The Genetics of Infant Growth and Later Obesity

描述(申请人提供)：在美国和全世界，儿童肥胖是一个严重的公共健康问题。考虑到肥胖一旦出现就相对棘手，必须将注意力集中在早期预防上，新证据表明，生命最初几年的增长率是日后肥胖风险的重要早期预测指标。众所周知，生长性状和肥胖风险都受到遗传因素的严重影响，理论和经验都有理由怀疑这些性状共享与胰岛素信号相关的共同遗传途径。需要有关个人在婴儿期生长的系列数据以及后来的后续数据，才能充分确定婴儿快速生长与儿童肥胖之间是否存在遗传基础。这项拟议的合作研究将Pels纵向研究中675个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，以确定与婴儿生长相关的基因及其对儿童和青少年期间BMI和超重风险的可能多效性影响。Pels纵向研究是世界上运行时间最长的生长和发育研究。这项研究有5个目标。具体目标1的目标是将已经收集的表型和基因型数据集扩大约50%，以增加我们解决假设的统计能力。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，对婴儿喂养方式、胎龄、产妇年龄、产次以及母亲或父亲的大小进行调整。具体目标3的目标是进行量化遗传分析，以量化对婴儿生长速度和后来的体重指数的独特和共同的多基因影响，同时考虑到性别和年龄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)，并评估它们对儿童和青少年BMI的潜在影响。最后，具体目标5的目标是通过使用额外的STR和一组超过3,000个SNP来精细绘制它们周围的1-LOD支持间隔，更仔细地检查在我们的初步研究中已经确定的QTL和在本项目过程中确定的QTL。将进行关联研究，以衡量这些多态对早期生长特征和儿童/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有了更彻底的了解，针对个别病例量身定做的关于婴儿生长和喂养的有效临床指南可能更容易设计。

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.