BACKGROUND: The glucagon-like peptide-1 receptor () is a key regulator of glucose metabolism and appetite and a major therapeutic target for type 2 diabetes (T2D) and obesity. Genetic studies have implicated thelocus in both body mass index (BMI) and T2D, but it remains unclear whether their underlying genetic associations are the same. GLP1R GLP1R
METHODS: We analyzed 431,107 participants of genetically inferred European ancestry from the Million Veteran Program. Within ± 500 kb of, we performed locus-wide linear regression models for BMI and logistic regression models for T2D, adjusted for age, sex, and 10 principal components. We identified primary and secondary BMI sentinel variants using conditional analyses and evaluated their associations with T2D. Bayesian fine-mapping was used to construct credible sets oflocus for BMI and T2D. GLP1R GLP1R
RESULTS: Conditioning on the primary sentinel variant rs12213929 (upstream ofβ = 0.11; 95% CI 0.09-0.14; p = 1.94×10), we identified a secondary variant (rs13216992, intron of) independently associated with BMI (β = 0.10; 95% CI 0.07-0.13; p = 7.88×10). The two sentinel variants showed low linkage disequilibrium (r= 0.03). A two-variant allelic burden score (0-4; sum of the rs12213929 G-allele count and rs13216992 C-allele count) showed that participants with 4 risk alleles had 0.47 kg/mhigher BMI than those with 0 risk alleles (95% CI 0.39-0.55; p < 2×10). Both variants were associated with higher T2D risk, but with distinct patterns after BMI adjustment: the rs12213929-T2D association persisted after adjustment for BMI (OR = 1.02; 95% CI 1.01-1.03; p = 0.0004), whereas the rs13216992-T2D association was fully attenuated (OR = 1.00; 95% CI 0.99-1.01; p = 0.68). Fine-mapping identified a compact 95% BMI credible set of 17 variants and a broader 95% T2D credible set of 42 variants, with all BMI credible variants contained within the T2D set. GLP1R, GLP1R -17 -14 2 2 -16
CONCLUSIONS: Thelocus harbors at least two independent BMI-associated variants that exhibit heterogeneous relationships with T2D: rs12213929 influences T2D risk partly through BMI-independent pathways, whereas rs13216992 appears to act predominantly via adiposity. These findings refine the genetic architecture at this key therapeutic target gene and provide a foundation for functional and pharmacogenomic studies to determine whethervariation can inform precision prevention and treatment of obesity and T2D. GLP1R GLP1R
