The objective of the proposed research is to investigate how genetic variation influences weight-related traits during the transition from adolescence to adulthood - a critical risk period for weight gain. This is a continuing NIH grant, R01 HD057194, which is almost a decade old, that is now focused on low frequency coding variants. We capitalize on nationally representative, ethnically diverse, prospective and well-characterized data on 10,581 individuals from the National Longitudinal Study of Adolescent Health (Add Health) to assess the association between weight-related traits and coding variants across a 15-year lifecycle period of dramatic weight gain between adolescence and adulthood. We combine our data with extant exome data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n>91,000) and with two well-characterized, age-matched cohorts with exome data (China Health and Nutrition Survey, CHNS n=1,951; Cebu Longitudinal Health and Nutrition Survey, CLHNS, n=1,691) living under different environmental conditions but experiencing high levels of weight gain analogous to Add Health. Using all three datasets, we are working to determine the genetic and epidemiological architecture of causal variants; identify functional SNPs and genes. We are using advanced and innovative statistical modeling, examine differential genetic effects by age, time, and under varying environmental circumstances to downstream cardiometabolic risk factors (diabetes-, blood pressure-, and inflammatory-related markers). A primary focus of our work is testing novel hypotheses on tempo and timing of risk as well as address each piece of the complex system linking genetic markers, weight-related outcomes, and cardiometabolic risk factors, in the context of a variety of environmental and behavioral confounders.