In 2002, over 43 million Americans over the age of 50 years had osteoporosis or osteopenia. That number is expected to increase to 61 million by 2020. Osteoporosis may have its origins during childhood growth and development, when the human skeleton undergoes rapid changes caused by the modeling and remodeling of bone. Bone mineral accretion occurs as 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 and development is likely to lead to suboptimal peak bone mass and osteoporosis later in life. Identifying the factors that influence bone mineral accretion during childhood has important implications for prevention of this common, disabling disorder. Most of what is known about childhood bone health is based on measures of bone mineral content (BMC) or density (BMD). A single BMC measurement reflects the lifetime of bone mineral acquisition to that point, and the cumulative outcome of all the factors that influenced bone acquisition. In contrast, bone mineral accretion, the change in BMC in a given time period reflects the recent factors influencing bone formation and resorption. Bone accretion occurs at a low rate prior to the adolescent growth spurt in height. During and after the adolescent growth spurt there is a sharp increase in bone accretion followed by a gradual decline. These distinct patterns of bone accretion suggest that bone accretion may be under different regulatory control at different phases of development. The goal of this study is to use genome wide association techniques to identify genetic variants associated with BMC status (BMC relative to age) and bone accretion, and determine if these genetic variants differ from childhood to young adulthood. The proposed study will take advantage of biological samples and data collected by the NICHD Bone Mineral Density in Childhood Study, a multi-center, longitudinal study of >2,000 children and adolescents who have undergone annual BMD measurements for 3 to 7 years, along with assessment of growth, puberty status, dietary intake, physical activity and skeletal maturation. An additional 500 Caucasian children will be enrolled in the proposed study following identical procedures. A high-density tag-SNP array will be used to study genetic variants, including CNVs, that influence BMC and bone accretion. A discovery cohort of 945 Caucasian subjects will be analyzed and replication of the findings will be subsequently tested in the new Caucasian cohort (n=500) and further explored in the Hispanic subset (n=284). Signals that are successfully replicated will then be refined in the African-American (AA) sample (n=435), as the degree of linkage disequilibrium is lower in this group. Those variants identified in both AA and non-AA samples are likely to represent more universally important genes, and pathways for diagnosis, prevention, and treatment of bone acquisition abnormalities.
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 study, in cooperation with the existing NICHD multi-center, multi-ethnic longitudinal Bone Mineral Density in Childhood Study, will conduct a genome wide association study of bone mineral status and bone accretion during childhood in order to identify the genetic determinants of bone health early in life with the ultimate goal of identifying new pathways for osteoporosis prevention.
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|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|
|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; Elci, Okan et al. (2016) Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood. J Bone Miner Res 31:1504-12|
|Chesi, Alessandra; Mitchell, Jonathan A; Kalkwarf, Heidi J et al. (2015) A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius. Hum Mol Genet 24:5053-9|
|Mitchell, Jonathan A; Chesi, Alessandra; Elci, Okan et al. (2015) Genetics of Bone Mass in Childhood and Adolescence: Effects of Sex and Maturation Interactions. J Bone Miner Res 30:1676-83|