GIPR and GLP-1R agonism as potential behavioral catalysts: a drug-target Mendelian randomization study

Abstract Background The potential of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists to modulate health behaviors remains underexplored. Methods Using a two-sample drug-target Mendelian randomization (MR) design, we instrumented GLP-1R and GIPR activation via cis-genetic variants associated with HbA1c and BMI, both obtained from two independent GWAS datasets. We systematically assessed effects of GLP-1R and GIPR agonism on 19 outcomes across 5 behavioral domains (dietary preferences, substance use and addictive behaviors, physical activity and sedentary traits, sleep characteristics, and affective mood states). Steiger tests and bidirectional MR were employed to validate the direction of causality. Meta-analysis was used to quantify the findings from cis-MR analyses in the primary and replication cohorts, whereas eQTL-based MR analysis was performed for further validation. Finally, colocalization analyses were applied to evaluate evidence for shared causal variants. Results In cis-MR analysis, GIPR activation through BMI reduced fatty food liking (ORprimary = 0.253 [0.149–0.430]; ORreplication = 0.553 [0.453–0.674]; ORmeta = 0.502 [0.417–0.605]) and increased vegetables liking (ORprimary = 1.696 [1.337–2.150]; ORreplication = 1.273 [1.150–1.409]; ORmeta = 1.331 [1.212–1.461]), fruit liking (ORprimary = 2.305 [1.578–3.365]; ORreplication = 1.553 [1.363–1.770]; ORmeta = 1.620 [1.431–1.833]), and whole grain cereal liking (ORprimary = 2.686 [1.401–5.147]; ORreplication = 1.591 [1.275–1.987]; ORmeta = 1.680 [1.362–2.073]). All of these associations passed the Steiger directionality test. eQTL-based validation supported the robustness of these findings; strong colocalization associations between BMI and fatty food liking, vegetables liking, fruit liking, and whole grain cereal liking in the GIPR locus were observed. Beyond the GIPR–BMI dietary block, exploratory suggestive signals that were not supported by colocalization analysis were also observed in other behavioral domains, including, but not limited to, reducing depression through GIPR-HbA1c/GLP-1R–BMI and reducing smoking dependency through GLP-1R–HbA1c. Conclusions The GIPR–BMI–dietary preference axis emerged as the most robust finding, with convergent support across cis‑MR, eQTL-based MR validation, and colocalization, suggesting that the GIPR–BMI pathway may act as a behavioral catalyst specifically for healthier dietary choices.