Genomic search for bone mass QTLs

骨量 QTL 的基因组搜索

• 批准号: 7354757
• 负责人: HONG-WEN DENG
• 金额: $ 58.76万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354757
• 关键词: Bone Density; Candidate Disease Gene; Caucasians; Caucasoid Race; Child; Chromosome Mapping; DNA Microarray Chip; DNA Microarray format; Data; Development; Environment; Family; Gender; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Epistasis; Genetic Heterogeneity; Genome; Genomics; Genotype; Grant; Heritability; Human Genome; Individual; Knowledge; Lod Score; Maps; Microsatellite Repeats; Mutation; Nuclear Family; Osteoporosis; Parents; Phenotype; Positioning Attribute; Preventive Intervention; Public Health; Recruitment Activity; Research Personnel; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Solid; Testing; Tissue-Specific Gene Expression; United States National Institutes of Health; Variant; base; bone; falls; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; imprint; programs

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.

描述（由申请人提供）：骨质疏松症是一个重大的公共卫生问题，其主要特征是骨密度低。骨密度具有很强的遗传决定力，遗传率约为60%。在过去的9年里，我们积累了前所未有的大量样本。我们能够利用多种互补的方法，以非常高的能力和确定性确定骨密度变异的基因组区域。我们从361个高加索血统中招募了4259名受试者并进行了表型分析。对所有受试者进行了全基因组411个微卫星（MS）标记的基因分型。我们对全基因组扫描（WGS）和遗传上位性进行了初步分析。确定了几个与骨密度密切相关的基因组区域。在本项目中，我们要求支持：1)在WGS分析中，进行复杂、彻底和全面的连锁分析，以研究遗传异质性（包括印迹）、基因与基因（GxG）和基因与环境（GxE）的相互作用；2)基因型密集MS标记，以饱和WGS中发现的潜在显著区域（即LOD评分> 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，测试在早期研究中至少显示与BMD有关联的标记的联系；4)对我们在上述WGS分析中确定的连锁区域内的基因表达数据（已经获得）进行重点分析，并进行RT-PCR，推断位置和功能候选基因；5)测试从上述分析中发现/推断出的最有希望的候选基因与800个高加索核心家庭的骨密度变化的关系(-700个核心家庭已经被招募；其余100个家庭的招募由NIH资助，预计将于2006年9月1日完成。确定BMD变异的基因组区域和候选基因对于揭示潜在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制图和关联研究奠定坚实的基础。它将加快表征突变和功能产物潜在的骨质疏松症的风险，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。这一知识对于基于个体特定基因型的骨质疏松症预防干预和/或治疗的发展至关重要。