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: 8118736
• 负责人: DOUGLAS P. KIEL
• 金额: $ 48.62万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118736
• 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; 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）：骨质疏松症影响美国超过2800万人，骨质疏松症相关发病率的终生风险高于女性乳腺癌、子宫内膜癌和卵巢癌的综合风险。在这个国家，骨质疏松症患者的医疗保健支出每年近130亿美元;因此，确定对骨骼健康重要的遗传因素将提高对骨质疏松症病因的理解，并可能导致未来预防和治疗该疾病的新疗法。以前，我们已经进行了全基因组关联荟萃分析的骨表型，包括骨矿物质密度（BMD）和骨质疏松性骨折的成年高加索受试者1虽然超过30个位点达到全基因组意义（5 × 10 - 8），并在高加索人群中复制，在这些位点的骨质疏松症的病理生理学的因果变异仍然需要阐明。因此，为了鉴定潜在的致病变异，我们建议对来自Fracket研究的325名BMD最低值个体的靶向基因组区域（通过GWAS鉴定）进行重新测序。这项重新测序工作将与一个重新测序项目（442例病例和712例对照）相结合，该项目目前正在通过支持遗传流行病学中心脏和衰老研究队列（CHARGE）财团的这项工作的资助，在非常有限的Fragrant受试者样本中进行。通过对脆性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，将提供足够的功效，能够检测出可能影响骨密度表型的低频率和罕见变异。为了重复测序结果，我们将对来自Fragrance骨质疏松研究队列的2,500名重新测序个体的额外家庭成员以及来自独立队列（鹿特丹研究）的3,000名个体（1,500例具有最低BMD的病例和1,500例具有最高BMD的对照）进行基因型相关的新变体。我们的提案利用了来自Fragmentary研究、鹿特丹研究以及CHARGE和GEFOS联盟的独特的、现有的临床、流行病学和遗传数据。我们提出的项目高度响应PAR 09 - 135的范围，将高通量下一代深度测序技术应用于我们之前的GWAS（迄今为止BMD最大的GWAS荟萃分析）的全基因组显著相关基因座的随访。我们提出的目标有可能揭示更多的骨质疏松症尚未解释的遗传性。确定对骨骼健康重要的遗传因素将提高对骨质疏松症病因的理解，并可能导致未来预防和治疗这种疾病的新疗法。 公共卫生关系：这项研究与公共卫生有关，因为它将能够识别增加骨质疏松症风险的新基因，这可能最终导致更好地识别骨折风险增加的个体。新发现的基因将确定以前未知的疾病途径，可能导致骨质疏松症的新治疗方法。