Genetics of Bone Structure and Metabolism

描述（由申请人提供）：骨质疏松症，一种以骨量和骨密度的进行性、与年龄相关的减少、正常骨结构的破坏以及随之而来的骨强度降低为特征的疾病，导致骨折易感性增加。在老年人中，骨质疏松性骨折与大量合并症和死亡率相关。随着世界人口老龄化，骨质疏松症带来的人类痛苦和经济成本预计将急剧增加。在发达的工业化国家，如美国、加拿大和欧盟国家，对骨质疏松症的研究已经阐明了饮食、行为和环境因素对年龄相关骨折风险的影响，并开始揭示遗传基础。然而，大多数对骨质疏松风险基因的研究都不够充分，而且在发展中国家，与骨质疏松有关的研究尚处于起步阶段或根本不存在。我们建议对来自发展中国家尼泊尔东部吉瑞尔人群体中影响骨骼相关表型变异的基因进行首次全基因组连锁和关联研究。由于已有2000个成员在400多个标记位点上进行了基因分型，单一的、完整的、非近亲繁殖的吉雷尔家系目前是基因组扫描研究中最大、最强大的数据集。(1)我们将对所有2000名患者进行广泛的骨相关特征表征，包括骨超声衰减，使用双能x线吸收仪评估的3个区域（股骨近端、腰椎和前臂）的骨矿物质密度，以及与骨形成、骨周转率和代谢相关的12种生物标志物。(2)我们将使用定量遗传分析技术来确定每个骨相关性状中可归因于基因的变异量，并评估常见基因对骨相关表型对的影响程度（多效性）。(3)我们将进行全基因组连锁分析，将每种骨相关表型的基因以及影响多种表型的多效基因定位到特定的染色体区域。(4)我们将对1000名参与者进行约55万个单核苷酸多态性的基因分型，并使用新颖的、基于家系的遗传关联方法为所有qtl提名和优先考虑候选基因。(5)最后，使用相同的分析方法和SNP标记集，我们将对1000名欧美参与者进行分析，以验证我们的发现，这些参与者分别参与了Fels纵向研究中骨质疏松相关性状的遗传学研究。本项目的目标是定位、鉴定和表征影响骨骼相关表型的qtl，提名可能导致这些性状变异的位置候选基因，以及，通过扩展，骨质疏松症人群由该项目的共同研究者指导。风险——对一般人类的风险，以及对来自世界上一个研究不足地区的人群产生更具体影响的风险。公共卫生相关性：随着世界人口老龄化，与骨质疏松症相关的人类痛苦和经济成本都将急剧增加。因为它将使用为此目的而组装的最强大的家族数据集，该项目将增强对影响骨密度和代谢测量的基因身份的了解，从而预测骨质疏松性骨折的风险。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: As the world's population ages, both the human suffering and economic costs associated with osteoporosis will increase dramatically. Because it will use the most powerful family data set assembled for this purpose, this project will enhance knowledge about the identities of genes affecting measures of bone density and metabolism that predict risk of osteoporotic fracture.