Fig. 2: Study overview. | Molecular Psychiatry

Fig. 2: Study overview.

From: Genetically modeled GLP1R and GIPR agonism reduce binge drinking and alcohol-associated phenotypes: a multi-ancestry drug-target Mendelian randomization study

Fig. 2

This study used summary-level GWAS data relating to glycated hemoglobin (HbA1c) and body mass index (BMI) to construct genetic instruments modeling GLP1R and GIPR agonism. We constructed three instrument types: one proxying GLP1R agonism; one proxying GIPR agonism; and one combined instrument proxying dual GLP1R and GIPR agonism. Each instrument type included multiple exposure sources mimicking the expected physiological responses to pharmacological modulation of the targets (lowered glycated hemoglobin [HbA1c], reduced body mass index [BMI], and GLP1R or GIPR gene expression in the cortex). Instrument sets for each BMI and HbA1c exposure were constructed in two independent GWAS summary statistics (UK Biobank [plus GIANT for BMI] and the Million Veterans Program [MVP]). After instrumentation and validation with the primary clinical indications for GLP1R and GIPR agonism (type 2 diabetes and obesity), and assessing their impact on liver health, we obtained a selection of outcomes related to alcohol use disorder (AUD) and alcohol consumption behavior to assess the impact of GLP1R and GIPR agonism. We contextualized the alcohol-related analyses by analyzing other substance use disorders and investigating outcomes related to self-reported food liking. Because of the availability of large sample sizes and the most relevant endpoints, we used data from European ancestry as the main analysis set, but we also performed analyses using East Asian and African ancestry data sources. Finally, for all drug-target MR estimates demonstrating evidence of a relationship (main drug-target MR method P < 0.05), we performed colocalization analyses to assess evidence of shared causal variants between the biomarker exposures and outcomes in the GLP1R and GIPR genomic loci. MR Mendelian Randomization, GLP1R Glucagon-like peptide-1 receptor, GIPR glucose-dependent insulinotropic polypeptide receptor, NAFLD Non-alcoholic fatty liver disease, ALD Alcohol-related liver disease, SNP Single nucleotide polymorphism, BMI Body mass index.

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