Linkage disequilibrium mapping and positional cloning for gene identification in osteoporotic families

骨质疏松症是一种常见的慢性疾病，伴有疼痛、功能丧失和死亡。患者通常会出现脊柱、髋部或腕部骨折。椎骨骨折可能导致慢性背痛和畸形。呼吸和消化系统的健康也会受到损害。相比之下，髋部骨折可能需要手术，降低活动能力和住院治疗。鉴于社区一般健康状况的改善和寿命的延长，这种疾病的发病率和公共卫生资金的消耗将在今后几年继续大幅增加。目前，澳大利亚每年的成本为75亿美元。制定有效的预防战略至关重要。该项目旨在通过确定与疾病易感性相关的主要基因来实现这一目标。骨质疏松症一词涵盖了许多异质性综合征，包括少年骨质疏松症、继发性骨质疏松症（如皮质类固醇诱导）和绝经后骨质疏松症。在后来的广泛分组中，有证据表明有很强的家族联系。先前的研究表明，有骨折家族史的人发生骨折的风险会增加四倍以上。此外，对双胞胎的研究一直表明，骨质疏松性骨折的最大危险因素骨矿物质密度是强烈遗传的。这一数据证实了这种疾病在某些个体中的遗传基础。我们已经完成了两个全基因组筛选项目，对所研究家庭的遗传连锁分析突出了基因组的四个区域，这些区域可能包含与疾病过程有关的基因。在这个项目中，我们将精细绘制这些区域，并确定负责观察到的连锁的基因。我们将使用一种称为定位克隆的技术来发现基因的身份，并将描述基因的遗传变异（多态性）如何导致骨量减少和骨质疏松性骨折。

Osteoporosis is a common chronic disease with associated pain, loss of function and death. Patients with the disease commonly experience spine, hip or wrist fracture. Fracture of vertebrae may result in chronic back pain and deformity. Respiratory and digestive health are then also compromised. In comparison, hip fracture may lead to a need for surgery, reduced mobility and institutionalization. In view of improved general community health and increased longevity, the incidence of this disease and the drain on public health funding will continue to increase substantially in coming years. Presently the cost in Australia is $7.5 billion per annum. Instituting effective prevention strategies is essential. This project aims to contribute to this goal by identifying a major gene(s) involved in disease susceptibility. The term osteoporosis covers a number of heterogeneous syndromes including juvenile osteoporosis, secondary osteoporosis (e.g. corticosteroid induced) and postmenopausal osteoporosis. In this later broad grouping there is evidence of a strong familial association. Previous work has shown that a family history of fracture increases your risk of fracture more than four fold. Furthermore, studies in twins have persistently shown that bone mineral density, the largest risk factor for osteoporotic fracture, is strongly inherited. This data confirms a genetic basis for the disease in some individuals. We have completed two whole genome screen projects and genetic linkage analysis in the families studied has highlighted four regions of the genome, which may harbour genes involved in the disease process. In this project we will fine map these regions and identify the genes that are responsible for the observed linkage. We will use a technique called positional cloning to discover the identity of the gene(s) and will characterise how genetic variation (polymorphism) in the gene leads to reduced bone mass and osteoporotic fracture.