Sex-Specific Effects of GLP-1R Variants on BMI and Obesity Treatment Response

Abstract Genetic variants may affect the body mass index (BMI) and the effectiveness of obesity treatments. However, it remains largely unclear whether these effects differ between men and women. Thus, this study investigates genetic variants in incretin-related genes ( GIP , GIP-R , GCG , GCG-R and GLP-1R ) using sex-stratified genetic and functional approaches. First, sex-specific genome-wide association study data were analysed to identify variants with a sex-specific effect on BMI. Identified variants were then examined in an independent cohort of adults undergoing bariatric surgery and functionally assessed in a cellular model. Finally, all genes were screened for rare variants in children and adolescents with severe obesity. Nine highly linked variants within GLP-1R showed stronger effects on BMI in men than in women. Among these, only rs1042044 (p.Leu260Phe) is located in the coding region. In a cohort of 807 bariatric surgery patients, rs1042044 showed a nominal association with achieving a weight loss of more than 10%, particularly in women. However, no differences in receptor internalisation were observed between wildtype and mutant GLP-1R in vitro . Additionally, 26 variants were identified across the genes in a paediatric cohort. Future studies should incorporate sex-stratified analyses to uncover putative sex-dependent genetic modifiers of BMI and weight loss outcomes.