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

描述（由申请人提供）：骨质疏松症在美国影响着超过2800万人，骨质疏松症相关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总风险。在这个国家，骨质疏松症患者的医疗保健支出每年将近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。此前，我们对成年白种人的骨表型（包括骨矿物质密度（BMD）和骨质疏松性骨折）进行了全基因组关联荟萃分析1。尽管超过30个基因座具有全基因组意义（5x10-8），并在白种人人群中得到了复制，但这些基因座中涉及骨质疏松症病理生理的因果变异仍有待阐明。因此，为了确定潜在的因果变异，我们建议对来自Framingham研究的325名骨密度最低个体的目标基因组区域（通过GWAS鉴定）进行重新测序。这项重测序工作将与一个重测序项目（442例病例和712例对照）相结合，该项目目前正在弗雷明汉受试者的一个非常有限的样本中进行，该项目获得了遗传流行病学心脏和衰老研究队列（CHARGE）联盟的资助。通过对Framingham骨质疏松症研究中的其他受试者进行重测序，我们的总样本量为1,379，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。为了重复测序结果，我们将对来自弗雷明汉骨质疏松症研究队列的另外2500名重测序个体的家庭成员以及来自鹿特丹研究的独立队列的3000名个体（1500例骨密度最低，1500例对照，骨密度最高）进行基因型相关的新变异。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、现有的临床、流行病学和遗传数据。我们提议的项目高度响应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（迄今为止最大的BMD GWAS荟萃分析）中全基因组重要相关位点的后续研究。我们提出的目标有可能揭示骨质疏松症中更多尚未解释的遗传性。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。

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.