中老年人群易发生骨质疏松。脆性骨折是其常见并发症，病人生命质量下降，残疾率和病死率高。除了高龄、酗酒、缺乏体育锻炼等因素，其与遗传密切相关。Wnt/β-catenin信号通过促进成骨细胞发育、分化和上调OPG基因表达等参与调控骨骼发育，其通路上的许多基因与骨质疏松的发生相关。R-spondin蛋白家族成员可激活Wnt/β-catenin信号，促进骨组织形成，对于骨质疏松的治疗具有前景作用。基于此，我们拟设计多中心两阶段病例对照研究，借助生物信息学技术，筛选60岁以上人群R-spondin/Wnt信号网络中骨质疏松和/或骨折易感基因遗传变异位点；并对鉴定得到的变异位点进行生物学机制深入探讨，尤其是位于非编码区域，具有潜在调控功能的SNPs和具有基因-基因交互作用的SNP的分子机制，结合统计学方法分析基因-基因、基因-环境交互作用；从而为骨质疏松高危人群的鉴别及疾病基因治疗提供科学依据。

Osteoporosis is widely prevalent among elderly people with aging and/or menopause. Fracture is the most frequent complication of osteoporosis, lowering the life quality and resulting in disability and fatality of patients. Ageing, alcohol, lack of physical exercises and heredity etc. are important risk factors for osteoporosis. The Wnt/β-catenin signaling plays an important role in bone development by promoting osteoblast development and differentiation, as well as up-regulating the OPG gene expression. Many genes in Wnt/β-catenin signaling pathway have been identified susceptible genes related to osteoporosis incidence. By activating Wnt/β-catenin signaling pathway, the recently discovered R-spondin family members can promote bone formation, presenting as the prospective treatment agent for osteoporosis. Therefore, a two-stage multi-center case-control study is designed to identify the osteoporosis- and/or osteoporotic fracture-related single nucleotide polymorphisms (SNPs) of critical genes involved in the R-spondin/Wnt signaling network by using the bioinformatics technology. Biological mechanisms of the identified SNPs will also be explored, especially that of the SNPs locating on non-coding regions, which have potential modification functions and gene-gene interactions. Statistical methods will be applied for analysis on the gene-gene and gene-environment interactions. Our findings will present scientific evidence for screening people who are among high risk of osteoporosis and/or fracture, as well as for the future gene therapy to osteoporosis.