The Genetics of Infant Growth and Later Obesity

描述（由申请人提供）：儿童肥胖症是美国和全球严重的公共卫生问题。鉴于肥胖一旦出现就相对难以控制，必须将注意力集中在早期预防上，新的证据表明，生命最初几年的生长速度是后期肥胖风险的重要早期预测因素。已知生长性状和肥胖风险都受到遗传因素的严重影响，并且有理论和经验原因怀疑这些性状共享与胰岛素信号传导相关的共同遗传途径。为了充分确定婴儿快速生长与儿童肥胖之间的关联是否存在遗传基础，需要相关个体婴儿期生长的系列数据沿着以及随后的随访数据。这项拟议的合作研究将来自世界上运行时间最长的生长和发育研究Pels纵向研究中675名相关个体的连续生长和BMI数据与最先进的统计和分子遗传学方法配对，以确定参与婴儿生长的基因及其对BMI的可能多效性影响以及儿童和青少年时期超重的风险。研究有五个目标。具体目标1的目标是将已经组装的表型和基因型数据集扩展约50%，以增加我们的统计能力来解决我们的假设。具体目标2的目标是记录婴儿生长（0-3岁）与儿童BMI和肥胖（3-20岁）之间的表型关系，调整婴儿喂养方式、胎龄、母亲年龄、产次和母亲或父亲体型。具体目标3的目标是进行定量遗传分析，以量化对婴儿生长速度和后来的BMI的独特和共享的多基因效应，同时考虑性别和年龄特异性差异以及遗传印记的潜在影响。具体目标4的目标是通过连锁分析确定影响婴儿生长的染色体区域（QTL），并评估其对儿童和青少年BMI的潜在影响。最后，具体目标5的目标是更仔细地检查在我们的初步研究中已经确定的QTL，以及在本项目过程中通过使用额外的STR和一组超过3,000个SNP对它们周围的1-LOD支持区间进行精细定位而确定的QTL。将进行关联研究以测量这些多态性对早期生长性状和儿童/青少年BMI的影响。随着对婴儿期生长速度的遗传决定因素及其在整个生命周期中对生长和体重的持续影响的更透彻理解，针对个别情况设计有效的婴儿生长和喂养临床指南可能会更容易。

DESCRIPTION (provided by applicant): 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.