Lifelong genetic differences associated with GLP-1 receptor activity suggest potential mental health benefits beyond weight and glucose control, but clinical evidence remains needed.
Study: Glucagon-like peptide-1 receptor activation and mental health: a drug-targeted Mendelian randomization study. Image credit: Bacsica / Shutterstock
In a recent “article in press” published in the journal Translational Psychiatryinvestigators evaluated the relationship between genetically predicted activation of the glucagon-like peptide-1 receptor (GLP-1R) and mental health outcomes.
GLP-1R fighters (GLP-1RAs) can effectively lower blood glucose and body weight and have beneficial cardiovascular and mortality outcomes in randomized controlled trials. These agents act on the vagal afferents, hypothalamus, and hindbrain, suppressing food intake and reducing body weight. However, obesity drugs that act on the central nervous system (CNS) could cause psychiatric effects.
For example, the phentermine-topiramate combination increases anxiety and depression. However, GLP-1RAs found to moderately reduce depressive symptoms in people with type 2 diabetes (T2D), obesity or overweight. Additionally, animal studies, observations, and genetic studies suggest benefits from GLP-1RAs in people with alcohol use disorder, although randomized trials have produced mixed results, with ongoing trials evaluating their effectiveness in people with substance use disorders (Suds) and mental illness.
About the Study
In the present study, the researchers examined associations between genetically predisposed GLP-1R activation and mental health outcomes. The study used data from publicly available genome-wide association studies (GWAS). Genital organs for GLP-1R Activation was selected based on associations with traits associated with target drug effects, such as body mass index (BMI) and glycated hemoglobin (HbA1c).
Genetic associations with HbA1c and BMI were received from a GWAS of the United Kingdom Biobank (UKB) and a meta-analysis of the Genetic Investigation of Anthropometric Traits (GIANT) study and UKBrespectively. Genetic variations in or near the GLP1R gene associated with BMI or HbA1c with genome-wide significance were used for primary analyses. A failure GLP1R variant (rs10305492) associated with T2D and fasting glucose was used in secondary analyses.
Genetic associations with mental health outcomes came from the largest GWAS. The primary results were; Sudsthe spectrum of well-being and mental health disorders such as 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 IIand postpartum depression) and the four dimensions of mental well-being (positive affect, depressive symptoms, life satisfaction, and neuroticism). Identification of Alcohol Use Disorders Test totals, alcohol consumption, and alcohol problem scores were also assessed. In addition, the correlations between GLP-1R Activation and coronary heart disease and parental mortality, a proxy for all-cause mortality, were investigated, as GLP-1RAs have been reported to reduce cardiovascular events and deaths.
For replication analysis, genetic associations from the FinnGen dataset were used. The researchers performed a Mendelian randomization with target drug (MR) analysis. The F statistic was used to assess the power of the instrument and MR Estimates were obtained using inverse variance weighting. A Bonferroni-corrected significance threshold of p < 0.005 was applied to primary outcomes. Pairwise co-localization analyzes were performed to assess whether associations were driven by a common causal variant.
Findings
Genetic variants used in the initial analysis for BMI were rs4714290 and rs17757975 and the variant used for HbA1c was rs10305518. Genetically predicted lower HbA1c and lower BMI via GLP-1R Activation yielded point estimates consistent with lower CHD risk and lower parental mortality, a proxy for all-cause mortality, although confidence intervals were large. Genetically predicted lower BMI via GLP-1R Activation was associated with better well-being, including better life satisfaction, lower neuroticism, fewer depressive symptoms, and greater positive affect. The overall well-being score was 0.06 standard deviations higher per genetically predicted 1 kg/m² decrease in BMI.
Further, genetically predicted lower BMI was associated with reduced risks MDD, BDand BD I after correction for multiple comparisons, while correlations with Sudspostpartum depression, ADHDand BD II were suggestive. In the genetic analysis, each predicted genetic 1 kg/m² lower BMI through GLP-1R Activation was associated with approximately 18% lower odds of major depressive disorder and 39% lower odds of bipolar disorder. The association with MDD appeared stronger in women than in men, although the formal test for gender difference was not statistically significant. Genetically predicted lower HbA1c via GLP-1R activation showed limited associations with mental well-being and Suds. It showed suggestive associations with a reduced risk of Tourette syndrome but a higher risk of anorexia nervosa.
The poor reasoning variant was not available for the well-being spectrum analysis and showed little evidence of association with the assessed mental health outcomes. At FinnGen, the BMI-related GLP-1R proxy was associated with reduced risks PTSD, ADHD, BDalcohol dependence, substance abuse and MDD. Genetically predicted lower HbA1c showed limited association with mental health outcomes, except MDD. Tracking analytics for BMI and significant results revealed posterior probabilities of 76.9% for MDD59.3% for the welfare spectrum and 45.9% for BD. These estimates were below the predefined threshold of 80% for detection. Conditional analyzes exceeded 80% for the spectrum of well-being and BDbut no MDDsuggesting that limited statistical power may have influenced the results.
conclusions
In short, the findings provide genetic evidence of associations between BMI-related GLP-1R activation and reduced risks BD and MDDas well as a better spectrum of well-being. Furthermore, there was suggestive evidence of an association between GLP-1R activation and lower risk Suds.
The analysis was based on Mendelian randomization assumptions, which were used only in a small number GLP1R-area tools and could not completely rule out effects from neighboring genes or other biological pathways. It also modeled lifelong genetic differences despite the short-term effects of intake GLP-1RAs. These results may inform psychiatric safety research and potential repurposing opportunities GLP-1RAsespecially in people with mental health disorders, but randomized clinical trials are needed to determine whether genetic associations translate into treatment benefits.
