New insights from GWAS on longitudinal and cross-sectional BMI and related phenotypes in admixed children with Native American and European ancestries

Body-mass index (BMI) is a well-known marker of adiposity across all ages. The genetic architecture of BMI has been thoroughly studied among adults. In contrast, there are a few genome-wide association studies (GWAS) on children. Further, GWAS on children have been performed almost exclusively in Europeans at single ages. We aimed to better understand the genetic architecture of BMI trajectory across ages and how BMI is affected by Native American genetic ancestry. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed Chilean children with mostly European and Mapuche Native American genetic ancestry. We focused on BMI and two traits that occur at the minimum of the childhood BMI growth trajectory, namely, age at adiposity rebound (Age-AR) and BMI at adiposity rebound (BMI-AR). We found several variants in the immune gene HLA-DQB3 that are strongly associated with BMI at ages 1.5-2.5 years old, but not at other ages. We also identified a variant in the sex-determining gene DMRT1 significantly associated with Age-AR (P = 9.8 x 10-9). Further, BMI was significantly higher in Mapuche than in European children at all ages between 5.5 and 16.5 years old, but not before. Finally, Age-AR was significantly lower (P = 0.013) by 1.64 years in the Mapuche children compared with Europeans.