Variants in the LEPR Gene Are Nominally Associated With Higher BMI and Lower 24‐h Energy Expenditure in Pima Indians

Genome‐wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population‐based samples for association analyses with obesity‐related phenotypes. Selected variants (n = 80) spanning these genes were genotyped in a sample of full‐heritage Pima Indians (n = 2,842) and several common variants including rs2025804 were nominally associated with BMI (P = 0.05–0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full‐heritage Pima Indian sample were genotyped in a second sample of mixed‐heritage Native Americans (n = 2,969) and three of the variants showed nominal replication (P = 0.03–0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P = 0.0003–0.0001). A subset of these individuals (n = 403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24‐h energy expenditure (24hEE) as assessed in a human respiratory chamber (P = 0.0007 adjusted for age, sex, fat mass, fat‐free mass, activity, and family membership). We conclude that common noncoding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans.