Genome Wide Association Study of Bone Mineral Accretion During Childhood

描述（由申请人提供）：2002年，超过4300万50岁以上的美国人患有骨质疏松症或骨质减少症。到2020年，这一数字预计将增加到6100万。骨质疏松症可能起源于儿童生长和发育期间，此时人体骨骼经历由骨骼建模和重塑引起的快速变化。骨矿物质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。在生长和发育的关键时期未能达到最佳骨矿物质增加可能导致在以后的生活中骨量峰值和骨质疏松症。确定影响儿童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。大多数关于儿童骨骼健康的知识都是基于骨矿物质含量（BMC）或密度（BMD）的测量。一个单一的BMC测量反映了骨矿物质获取的生命周期，以及影响骨获取的所有因素的累积结果。相反，骨矿物质增加，在给定的时间段内BMC的变化反映了影响骨形成和吸收的最新因素。在青春期身高突增之前，骨增长率较低。在青春期生长突增期间和之后，骨增生急剧增加，随后逐渐下降。这些不同的骨生长模式表明，骨生长可能在不同的发展阶段受到不同的调控。这项研究的目的是使用全基因组关联技术来识别与BMC状态（BMC相对于年龄）和骨增生相关的遗传变异，并确定这些遗传变异是否从儿童期到青年期都不同。拟议的研究将利用NICHD儿童期骨矿物质密度研究收集的生物样本和数据，该研究是一项多中心纵向研究，研究对象为2,000多名儿童和青少年，他们沿着接受了3至7年的年度BMD测量，并评估了生长、青春期状态、饮食摄入、体力活动和骨骼成熟。另外500名白人儿童将按照相同程序入组拟定研究。高密度tag-SNP阵列将用于研究影响BMC和骨增生的遗传变异，包括CNV。将对945例白人受试者的发现队列进行分析，随后将在新的白人队列（n=500）中检测结果的重复性，并在西班牙裔亚组（n=284）中进一步探索。成功复制的信号将在非裔美国人（AA）样本（n=435）中进行细化，因为该组的连锁不平衡程度较低。在AA和非AA样品中鉴定的那些变体可能代表更普遍重要的基因，以及用于诊断、预防和治疗骨获得异常的途径。

DESCRIPTION (provided by applicant): 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.