1476-P: Genetic Relationships between Puberty Onset and Type 2 Diabetes

Early puberty onset is a risk factor for type 2 diabetes (T2D). In this study we aimed to determine whether these phenotypes are associated via genetic variation that contributes to both T2D and puberty onset. We, thus, investigated the associations of a polygenic score (PS) for T2D and a PS for age of menarche (AAM) with parameters of adolescent growth and T2D status in an Indigenous population from the Southwestern US with a high T2D prevalence. Genotypic and clinical data were obtained from a longitudinal study. Two key parameters of the adolescent growth spurt, including age at take-off (ATO) and age at peak velocity (APV), were derived from the Preece-Baines growth model, a parametric growth curve for longitudinal height data. PSs were constructed using imputed genotypes, where variants for the T2D-PS (n=289) and the AAM-PS (n= 275) were selected from genome-wide significant variants in European meta-analyses (DIAGRAM Consortium and Reprogen Consortium, respectively). Associations between PS and T2D status (N=7659) were adjusted for age, sex, birth year and the first 5 genetic PCs. Associations with ATO and APV (N=787) were adjusted for birth year, sex, maternal diabetes and the first 5 genetic principal components (PCs). Associations were calculated using linear mixed models, accounting for genetic relationships. The T2D-PS had a significant, positive association with T2D (OR=1.47 per SD [95% CI 1.38, 1.57]; p=4.05×10⁻³⁰). We found no association of the T2D-PS with ATO (p=0.11) nor APV (p=0.20). Conversely, genetically-predicted later puberty onset (AAM-PS) had a significant, inverse association with T2D (OR=0.92 per SD [95% CI 0.86, 0.98]; p=0.0194). The AAM-PS also associated with ATO (r=0.11, p=0.0013) and APV (r=0.13, p=1.8×10⁻⁰⁴). Our results suggest that many variants that associate with AAM and T2D in large European cohorts also affect these traits in this Indigenous population. They also support the notion that variants that associate with early puberty onset also confer susceptibility to T2D.