GENETIC, SOMATIC AND MATURATIONAL INFLUENCES ON PEDIATRIC SKELETAL HEALTH

描述(申请人提供)：儿童成长和发展的一个基本方面是建立和维持一个强大的骨骼。儿童时期骨量的调节受遗传和环境因素的影响。其中一些因素直接作用于骨骼，而另一些因素则通过生长和发育的其他方面进行调节，例如身体尺寸的增加或骨骼成熟的速度。由于许多成人疾病，包括骨骼系统的疾病，在成年期的不同时期都有明显的先兆，因此更好地了解影响儿童时期骨形成的因素是很重要的。其中最重要的是对骨骼健康指标(质量和力量)的直接遗传影响，以及相关的躯体和成熟对儿童骨骼健康的影响。这项拟议的研究利用了来自FELS纵向研究的广泛和独特的系列儿童骨骼质量、体细胞和成熟数据，以及最先进的统计和分子遗传学方法，以确定与骨骼质量积累有关的基因，并确定基因对儿童骨骼质量、身体习性和骨骼成熟可能的多效性影响。这项拟议研究的最终目标是在躯体生长和骨骼成熟的背景下确定与儿童骨骼健康有关的基因。这将通过四个具体目标来实现：目标1将建立一个表型数据集，描述儿童骨骼质量和强度，同时测量儿童关键成骨时期的躯体生长和骨骼成熟。骨骼数据将从220个家庭1025名儿童的16,000多张现有手部X光照片中收集。对于每一次X光检查，身体数据(身高、体重和BMI)和骨龄评估都可以从FELS纵向研究数据集中获得。目标2的目标是进行定量遗传分析，以确定骨骼质量的遗传力和遗传相关性，以及儿童时期躯体生长和骨骼成熟的衡量标准。目标3的目标是通过遗传连锁来确定染色体区域(数量性状基因座；QTL)，这些区域含有负责儿童时期骨骼质量积累的基因，同时考虑到身体生长和骨骼成熟的衡量标准。最后，目标4的目标是基于目标3中确定的QTL的基因发现。拟议的研究将提供对儿童和青年时期关键时期骨形成的遗传结构的透彻理解。在公共卫生方面，拟议研究的目标特别及时。儿科骨骼健康的重要性日益得到承认，不仅对儿童健康至关重要，而且在生命后期也是如此。儿童时期骨骼健康、躯体发育和成熟的任何共同的遗传病因的确定可能被证明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.