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健康问题，其主要特征是低骨密度(BMD)。BMD具有很强的遗传决定力，遗传度为60%。在过去的9年里，我们积累了前所未有的大样本。我们有能力使用多种互补的方法，以极高的能力和确定性识别骨密度变异背后的基因组区域。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鉴定。所有受试者都接受了全人类基因组中411个微卫星(MS)标记的基因分型。我们进行了全基因组扫描(WGS)和遗传上位性的初步分析。确定了几个与BMD有很强关联的基因组学区域。在这个项目中，我们请求支持：1)进行复杂、全面和全面的连锁分析，以调查我们的WGS分析中的遗传异质性(包括印迹)、逐个基因(GXG)和逐个环境(GxE)的交互作用；2)利用我们的WGS中发现的潜在重要区域(即LOD分数和GT；1.9)饱和基因密集型MS标记，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，测试已在早期研究中至少显示出与BMD关联的标记的连锁；4)对上述WGS分析中确定的连锁区域内的基因表达数据(已获得)进行重点分析并进行RT-PCR，以推断位置和功能候选基因；5)测试从上述分析中确定/推断的最有希望的候选基因与800个高加索核心家庭(-700个核心家庭已被招募；其余100个家庭的招募正在由NIH持续拨款支持，预计于9月1日完成)的骨密度变异。1,2006年。确定基因组区域和BMD变异的候选基因对于揭开骨质疏松风险的遗传变异具有重要意义。这将为进一步的精细绘图和关联研究奠定坚实的基础。它将加快确定导致骨质疏松症风险的突变和功能产物的特征，并有助于研究导致骨质疏松症的遗传和环境原因之间的相互作用。这一知识对于制定可能基于个人特定基因类型的骨质疏松症预防干预措施和/或治疗措施至关重要。

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.