Genetics of Bone Structure and Metabolism

项目总结 骨质疏松症，一种以进行性的、与年龄相关的骨量和密度下降为特征的疾病， 正常骨骼结构的破坏，以及随之而来的骨骼强度的降低，导致 对骨折的敏感性。在老年人中，骨质疏松性骨折与实质性 共病和死亡率。随着世界人口老龄化，随之而来的人类苦难和经济 预计治疗骨质疏松症的费用将大幅增加。老年人骨质疏松症的研究进展 发达的工业化国家如美国、加拿大和欧盟国家已经阐明了 饮食、行为和环境因素对年龄相关骨折风险的贡献 也开始解开基因基础。然而，大多数搜索骨质疏松症的风险 基因不是最理想的动力，发展中国家与骨质疏松相关的研究 初生的或不存在的。 我们建议对基因进行首次联合的全基因组连锁和关联研究 影响发展中国家人群骨相关表型变异的研究 尼泊尔东部。已经有2000名成员在400多个标记基因座上进行了基因分型， 非自交系Jirel系谱是目前可用于基因组的最大和最强大的数据集 扫描研究。(1)我们将对所有2000个个体进行广泛的骨骼相关特征描述 包括骨超声对跟骨的衰减，3个区域(近端)的骨矿密度 股骨、腰椎和前臂)使用双能X射线吸收测量仪和12个生物标志物进行评估 与骨形成、翻转和新陈代谢有关。(2)我们将使用定量遗传分析 确定每个骨骼相关性状的变异量的技术可归因于 并评估常见基因对骨相关表型的影响程度 (多效性)。(3)我们将进行全基因组连锁分析，以定位每一块骨骼的基因 相关的表型-以及影响多种表型的多效性基因-到特定的 染色体区域。(4)我们将为大约550,000名单人参与者中的1000人进行基因分型 核苷酸多态，并使用新的、基于谱系的遗传关联方法来提名和 对所有QTL的位置候选基因进行优先排序。 (5)最后，使用同样的分析方法和 SNP标记集，我们将在1000名欧美参与者中进行分析，以验证我们的发现 FELS纵向研究中一项单独资助的骨质疏松相关性状遗传学研究 这个项目的目标是本地化， 影响骨相关表型的QTL的识别和特征，提名 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 由该项目的联合调查员指导的人口。 风险--在一般人类中，以及那些对未被研究的人有更具体影响的人 世界上的一个地区。

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.