More than 40 million Americans over age 50 years have osteoporosis or osteopenia. Osteoporosis has origins during childhood since bone mineral accretion during growth and development is a critical determinant of the risk of osteoporosis later in life. Bone accretion is a consequence of bone formation occurring at a faster pace than resorption, resulting in both increasing size and greater mineral content of skeletal components. Failure to achieve optimal bone mineral accretion during the critical period of growth results in suboptimal peak bone mass (PBM), contributing to low bone mass and osteoporosis later in life. Identifying the factors that influence bone mineral accretion during childhood and adolescence has important implications for prevention of this common, disabling disorder. Little is known about the genetic factors that regulate bone mineral accretion and bone mineral status during growth and development, and the timing of their effects. The genetic regulation of pediatric bone acquisition may differ from bone loss later in life, so to fully understand risk factors for osteoporosis across the life cycle it is necessary to characterize the genetic factors operant during childhood. The National Institute of Child Health and Development (NICHD) Bone Mineral Density in Childhood (BMDC) Study was initiated in 2001 to establish national reference standards for BMD and bone accrual for children ages 6 years and older. The initial cohort of 1554 subjects (ages 6 to 16) was later enriched with an additional 452 subjects 5 and 19 years of age to further strengthen the reference data. The BMDC Study cohort was evaluated annually until March 2010. This cohort is completely unique in the international arena, due to its size, age range, extent and quality of data, and the longitudinal nature of the study design The original aims of the parent grant (R01 HD058886-01A2) involve the collection of DNA from participants of this multi-center BMDC Study to perform a genome wide association study (GWAS) to identify genetic variants associated with bone mineral accretion and bone mineral status, and to determine if these genetic variants differ from childhood to young adulthood. The subjects have been successfully recruited and we are now poised to proceed with our GWAS. The purpose of this supplement is to enrich the original parent grant with data generated by whole genome sequencing, a new cutting edge technique that has recently become feasible for large scale studies. The parent R01 covers costs for genome wide single nucleotide polymorphism (SNP) genotyping to achieve the proposed aims. However, it is clear that if our study is to be truly transformative we should leverage the most state-of-the-art laboratory and statistical techniques to determine genetic variation across the human genome in these subjects i.e. whole genome sequencing. As such, we are applying for supplemental funds to make whole genome sequencing feasible for a strategically sampled subset of our cohort.

Public Health Relevance

Osteoporosis, a common condition that affects up to 30% of women and 12% of men, likely has its origins in childhood as a result of inadequate bone mineral accretion. Bone density and risk of osteoporosis have a strong heritable component, but little is known about the genetic determinants of bone mineral status and bone accretion during childhood. This supplement would enable substantial DNA sequencing of the NICHD multi- center, multi-ethnic longitudinal Bone Mineral Density in Childhood Study cohort, and combined with the parent study, will result in a genome wide survey using a combination of genome wide SNP genotyping and next generation sequencing in order to identify the genetic determinants of bone health early in life with the ultimate goal of identifying new pathways for osteoporosis prevention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Winer, Karen
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Children's Hospital of Philadelphia
United States
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Cousminer, Diana L; Mitchell, Jonathan A; Chesi, Alessandra et al. (2018) Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood. J Bone Miner Res 33:430-436
Mitchell, Jonathan A; Chesi, Alessandra; McCormack, Shana E et al. (2018) Physical Activity and Bone Accretion: Isotemporal Modeling and Genetic Interactions. Med Sci Sports Exerc 50:977-986
Hong, Jaeyoung; Hatchell, Kathryn E; Bradfield, Jonathan P et al. (2018) Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations. J Clin Endocrinol Metab 103:1380-1392
Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L et al. (2017) Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. Nat Commun 8:121
McCormack, Shana E; Cousminer, Diana L; Chesi, Alessandra et al. (2017) Association Between Linear Growth and Bone Accrual in a Diverse Cohort of Children and Adolescents. JAMA Pediatr 171:e171769
Chesi, Alessandra; Mitchell, Jonathan A; Kalkwarf, Heidi J et al. (2017) A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites. J Bone Miner Res 32:1274-1281
McCormack, Shana E; Chesi, Alessandra; Mitchell, Jonathan A et al. (2017) Relative Skeletal Maturation and Population Ancestry in Nonobese Children and Adolescents. J Bone Miner Res 32:115-124
Mitchell, Jonathan A; Chesi, Alessandra; Elci, Okan et al. (2016) Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density. J Bone Miner Res 31:789-95
Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire et al. (2016) Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Hum Mol Genet 25:389-403
Mitchell, Jonathan A; Chesi, Alessandra; McCormack, Shana E et al. (2016) Rare EN1 Variants and Pediatric Bone Mass. J Bone Miner Res 31:1513-7

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