Examination of Co-inheritance of Bone Mineral Density, IGF-1 and Lifespan

描述（由申请人提供）：在美国女性中，骨质疏松性骨折的年发病率高于心脏病发作、中风和乳腺癌的总和。骨矿物质密度（BMD）是骨折风险的最强预测因子之一，研究表明，高达80%的变异可以由遗传因素解释。许多BMD的数量性状基因座（QTL）已经在小鼠和人类中定位，但缺乏实际的基因鉴定。本申请的目的是更好地鉴定和定位小鼠中这些骨相关QTL，并鉴定一些潜在的候选基因。小鼠是绘制复杂性状基因图谱的极好模型，但用于QTL分析的遗传图谱中存在许多错误，阻碍了寻找这些基因的努力。一个新的和校正的小鼠遗传图谱现在是可用的。我们已经收集了18个小鼠作图杂交的原始数据，并将使用这个新的图谱重新计算骨密度、几何形状和强度等骨相关性状的QTL。然后将一套生物信息学分析技术系统地应用于骨骼遗传学研究，包括Meta分析、QTL-QTL互作、组合杂交分析、比较基因组学和区组单倍型分析等。基于这种生物信息学分析，我们将集中精力确定最有希望的QTL的基因。通过集中于控制多种表型的一个分子途径，并使用这些表型的QTL的共定位来缩小QTL区间，可以帮助找到BMD QTL基因。年轻时的BMD与血清胰岛素样生长因子-1（IGF-1）呈正相关，与中位寿命呈负相关。我们将集中在两个额外的QTL，这三个表型的QTL已共同定位使用精细作图杂交和生物信息学，以确定这两个QTL的基因。总之，我们将使用先进的遗传分析和综合表型方法来更好地识别BMD的候选基因。公共卫生相关性：这项研究将帮助我们更好地了解控制骨密度和骨质疏松症的基因是什么。了解骨质疏松症的遗传学将导致新的和更好的治疗方法，并提高我们筛选和预防这种常见和使人衰弱的疾病的能力。

DESCRIPTION (provided by applicant): In women in the US, the annual incidence of osteoporotic fracture is greater than for heart attack, stroke and breast cancer combined. Bone mineral density (BMD) is one of the strongest predictors of fracture risk and studies have demonstrated that up to 80% of the variance can be explained by heritable factors. Many quantitative trait loci (QTL) for BMD have been mapped in mice and humans, but actual gene identification is lacking. The goal of this application is to better identify and map these bone related QTL in mice and to identify some of the underlying candidate genes. The mouse is an excellent model for mapping genes that underlie complex traits, but the effort to find these genes has been hampered by a number of errors in the genetic map used for QTL analysis. A new and corrected mouse genetic map is now available. We have collected the raw data from 18 mouse mapping crosses and will use this new map to recalculate QTL for the bone related traits of BMD, geometry and strength. Then a set of bioinformatic analysis techniques will be systematically applied to bone genetics including meta-analysis, QTL-QTL interaction, combined-cross analysis, comparative genomics and block haplotyping. Based on this bioinformatics analysis, we will then focus on identifying the genes for the most promising QTL. Finding BMD QTL genes could be aided by focusing on one molecular pathway that controls a variety of phenotypes and to use co-mapping of QTL for these phenotypes to narrow the QTL interval. BMD at a young age positively correlated with serum insulin-like growth factor-1 (IGF-1) and negatively correlated with the median lifespan. We will focus on two additional QTL where QTL for these three phenotypes have been co-mapped using both fine mapping crosses and bioinformatics to identify the genes underlying these two QTL. In summary, we will use both advanced genetic analyses and a combined phenotypes approach to better identify candidate genes for BMD. PUBLIC HEALTH RELEVANCE: This research will help us better comprehend what the genes are that control bone mineral density and osteoporosis. Understanding the genetics of osteoporosis will lead to new and better treatments and improve our ability to screen for and prevent this common and debilitating disease.