GENETIC, SOMATIC AND MATURATIONAL INFLUENCES ON PEDIATRIC SKELETAL HEALTH

描述（由申请人提供）：儿童生长和发育的一个基本方面是建立和维护一个强大的骨骼。儿童时期骨骼质量的调节受到遗传和环境因素的影响。这些因素中的一些直接作用于骨骼，而另一些则通过生长和发育的其他方面介导，例如身体尺寸的增加或骨骼成熟的克里思。由于许多成人疾病都有重要的童年前因，包括那些可以在成年期不同时间表现出来的骨骼系统疾病，因此更好地了解儿童时期影响骨骼形成的因素非常重要。其中最重要的是对骨骼健康（质量和强度）的直接遗传影响，以及对儿童骨骼健康的相关躯体和成熟影响。拟议的研究利用广泛而独特的系列儿童骨骼质量，来自Fels纵向研究的躯体和成熟数据，以及最先进的统计和分子遗传学方法，以确定参与骨骼质量积累的基因，并确定基因对儿童骨骼质量，体型和骨骼成熟的可能多效性影响。这项研究的最终目标是确定在儿童骨骼健康的背景下，体细胞生长和骨骼成熟的基因。这将通过四个具体目标来实现：目标1将建立一个表征儿科骨骼质量和强度的表型数据集，同时测量儿童关键骨形成时期的躯体生长和骨骼成熟。Skeleton数据将从220个家庭的1，025名儿童的16，000多张现有手部X光照片中收集。对于每次X线检查，可从Fels纵向研究数据集中获得躯体数据（身高、体重和BMI）和骨龄评估。目标2的目标是进行定量遗传分析，以确定遗传力，和遗传之间的相关性，骨骼质量和措施的躯体生长和骨骼成熟的过程中的儿童。目的3的目标是通过遗传连锁，确定染色体区域（数量性状位点; QTL）窝藏基因负责积累的骨骼质量在儿童时期，同时占身体生长和骨骼成熟的措施。最后，目标4的目标是基于目标3中鉴定的QTL的基因发现。这项拟议中的研究将提供一个彻底的了解遗传结构的骨骼建设在关键时期的儿童和青年成年。在公共卫生方面，拟议研究的目标特别及时。儿童骨骼健康的重要性越来越被认为是至关重要的，不仅对儿童健康，而且在生命的后期阶段。儿童时期骨骼健康、躯体生长和成熟的任何共同遗传病因的鉴定可能对评估儿童和成人的骨骼健康至关重要。

DESCRIPTION (provided by applicant): A fundamental aspect of childhood growth and development is the buildup and maintenance of a strong skeleton. The regulation of skeletal mass during childhood is influenced by genetic and environmental factors. Some of these factors act directly upon the skeleton, while others are mediated through other aspects of growth and development such as increases in body size or the tempo of skeletal maturation. Because there are significant childhood antecedents to many adult diseases, including those of the skeletal system that can manifest at different times during adulthood, it is important to better understand the factors affecting bone-building during childhood. Foremost among these are direct genetic influences on measures of skeletal health (mass and strength), and associated somatic and maturational influences on pediatric skeletal health. The proposed study leverages extensive and unique serial childhood skeletal mass, somatic and maturation data from the Fels Longitudinal Study, and state-of-the-art statistical and molecular genetic approaches, to identify genes involved in the accumulation of skeletal mass, and to identify possible pleiotropic effects of genes on pediatric skeletal mass, body habitus, and skeletal maturation. The ultimate goal of the proposed study is to identify genes involved in pediatric skeletal health in the context of somatic growth and skeletal maturation. This will be accomplished through four specific aims: Aim 1 will establish a phenotypic dataset characterizing pediatric skeletal mass and strength, with concurrent measures of somatic growth and skeletal maturation during critical bone-building periods of childhood. Skeletal data will be collected from over 16,000 existing hand radiographs from 1,025 children in 220 families. For each x-ray visit, somatic data (height, weight, and BMI) and assessments of skeletal age are available from the Fels Longitudinal Study dataset. The goal of Aim 2 is to conduct quantitative genetic analyses to identify the heritability of, and genetic correlations between, skeletal mass and measures of somatic growth and skeletal maturation over the course of childhood. The goal of Aim 3 is to identify, through genetic linkage, chromosomal regions (quantitative trait loci; QTL) harboring genes responsible for the accumulation of skeletal mass during childhood, while simultaneously accounting for measures of somatic growth and skeletal maturation. Finally, the goal of Aim 4 is gene discovery based on QTL identified in Aim 3. The proposed study will provide a thorough understanding of the genetic architecture of bone- building during the critical periods of childhood and young adulthood. In terms of public health, the goals of the proposed study are particularly timely. The importance of pediatric skeletal health is becoming recognized as critical, not only for child health, but also during later stages of life. The identification of any shared genetic etiology of skeletal health, somatic growth and maturation during childhood may prove critical for the assessment of skeletal health in children and adults.