Genetics of Bone Structure and Metabolism

项目摘要 骨质疏松症是一种以骨质量和密度的进行性、年龄相关性下降为特征的疾病， 正常骨结构的破坏和随之而来的骨强度的降低，导致骨密度的增加， 对断裂的敏感性。在老年人中，骨质疏松性骨折与大量的 并发症和死亡率。随着世界人口老龄化，随之而来的人类苦难和经济危机将继续存在。 预计骨质疏松症的费用将急剧增加。老年人骨质疏松症的研究 像美国这样的发达工业化国家，加拿大和欧盟。各国阐明了 饮食、行为和环境因素对与年龄相关的骨折风险的贡献，并已 也开始解开基因的基础。然而，大多数对骨质疏松症风险的搜索 基因不是最佳动力，发展中国家的糖尿病相关研究 新生或不存在。 我们建议对基因进行首次联合全基因组连锁和关联研究 影响来自发展中国家的人群中骨相关表型的变异： 尼泊尔东部。2000名成员已经在400多个标记位点进行了基因分型， 非近交Jirel谱系目前是基因组可用的最大和最强大的数据集 扫描研究(1)我们将对所有2000名个体进行广泛的骨骼相关特征的描述 包括跟骨的骨超声衰减、3个区域（近端）的骨矿物质密度 股骨、腰椎和前臂）和12种生物标志物 与骨形成、骨转换和骨代谢有关。(2)我们将使用定量遗传分析 技术，以确定在每一个骨相关性状的变化量，这是由于 基因，并评估共同基因影响骨相关表型对的程度 （多效性）。(3)我们将进行全基因组连锁分析，以定位每个骨骼的基因， 相关的表型-以及影响多种表型的多效性基因-对特定的 染色体区域(4)我们将对1000名参与者进行基因分型， 核苷酸多态性，并使用新的，基于谱系的遗传关联方法来提名和 优先考虑所有QTL的位置候选基因。 (5)最后，使用相同的分析方法和 SNP标记集，我们将进行分析，以验证我们的研究结果在1000名欧美参与者， 在Fels纵向研究中， 这个项目的目标是本地化， 影响骨相关表型的QTL的鉴定和表征， 位置候选基因可能导致这些性状的变异，进而导致骨质疏松症 由该项目的共同研究者指导的人群。 风险-在一般人类中，以及那些对未充分研究的人群具有更具体影响的人群 世界的一个地区。

PROJECT SUMMARY Osteoporosis, a disorder characterized by progressive, age-related decreases in bone mass and density, disruption of normal bone architecture, and consequent reduction in bone strength, results in increased susceptibility to fracture. In older persons, osteoporotic fracture is associated with substantial comorbidity and mortality. As the world's population ages, the attendant human suffering and economic costs of osteoporosis are predicted to increase dramatically. Research on osteoporosis in the developed, industrialized countries like the U.S., Canada, and the E.U. nations has elucidated the contributions of dietary, behavioral, and environmental factors to age-related fracture risks and has begun to unravel the genetic underpinnings as well. However, most searches for osteoporosis risk genes are less than optimally powered and osteoporosis-related research in developing countries is nascent or nonexistent. We propose to conduct the first combined whole genome linkage and association study for genes affecting variation in bone-related phenotypes in a population from a developing country: the Jirels of Eastern Nepal. With 2000 members already genotyped at over 400 marker loci, the single, unbroken, non-inbred Jirel pedigree currently is the largest and most powerful dataset available to a genome scanning study. (1) We will characterize all 2000 individuals for a broad range of bone-related traits including bone ultrasound attenuation of the calcaneous, bone mineral densities in 3 regions (proximal femur, lumbar spine, and forearm) assessed using dual-energy X-ray absorptiometry, and 12 biomarkers related to bone formation, turn-over, and metabolism. (2) We will use quantitative genetic analysis techniques to determine the amount of variation in each of the bone-related traits that is attributable to genes and assess the degree to which common genes influence pairs of bone-related phenotypes (pleiotropy). (3) We will conduct genome-wide linkage analysis to localize genes for each of the bone related phenotypes - as well as pleiotropic genes affecting multiple phenotypes - to specific chromosomal regions. (4) We will genotype 1000 of the participants for approximately 550,000 single nucleotide polymorphisms and use novel, pedigree-based genetic association methods to nominate and prioritize positional candidate genes for all QTLs. (5) Finally, using these same analytical methods and SNP marker sets, we will perform analyses to validate our findings in 1000 Euro-American participants of a separately funded study of the genetics of osteoporosis-related traits in the Fels Longitudinal study The goals of this project are the localization, identification, and characterization of QTLs influencing bone-related phenotypes, the nomination of positional candidate genes likely contributing to variation in these traits - and, by extension, osteoporosis population directed by co-investigators on this project. risk - in humans in general, as well as those with effects more specific to peoples from an understudied region of the world.