Childhood obesity is a serious public health problem in the US and worldwide. Given the relative intractability of obesity once it arises, attention must focus on early prevention, and new evidence indicates that growth rate during the first few years of life is an important early predictor of later obesity risk. Both growth traits and obesity risk are known to be heavily influenced by genetic factors, and there is both theoretical and empirical cause to suspect that these traits share a common genetic pathway related to insulin signaling. Serial data on growth during infancy among related individuals along with later follow-up data are required to fully determine whether or not there is a genetic basis for the association of rapid infant growth with childhood obesity. The proposed collaborative study pairs the serial growth and BMI data from 675 related individuals in the Pels Longitudinal Study, the longest-running study of growth and development in the world, with state-of-the-art statistical and molecular genetic approaches to identify genes involved in infant growth and their possible pleiotropic effects on BMI and the risk of overweight during childhood and adolescence. The study has 5 aims. The goal of Specific Aim 1 is to expand the phenotypic and genotypic dataset already assembled by approximately 50% so as to increase our statistical power to address our hypotheses. The goal of Specific Aim 2 is to document the phenotypic relationships between infant growth (age 0-3 years) and childhood BMI and obesity (from 3-20 years of age), adjusting for mode of infant feeding, gestational age, maternal age, parity, and maternal or paternal size. The goal of Specific Aim 3 is to conduct quantitative genetic analyses to quantify the unique and shared polygenic effects on infant growth rate and later BMI, taking account of sex and age-specific differences, as well as the potential impact of genetic imprinting. The goal of Specific Aim 4 is to identify, through linkage analysis, chromosomal regions (QTL) that influence infant growth, and to assess their potential effects on childhood and adolescent BMI. Finally, the goal of Specific Aim 5 is to examine more closely the QTL already identified in our preliminary studies and the QTL identified in the course of this project by fine-mapping the 1-LOD support intervals surrounding them using additional STRs and a battery of over 3,000 SNPs. Association studies will be conducted to measure the influence of these polymorphisms on early growth traits and childhood/adolescent BMI. With a more thorough understanding of the genetic determinants of growth rate in infancy, and their sustained effects on growth and body weight across the lifespan, effective clinical guidelines on infant growth and feeding, tailored to individual cases, may be easier to design. ? ? ?
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