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）：骨质疏松症在美国影响超过2800万人，与骨质疏松相关的发病率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。该国骨质疏松患者的医疗保健支出每年接近130亿美元；因此，确定对骨骼健康重要的遗传因素将改善对骨质疏松症的病因的理解，并可能导致新的治疗方法以预防和治疗疾病。以前，我们在成年高加索受试者的骨表型（包括骨矿物质密度（BMD）和骨质疏松性骨折）上进行了全基因组关联荟萃分析，尽管有30个基因座达到了基因组的显着性（5x10-8），但仍在涉及的杂种中，涉及众多的杂种，在基因组中的显着性（5x10-8），并被复制。阐明。因此，为了确定潜在的因果变异，我们建议在Framingham研究中重新序列靶向基因组区域（由GWAS鉴定）的325个个体）。这项重新定价的工作将与重新定制项目（442例和712个对照组）相结合，该项目目前正在弗雷明汉受试者样本中正在进行中，该项目通过赠款来支持这项工作，以支持这项工作，用于遗传流行病学（CHALL）财团的心脏和老化研究。通过在弗雷明汉骨质疏松症研究中重新定制其他受试者，我们的总样本量为1,379将提供足够的功率，以便能够检测到可能是影响骨密度表型的低频和稀有变体。为了复制测序结果，我们将在2500名来自弗雷明汉骨质疏松症研究队列中的重新测试个体的其他家庭成员以及3,000个个体（1,500例具有最低和1,500个对照组，BMD最高的BMD，BMD）中的2500个家族成员中，来自独立队列，来自独立队列。我们的建议利用弗雷明汉研究，鹿特丹研究以及Chunder和Gefos联盟的独特，现有的临床，流行病学和遗传数据。我们提出的项目对PAR 09-135的范围高度响应，在将高通量的下一代深层测序技术应用于我们以前的GWAS（到目前为止BMD迄今为止最大的GWAS元分析）中跟进全基因组的重要相关基因座。我们提出的目标有可能发现骨质疏松症中更多尚未遗忘的遗传力。识别对骨骼健康重要的遗传因素将改善对骨质疏松症的病因的理解，并可能导致新的治疗方法来预防和治疗这种疾病。 公共卫生相关性：这项研究与公共卫生有关，因为它将能够识别出增加骨质疏松症风险的新基因，这最终可能会更好地识别出增加骨折风险增加的个体。新发现的基因将识别以前未经引起的疾病途径，这可能会导致骨质疏松症的新治疗方法。