Genome Wide Association Study of Bone Mineral Accretion During Childhood

描述(申请人提供)：超过4000万50岁以上的美国人患有骨质疏松症或骨量减少症。骨质疏松症起源于儿童时期，因为生长和发育过程中的骨矿物质积累是晚年患骨质疏松症风险的关键决定因素。骨吸收是骨形成的速度快于吸收的结果，导致骨骼成分的大小增加和矿物质含量增加。在生长的关键时期未能达到最佳的骨矿物质积累会导致不理想的峰值骨量(PBM)，从而导致低骨量和晚年的骨质疏松。确定影响儿童和青春期骨矿物质积累的因素对预防这种常见的致残障碍具有重要意义。关于在生长和发育过程中调节骨矿物质积累和骨矿物质状态的遗传因素，以及它们的影响时间，人们知之甚少。儿童骨获得的遗传调控可能不同于晚年的骨丢失，因此，为了充分了解整个生命周期中骨质疏松症的危险因素，有必要对儿童时期起作用的遗传因素进行表征。国家儿童健康与发展研究所(NICHD)儿童骨密度(BMDC)研究于2001年启动，旨在为6岁及以上儿童建立骨密度和骨累积量的国家参考标准。最初的1554名受试者(6岁至16岁)后来又增加了452名5岁和19岁的受试者，以进一步加强参考数据。BMDC的研究队列每年进行一次评估，直到2010年3月。这一队列在国际上是独一无二的，由于其规模、年龄范围、范围和数据质量，以及研究设计的纵向性质，父母资助(R01 HD058886-01A2)的最初目标是从这项多中心骨髓基质细胞研究的参与者那里收集DNA，以进行全基因组关联研究(GWAS)，以确定与骨矿物质积累和骨矿物质状态相关的遗传变量，并确定这些基因变量在儿童和年轻人之间是否存在差异。受试者已被成功招募，我们现在准备继续进行我们的GWA。这一补充的目的是用全基因组测序产生的数据来丰富原始的父母拨款，全基因组测序是一种新的尖端技术，最近已成为一种适用于大规模研究的技术。母公司R01承担了全基因组单核苷酸多态(SNP)基因分型的费用，以实现拟议的目标。然而，很明显，如果我们的研究要真正具有变革性，我们应该利用最先进的实验室和统计技术来确定这些受试者中人类基因组的遗传变异，即全基因组测序。因此，我们正在申请补充资金，以使全基因组测序对我们队列中战略抽样的子集可行。 公共卫生相关性：骨质疏松症是一种常见的疾病，影响多达30%的女性和12%的男性，可能起源于儿童时期，原因是骨矿物质吸收不足。骨密度和骨质疏松症的风险有很强的遗传成分，但对儿童时期骨矿状态和骨积累的遗传决定因素知之甚少。这一补充将使NICHD多中心、多种族儿童纵向骨密度研究队列的大量DNA测序成为可能，并与父母研究相结合，将使用全基因组SNP基因分型和下一代测序相结合的方法进行全基因组调查，以确定生命早期骨骼健康的遗传决定因素，最终目标是确定预防骨质疏松症的新途径。

DESCRIPTION (provided by applicant): 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.