Targeted Sequencing of 3 Loci Associated with BMD in the Framingham Osteoporosis

Framingham 骨质疏松症中与 BMD 相关的 3 个位点的靶向测序

• 批准号: 8254457
• 负责人: DOUGLAS P. KIEL
• 金额: $ 48.54万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254457
• 关键词: Adult; Affect; Aging; Biology; Bone Density; Cardiovascular system; Caucasians; Caucasoid Race; Clinical; Cohort Studies; Comb animal structure; Complex; Computer Simulation; Control Groups; Country; DNA Resequencing; Data; Disease; Disease Pathway; Endometrial Carcinoma; Epidemiology; Etiology; Family member; Fracture; Frequencies; Functional disorder; Funding; Funding Opportunities; Future; Gene Frequency; Genes; Genetic; Genomic Segment; Genomics; Genotype; Gold; Grant; Health; Health Expenditures; Heart; Heritability; Individual; Lead; Length; Linkage Disequilibrium; Malignant neoplasm of ovary; Meta-Analysis; Methods; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Neck; Osteoporosis; Participant; Patients; Phenotype; Population; Predisposition; Proteins; Public Health; Reporting; Research; Resources; Risk; Sample Size; Sampling; Sampling Studies; Signal Transduction; Structure; Technology; Testing; United States; Validation; Variant; Woman; Work; bone; bone health; cohort; comparison group; cost efficient; disorder risk; follow-up; gene discovery; genetic element; genetic epidemiology; genome wide association study; genome-wide; improved; insight; lifetime risk; malignant breast neoplasm; men; next generation; novel; osteoporosis with pathological fracture; population based; prevent; public health relevance; trait

DESCRIPTION (provided by applicant): Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis- related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are nearly 13 billion dollars per annum; therefore, identifying genetic elements that are important to bone health will improve the understanding of the etiology of osteoporosis and may lead to novel treatments to prevent and treat the disease in the future. Previously, we have performed genome-wide association meta-analyses on bone phenotypes including bone mineral density (BMD) and osteoporotic fractures in adult Caucasian subjects1 Although more than 30 loci reached genome-wide significance (5x10-8) and were replicated in Caucasian populations, causal variants involved in the pathophysiology of osteoporosis in those loci still need to be elucidated. Therefore, to identify potential causal variants, we propose to re-sequence targeted genomic regions (identified by GWAS) in 325 individuals with the lowest extremes of BMD) from the Framingham Study. This resequencing effort will be combined with a resequencing project (442 cases and 712 controls) that is currently underway in a very limited sample of Framingham subjects through a grant supporting this work in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. By resequencing additional subjects in the Framingham Osteoporosis Study, our total sample size of 1,379 will provide sufficient power to be able to detect low frequency and rare variants that are likely to be the ones that affect bone density phenotypes. To replicate the sequencing findings, we will then genotype associated novel variants in 2,500 additional family members of the re-sequenced individuals from the Framingham Osteoporosis Study cohort as well as 3,000 individuals (1,500 cases with the lowest and 1,500 controls with highest extremes of BMD) from an independent cohort, the Rotterdam Study. Our proposal leverages unique, existing clinical, epidemiological and genetic data from the Framingham Study, the Rotterdam Study, as well as the CHARGE and GEFOS consortia. Our proposed project is highly responsive to the scope of the PAR 09-135 in applying high- throughput next generation deep sequencing technologies to follow-up genome-wide significant associated loci from our previous GWAS(the largest GWAS meta-analysis so far for BMD). Our proposed aims have the potential to uncover more of the as-yet unaccounted heritability in osteoporosis. Identifying genetic elements that are important to bone health will improve the understanding of the etiology of osteoporosis and may lead to novel treatments to prevent and treat this disease in the future. PUBLIC HEALTH RELEVANCE: This research is relevant to public health in that it will be able to identify new genes that increase the risk for osteoporosis which may eventually lead to better identification of individuals who are at increased risk for fracture. The newly discovered genes will identify previously unsuspected disease pathways that may lead to new treatments for osteoporosis.

描述（由申请人提供）：在美国，骨质疏松症影响着超过 2800 万人，并且骨质疏松症相关发病的终生风险高于女性患乳腺癌、子宫内膜癌和卵巢癌的综合风险。该国每年用于骨质疏松症患者的医疗保健支出近130亿美元；因此，识别对骨骼健康重要的遗传元件将提高对骨质疏松症病因的了解，并可能在未来带来预防和治疗该疾病的新疗法。此前，我们对成年白种人受试者的骨表型进行了全基因组关联荟萃分析，包括骨矿物质密度 (BMD) 和骨质疏松性骨折1。尽管有 30 多个位点达到全基因组显着性 (5x10-8) 并在白种人人群中进行了复制，但这些位点中涉及骨质疏松症病理生理学的因果变异仍需进一步研究。 阐明了。因此，为了识别潜在的因果变异，我们建议对弗雷明汉研究中 BMD 最低的 325 名个体的目标基因组区域（由 GWAS 识别）进行重新测序。这项重测序工作将与一项重测序项目（442 例病例和 712 例对照）相结合，该项目目前正在非常有限的 Framingham 受试者样本中进行，通过遗传流行病学心脏和衰老研究队列 (CHARGE) 联盟的一项拨款支持这项工作。通过对弗雷明汉骨质疏松症研究中的其他受试者进行重新测序，我们的总样本量为 1,379，这将提供足够的能力来检测可能影响骨密度表型的低频和罕见变异。为了复制测序结果，我们将对来自弗雷明汉骨质疏松症研究队列的重新测序个体的另外 2,500 名家庭成员以及来自鹿特丹研究的独立队列的 3,000 名个体（1,500 名具有最低 BMD 值的病例和 1,500 名具有最高 BMD 值的对照）的其他家庭成员进行基因分型。我们的提案利用了来自弗雷明汉研究、鹿特丹研究以及 CHARGE 和 GEFOS 联盟的独特的现有临床、流行病学和遗传数据。我们提出的项目对 PAR 09-135 的范围高度敏感，应用高通量下一代深度测序技术来跟踪我们之前的 GWAS（迄今为止 BMD 最大的 GWAS 荟萃分析）中的全基因组显着相关位点。我们提出的目标有可能发现更多尚未解释的骨质疏松症遗传性。识别对骨骼健康重要的遗传元件将提高对骨质疏松症病因的了解，并可能在未来带来预防和治疗这种疾病的新疗法。 公共健康相关性：这项研究与公共健康相关，因为它将能够识别增加骨质疏松症风险的新基因，这最终可能导致更好地识别骨折风险增加的个体。新发现的基因将识别以前未曾预料到的疾病途径，从而可能导致骨质疏松症的新治疗方法。