骨质疏松症是全球化的多基因复杂疾病，寻找其易感基因是解析其致病机理的关键和热点。近来，先进的全基因组关联研究（GWAS）发现一系列骨质疏松基因，然而，这些基因效应累积解释的疾病变异尚不足15%。面对"丢失的遗传力"，后GWAS时代迫切需要新思路、新方法深入挖掘海量基因组数据中潜藏的遗传信息。本项目将在前期工作基础上，在已有的两个中国人GWAS样本中，通过挖掘自身全基因组数据中的基因互作遗传信息、并整合数据库中不同层次生物分子互作信息和新一代测序数据，全方位构建分子互作网络，系统鉴定骨质疏松症易感基因；阳性结果在包含2000例中国人的独立样本中重复验证；对成功验证的网络，通过生物信息学分析和功能学实验探索其核心基因的内在机制。本项目从一个全新的视角鉴定骨质疏松新易感基因，能够发现传统GWAS无法检测到的遗传信息，为疾病遗传筛查防治提供新思路和新靶点，为后GWAS时代疾病遗传学研究开拓新途径。

Osteoporosis is a common complex disease worldwide. Identifying its susceptibility genes is the key and hotspot to discovering its pathogenesis. Recently, advanced genome-wide association studies (GWAS) have identified a number of susceptibility genes for osteoporosis. However, the genetic variations in osteoporosis explained by these genes collectively are less than 15%. In the fact of "missing heritability", it is necessary and important to proceed deep data mining in plentiful genome data using new methods and aspects in post GWAS era. In this project, based on our previous work, we will establish gene networks by exploring the gene-gene interaction information from our own whole genome data in two Chinese GWAS samples, integrating molecular interaction information from public databases, and combining next generation sequencing data, aiming to identify novel susceptibility genes for osteoporosis systematically. The significant results will be replicated in another independent sample containing 2000 Chinese subjects. For the gene networks successfully replicated, we will use bioinformatics analyses and functional experiments to discover the molecular mechanism for the key genes. The completion of this project will identify novel osteoporosis genes from a new aspect, and find the genetic information which missed by traditional GWAS. The results will help to understand the potential genetic determination of obesity. It will be also helpful to apply theoretical bases for early diagnosis, prevention and finding new drug target, and open a new avenue for genetic studies on complex diseases in post GWAS era.