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.
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