-cause mortality, was investigated.
Genetic associations from the FinnGen dataset were used for replication analyses. The researchers performed a Mendelian randomization (MR) analysis of drug targets. The F statistic was used to assess the strength of the instrument, and MR estimates were obtained using inverse variance weighting. A Bonferroni-corrected significance threshold of p < 0.005 was applied to the primary outcome. We performed pairwise colocalization analyzes to assess whether the associations were driven by shared causal variants.
Survey results
The genetic variants used in the primary analysis for BMI were rs4714290 and rs17757975, and the genetic variant used for HbA1c was rs10305518. Genetically predicted lower HbA1c and lower BMI by GLP-1R activation produced point estimates consistent with lower coronary artery disease risk and lower parental mortality as a proxy for all-cause mortality, although the confidence intervals were wide. Lower BMI due to genetically predicted GLP-1R activation was associated with improved well-being, including higher life satisfaction, less neuroticism, fewer depressive symptoms, and more positive emotions. Overall well-being scores were 0.06 standard deviations higher for every 1 kg/m2 genetically predicted decrease in BMI.
Furthermore, genetically predicted lower BMI was associated with lower risks of MDD, BD, and BD I after adjusting for multiple comparisons, and was associated with SUD, postpartum depression, ADHD, and BD II. Genetic analysis genetically predicted that GLP-1R activation lowers BMI by 1 kg/m2. This corresponds to approximately 18% lower odds of major depressive disorder and 39% lower odds of bipolar disorder. Although the association with MDD appeared to be stronger in women than in men, formal tests of gender differences were not statistically significant. Genetically predicted HbA1c reduction through GLP-1R activation showed limited association with mental health and SUD. It showed a suggestive association between a decreased risk of Tourette syndrome and an increased risk of anorexia nervosa.
Missense variants were not available for well-being spectrum analysis and showed little evidence of association with the mental health outcomes assessed. In FinnGen, BMI-related GLP-1R surrogates were associated with lower risk of PTSD, ADHD, BD, alcoholism, substance abuse, and MDD. Genetically predicted lower HbA1c showed limited association with mental health outcomes, except for MDD. Colocalization analysis of BMI and key outcomes revealed a posterior probability of 76.9% for MDD, 59.3% for well-being spectrum, and 45.9% for BD. These estimates were below the prespecified 80% threshold for colocalization. Conditional analyzes exceeded 80% for the well-being spectrum and BD, but not for MDD, suggesting that limited statistical power may have influenced the results.
conclusion
Taken together, our findings provide genetic evidence for an association between BMI-related GLP-1R activation and reduced risk of BD and MDD and a spectrum of better health outcomes. Furthermore, there was evidence suggesting an association between GLP-1R activation and reduced risk of SUD.
This analysis relied on Mendelian randomization assumptions, used only a small number of GLP1R region instruments, and could not completely exclude influences from neighboring genes or other biological pathways. We also modeled lifelong genetic differences rather than short-term effects of GLP-1RA intake. These results may inform research on psychiatric safety and potential repurposing opportunities for GLP-1RAs, particularly in people with mental health disorders, but randomized clinical trials are needed to determine whether genetic associations translate into therapeutic benefit.
Reference magazines:
- Yang G, Burgess S, Schooling CM. Glucagon-like peptide-1 receptor activation and mental health: A drug-targeted Mendelian randomized study. Translational psychiatry. Doi: 10.1038/s41398-026-04244-7, https://www.nature.com/articles/s41398-026-04244-7
