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

描述(申请人提供)：美国有2800多万人患有骨质疏松症，患骨质疏松症相关疾病的终生风险高于女性患乳腺癌、子宫内膜癌和卵巢癌的风险总和。美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，识别对骨骼健康至关重要的遗传因素将提高人们对骨质疏松症病因的了解，并可能导致未来预防和治疗这种疾病的新疗法。此前，我们对成年高加索受试者的骨表型进行了全基因组联合荟萃分析，包括骨密度(BMD)和骨质疏松性骨折1。尽管有30多个基因座达到全基因组意义(5x10-8)，并在高加索人群中复制，但这些基因座参与骨质疏松病理生理学的因果变异仍需阐明。因此，为了确定潜在的因果变异，我们建议对Framingham研究中的325个BMD最低端的个体的目标基因组区域(由GWAS确定)进行重新排序。这项重新测序工作将与一个重新测序项目(442个病例和712个对照)相结合，该项目目前正在非常有限的弗雷明翰受试者样本中进行，通过在遗传流行病学心脏和衰老研究(CHARD)财团中提供一笔赠款支持这项工作。通过对弗雷明翰骨质疏松症研究中的其他受试者进行重新排序，我们1379个样本的总容量将提供足够的能力，能够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，我们将在Framingham骨质疏松研究队列的2,500名重新测序的个体的另外2,500名家庭成员中以及来自独立队列鹿特丹研究的3,000名个体(骨密度最低的1,500名患者和骨密度最高的1,500名对照)中进行基因相关的新变种。我们的建议利用了来自Framingham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。我们建议的项目高度响应了PAR 09-135的范围，即应用高通量下一代深度测序技术来跟踪我们以前GWAs的全基因组显著相关基因座(迄今为止最大的GWASBMD荟萃分析)。我们提出的目标有可能揭示骨质疏松症中更多尚未被解释的遗传性。识别对骨骼健康很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那些面临更高骨折风险的个人。新发现的基因将识别以前从未被怀疑的疾病途径，这些途径可能会导致骨质疏松症的新疗法。

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.