Genome Wide Association Study of Bone Mineral Accretion During Childhood

描述（由申请人提供）：超过4000万50岁以上的美国人患有骨质疏松症或骨质减少症。骨质疏松症起源于儿童时期，因为生长和发育期间的骨矿物质积累是日后患骨质疏松症风险的关键决定因素。骨增生是骨形成的结果，骨形成的速度比吸收快，导致骨骼成分的尺寸增加和矿物质含量增加。在生长的关键时期未能实现最佳骨矿物质增加导致次优峰值骨量（PBM），从而导致日后的低骨量和骨质疏松症。确定影响儿童和青少年时期骨矿物质增加的因素对预防这种常见的致残性疾病具有重要意义。关于在生长和发育过程中调节骨矿物质增加和骨矿物质状态的遗传因素及其作用的时间知之甚少。儿童骨获得的遗传调节可能与以后生活中的骨丢失不同，因此为了充分了解整个生命周期中骨质疏松症的风险因素，有必要描述儿童时期的遗传因素。国家儿童健康与发展研究所（NICHD）儿童期骨矿物质密度（BMDC）研究于2001年启动，旨在建立6岁及以上儿童BMD和骨累积的国家参考标准。最初的1554例受试者（6 - 16岁）队列后来增加了另外452例5岁和19岁的受试者，以进一步加强参考数据。每年对BMDC研究队列进行评价，直至2010年3月。由于其规模、年龄范围、范围和数据质量，这一队列在国际竞技场上是完全独特的，和研究设计的纵向性质父母补助金的最初目的（R 01 HD 058886 - 01 A2）涉及从该多中心BMDC研究的参与者中收集DNA，以进行全基因组关联研究（GWAS）确定与骨矿物质增加和骨矿物质状态相关的遗传变异，并确定这些遗传变异是否从儿童期到青年期不同。受试者已经成功招募，我们现在准备继续进行GWAS。这种补充的目的是用全基因组测序产生的数据来丰富原始的母基金，全基因组测序是一种新的尖端技术，最近已成为大规模研究的可行方法。亲本R 01涵盖了全基因组单核苷酸多态性（SNP）基因分型的费用，以实现拟定的目标。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，使全基因组测序对我们队列中的一个战略抽样子集可行。 公共卫生相关性：骨质疏松症是一种常见的疾病，影响高达30%的女性和12%的男性，可能起源于儿童时期，由于骨矿物质积累不足。骨密度和骨质疏松症的风险有很强的遗传成分，但很少有人知道的遗传因素的骨矿物质状态和骨生长在儿童时期。这种补充将使NICHD多中心、多种族纵向儿童骨矿物质密度研究队列的大量DNA测序成为可能，并与母研究相结合，将使用全基因组SNP基因分型和下一代测序的组合进行全基因组调查，以确定生命早期骨骼健康的遗传决定因素，最终目标是确定骨质疏松症的新途径预防

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.