Abstract Body: Background: The glucagon-like peptide-1 receptor (GLP1R) gene has been implicated in metabolic regulation. GLP1R antagonists (GLP1-RAs) have been developed to treat type 2 diabetes (T2D) and obesity, and demonstrated broad clinical benefits in multiple cardiometabolic conditions. Recent genome-wide association studies (GWAS) have identified multiple GLP1R variants associated with T2D and body mass index (BMI), but the extent to which these associations represent independent genetic signals remains unclear.
Methods: We conducted fine-mapping of the GLP1R locus (± 500 kb) among 431,107 participants of European ancestry in the Million Veteran Program (MVP). Linear regression was used to identify sentinel variant associated with BMI, adjusting for age, sex, and ten principal components (PCs). Conditional analysis additionally adjusting for the primary BMI sentinel variant was performed to identify a secondary sentinel variant. Logistic regression models evaluated associations of each BMI variant with T2D risk: Model 1 adjusted for age, sex, and PCs; Model 2 additionally adjusted for BMI to test mediation; and Model 3 further adjusted for the alternate sentinel variant.
Results: Two independent variants at the GLP1R locus were identified. The primary sentinel variant rs12213929, located upstream of GLP1R in the DNAH8 region, was most strongly associated with BMI (β = 0.11; 95% CI 0.08-0.14; p = 1.9×10^-17). After conditioning on rs12213929, the secondary sentinel rs112102888 remained significant (β = 0.11; 95% CI 0.08-0.14; p = 2.6×10^-14), confirming two independent BMI signals. Both variants were also associated with T2D. For rs12213929, the association with T2D (OR = 1.03; 95% CI 1.02-1.04; p = 1.5×10^-9) persisted after adjustment for BMI and rs112102888, indicating a BMI-independent effect. In contrast, the rs112102888-T2D association (OR = 1.02; 95% CI 1.01-1.03; p = 0.0029) was attenuated following BMI adjustment (p = 0.59), implying BMI-mediated effects.
Conclusions: Fine-mapping identified two independent variants in GLP1R locus associated with BMI and T2D. The rs12213929-T2D association appears BMI-independent, whereas the rs112102888-T2D association is largely BMI-mediated. These findings highlight distinct genetic mechanisms linking GLP1R to adiposity and T2D which underscore the role of GLP1R in metabolic disease and may explain the cardiometabolic benefits of GLP1-RAs independent from weight-loss.