Genomic search for bone mass QTLs

描述（申请人提供）：骨质疏松症是一个主要的公共卫生问题，其主要特征是骨密度（BMD）低。BMD具有较强的遗传决定性，遗传率> 60%。在过去的9年里，我们积累了前所未有的大样本。我们能够使用多种互补方法以极高的功效和确定性来确定BMD变异的基因组区域。我们从361个高加索人家系中招募了4,259名受试者并进行了表型分析。所有受试者都进行了411个微卫星（MS）标记的基因分型，这些标记遍布整个人类基因组。我们对全基因组扫描（WGS）和遗传上位性进行了初步分析。几个基因组区域显示出强烈的连锁骨密度被确定。在这个项目中，我们要求支持1）追求复杂，彻底和全面的连锁分析，以调查遗传异质性（包括印记），基因与基因（GxG）和基因与环境（GxE）的相互作用在我们的WGS分析; 2）基因型密集的MS标记，以饱和潜在的显着区域（即，LOD得分> 1.9），并以更高的分辨率和确定性重新分析这些区域; 3）使用我们强大的大样本对在早期研究中至少显示出与BMD的暗示性连锁的标记进行连锁检测; 4）对我们的基因表达数据进行重点分析（已经获得的）在上述WGS分析中鉴定的连锁区域内的基因，并进行RT-PCR，以推断位置和功能候选基因; 5）在800个高加索核心家庭中测试从上述分析中鉴定/推断的最有希望的候选基因与BMD变化的关联（已经招募了约700个核心家庭;其余100个家庭的招募正在由NIH资助，预计将于9月完成。2006年1月1日。高准确性地鉴定BMD变异的基因组区域和候选基因对于揭示骨质疏松症潜在风险的遗传变异是重要的。这将为进一步的精细绘图和相关研究奠定坚实的基础。它将加快表征骨质疏松症风险的突变和功能产物，并有助于研究骨质疏松症的遗传和环境原因之间的相互作用。这方面的知识是必不可少的预防干预措施和/或治疗骨质疏松症的发展，可能是基于个人的特定基因型。

DESCRIPTION (provided by applicant): Osteoporosis is a major public health problem, which is mainly characterized by low bone mineral density (BMD). BMD has strong genetic determination with heritability > 60%. During the past 9 years, we have accumulated unprecedented large samples. We are in a position to identify genomic regions underlying BMD variation with exceptionally high power and certitude using multiple and complementary approaches. We have recruited and phenotyped 4,259 subjects from 361 Caucasian pedigrees. All the subjects have been genotyped for 411 microsatellite (MS) markers throughout the whole human genome. We performed preliminary analyses for whole genome scan (WGS) and for genetic epistasis. Several genomics regions showing strong linkage to BMD were identified. In this project, we request support to 1) pursue sophisticated, thorough and comprehensive linkage analyses to investigate genetic heterogeneity (including imprinting), gene by gene (GxG) and gene by environment (GxE) interactions in our WGS analyses; 2) genotype dense MS markers to saturate potentially significant regions (i.e., LOD scores > 1.9) found in our WGS and re-analyze these regions with higher resolution and certitude; 3) test linkage for markers that have shown at least suggestive linkage to BMD in earlier studies using our powerful large sample; 4) perform focused analyses on our gene expression data (already obtained) within linkage regions identified in the above WGS analyses and perform RT-PCR, to infer positional and functional candidate genes; 5) test most promising candidate genes identified/inferred from the above analyses for association with BMD variation in 800 Caucasian nuclear families (-700 nuclear families have already been recruited; recruitment of the remaining 100 families is being supported by an ongoing NIH grant and is expected to complete by Sept. 1, 2006. Identifying genomic regions and candidate genes for BMD variation with high certitude is important in unraveling genetic variants underlying risk of osteoporosis. It will form a solid basis for further fine mapping and association studies. It will expedite characterizing the mutations and the functional products underlying risk of osteoporosis, and help studies of interactions between genetic and environmental causes of osteoporosis. This knowledge is essential for the development of preventive interventions and/or cures for osteoporosis that may be based on individuals' specific genotypes.