Genome Wide Scans for Female Osteoporosis

骨质疏松症是最常见的代谢性骨病，也是一个主要的公共卫生问题， 其特征在于低骨矿物质密度（BMD）。骨密度的遗传率> 60%，涉及的特异性基因有 未知的argly女性的骨密度较低，患骨质疏松症的风险高于男性。我们以往的研究 表明某些骨质疏松症风险基因/基因组区域具有性别特异性。 该项目的目标主要是确定女性的骨质疏松症基因，其次是 评估男性样本中这些已鉴定基因的性别特异性。潜在的非遗传协变量和 将对相互作用进行评估，并对重要的相互作用进行调整。 使用我们在过去10年中积累的无关白人女性样本，我们建议 对女性重要的BMD基因进行强大的全基因组关联（WGA）扫描。我们早先 全基因组连锁扫描（WGLS）和荟萃分析、DMA微阵列和蛋白质组学获得的数据 研究，以及本SCOR项目2和3中获得的研究将用于指导对这一问题的重点分析。 WGA。 WGA中确定的300个最重要的基因/基因组区域将在800个 核心家庭（每个家庭有两个父母和至少两个年龄在25-45岁的子女），我们已经招募了 支持R 01 AR 050496。那些在传递不平衡检验（TDT）后仍显着的基因， 雌性后代（n=936）将在雄性后代（n=714）中进行TDT试验。那些仍然重要的基因 在男性中，骨质疏松症的风险在两性中都是常见的;否则，它们是女性特有的。 我们的假设是：BMD变异的性别特异性基因可以用强大的WGA检测到， TDT与之前的WGLS和我们的基因和/或蛋白质表达研究相补充时， 细胞我们将实现以下具体目标： 1)为了使用最新的Affyssin SNP芯片对400名健康女性进行强大的WGA研究， 400例BMD低的骨质疏松妇女（分别属于年龄匹配人群的前20%或后20%）; 2)为了比较从WGA获得的结果与WGLS和基因/蛋白表达数据（包括 在本SCOR的项目2和3中获得的数据）以及体内和体外研究的其他可用数据; 3)使用以下方法评估通过特定目的1和2获得的300个最有希望的基因/基因组区域： 800个核心家庭中约10，000个SNP，对女性后代进行了稳健的关联分析， 在雄性后代中，鉴定性别共同和雌性特异性BMD基因; 4)评价在其他人群（包括美国）中通过特异性目标3获得的最有希望的标志物 高加索人、黑人、一个以色列人群体、一个美国阿米什犹太人群体、墨西哥裔美国人和汉族人 中文. 确定人类BMD变异的基因，特别是对于女性，对于1）深入了解 骨质疏松症风险的基本分子机制，2）发现新的途径和目标， 治疗治愈; 3）识别遗传易感个体，以便未来的预防和干预措施 可以针对并基于个体的特定基因型。

Osteoporosis is the most prevalent metabolic bone disease and a major public health problem mainly characterized by low bone mineral density (BMD). BMD has a heritability > 60%.The specific genes involved are argely unknown. Women have lower BMD and higher risk to osteoporosis than men. Our previous studies have demonstrated that some osteoporosis risk genes/genomic regions are gender specific. The GOAL of this project is primarily to identify such osteoporosis genes for females and, secondarily, to assess the gender specificity of these identified genes in male samples. Potential none-genetic covariates and nteractions will be assessed and significant ones will be adjusted for. Using unrelated Caucasian female samples that we have accumulated in the past 10 years, we propose to conduct a powerful genome wide association (WGA) scan for BMD genes important for females. Our earlier data obtained in whole genome linkage scans (WGLS) and meta-analyses, DMA micoarray and proteomics studies, and those to be obtained in Projects 2 and 3 of this SCOR will be used to guide focused analyses of this WGA. The 300 most significant genes/genomic regions identified in the WGA will be followed for validation in 800 nuclear families (each with two parents and at least two offspring aged 25-45) that we have recruited by the support of R01AR050496. Those genes that remain significant after transmission disequilibrium test (TDT) in the female offspring (n=936) will be tested by TDT in the male offspring (n=714). Those genes that remain significant in the males are common for risk of osteoporosis in both sexes; otherwise, they are female specific. Our hypothesis is: sex-specific genes for BMD variation can be detected with a powerful WGA and robust TDT when complemented by previous WGLS and our gene and/or protein expression studies in major bone cells. We will fulfill the following Specific Aims: 1) To perform a powerful WGA study using latest Affymetrix SNP chips for 400 healthy women with high and 400 osteoporotic women with low BMD (belonging to aged matched population top or bottom 20%, respectively); 2) To compare the results obtained from the WGA with WGLS and gene/protein expression data (including those to be obtained in Projects 2 and 3 of this SCOR) and other available data of in vivo and in vitro studies; 3) To evaluate the 300 most promising genes/genomic regions obtained through Specific Aims 1 and 2 using ~10,000 SNPs in the 800 nuclear families with robust association analyses for female offspring and subsequently in male offspring, to identify sex-common and female-specific BMD genes; 4) To evaluate the most promising markers obtained through Specific Aim 3 in other populations, including US Caucasians, Blacks, one Israel population, one Amish Jewish population in US, Mexican Americans and Han Chinese. Identifying genes for human BMD variation, especially for women, is important for 1) gaining insights into the fundamental molecular mechanisms of risk to osteoporosis, 2) discovering new pathways and targets for therapeutic cures; 3) identifying genetically susceptible individuals, so that future preventions and interventions can be targeted to and based on individuals' specific genotypes.