GENETICS OF CHILDHOOD OBESITY

儿童肥胖的遗传学

基本信息

批准号：
6609724
负责人：
NANCY F. BUTTE
金额：
$ 57.65万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2005-06-30
项目状态：
已结题

项目摘要

Childhood obesity in the United States has dramatically increased in the past decade. The proportion of children exceeding the 95th and 85th percentiles for body mass index (BMI) is among the greatest in Mexican- Americans. Despite the high prevalence of obesity among Hispanic children, the genes underlying the heightened susceptibility to childhood- onset obesity in Hispanic populations have not been investigated. The specific goal of this project is to test the hypothesis that a number of genes, each with a measurable effect on the expression of childhood obesity, can be identified by the use of a systematic genomic screen. The specific aims are: l) to identify and phenotype 300 obese Hispanic probands (ages 4-18 y) and their biological parents and siblings, 2) to construct a 10 cM map for 1600 Hispanic individuals to be used in a genome-wide scan for loci that affect quantitative phenotypes of adiposity and energy expenditure using high-throughput genotyping techniques, 3) to perform a multipoint genome scan to find and localize QTLs that influence quantitative variation in adiposity. and energy expenditure in children by performing variance component linkage analysis, and 4) to use multivariate quantitative trait linkage analysis to test whether QTLs localized in Aim 3 have measurable pleiotropic effects across phenotypes. Our target sample will include 1600 genotyped individuals dispersed over 300 nuclear families with a minimum of three children, ascertained on the obese proband using a bivariate scheme (i.e., >95th percentile for BMI and >85th percentile for fat mass). Phenotyping will include anthropometry and body composition, as well as factors associated with the development of obesity: energy partitioning during growth, energy expenditure, physical fitness and activity. hormones, metabolites, and neurotransmitters. Anthropometry and body composition measurements will be repeated after 1y to determine body weight and fat change in the children. Approximately 360 hyper-variable STR markers will be typed for each individual to produce a 10 cM genome map. Multipoint linkage analysis using variance components methods will be applied to nuclear family data to search for QTLs influencing obesity-related phenotypes in Hispanic children. We will test the null hypothesis that the additive genetic variance due to a QTL equals zero (no linkage) by comparing the likelihood of this restricted model with that of a model in which the variance is estimated. This QTL method will be implemented in the program package SOLAR using estimation procedures from FISHER. Lastly, we will test for pleiotropic effects of obesity-related QTLs across phenotypes.

在过去的十年中，美国的儿童肥胖症已大大增加。超过体重指数（BMI）的第95％和第85个百分点的儿童比例是墨西哥人最大的。尽管西班牙裔儿童的肥胖症患病率很高，但尚未调查西班牙裔肥胖症易感性增强的基因。该项目的具体目标是检验以下假设：许多基因都可以通过使用系统的基因组筛选来鉴定出对儿童肥胖表达的可测量影响。具体目的是：l）识别和表型300肥胖的西班牙裔概率（4-18岁）及其亲生父母和兄弟姐妹，2）为1600个西班牙裔个体构建10 cm的映射，用于在基因组中用于基因组的基因组扫描中，用于基因座，这些基因群使用高级和能量实现的基因型基因群，以繁殖型基因型的高度实现基因型，以实现高级和能量的基因型，该型号是型基因型基因型的型基因型，该基因型的基因组型基因组的繁殖型基因型基因型型型基因型型基因组型，该基因组均具有多种型基因型基因型。找到并定位影响肥胖定量变化的QTL。通过进行方差组件链接分析和4）使用多元定量性状链接分析来测试AIM 3中定位的QTL是否具有跨表型的可测量的多效性效应来测试儿童的能量支出。我们的目标样本将包括1600个基因分型个体，分散了300多个核心家庭，最少有3个儿童，使用双变量方案在肥胖的探险中确定（即BMI的> 95％，脂肪质量为85％）。表型将包括人体测量法和身体组成，以及与肥胖发展相关的因素：生长过程中的能量分配，能量消耗，身体健康和活动。激素，代谢产物和神经递质。 1小时后将重复人体测量法和身体组成测量值，以确定儿童体重和脂肪的变化。将为每个人键入大约360个高变量标记，以产生10 cm的基因组图。使用方差成分方法的多点链接分析将应用于核家族数据，以搜索影响西班牙裔儿童中与肥胖相关表型的QTL。我们将通过将这种限制模型的可能性与估计方差的模型的可能性进行比较，即通过比较该限制模型的可能性来测试零假设，即QTL引起的加性遗传方差等于零（无链接）。该QTL方法将使用Fisher的估计程序在程序包太阳能中实现。最后，我们将测试跨表型肥胖相关QTL的多效性作用。