Bone Microarchitecture: The Framingham Osteoporosis Study

骨微结构：弗雷明汉骨质疏松症研究

• 批准号: 8631420
• 负责人: DOUGLAS P. KIEL
• 金额: $ 85.82万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631420
• 关键词: Aging; Alleles; Bioinformatics; Bone Density; Candidate Disease Gene; Chromatin Structure; Clinic; Code; Complement; Cost of Illness; DNA; Data; Deterioration; Disease; Elements; Encyclopedia of DNA Elements; Epidemiology; Exons; Family; Fracture; Functional RNA; Funding; Gene Expression Profile; Gene Frequency; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Gold; Grant; Heart; Human; Human Genetics; Individual; International; Lead; Maps; Measures; Meta-Analysis; Minor; Mutation; Nucleic Acid Regulatory Sequences; Open Reading Frames; Osteoporosis; Pathway interactions; Peripheral; Phenotype; Proteins; Public Health; Quantitative Trait Loci; Radial; Reporting; Research; Resolution; Risk; Sampling; Source; Testing; Tissue Sample; Variant; Work; X-Ray Computed Tomography; base; bone; bone cell; bone health; bone strength; clinical practice; cohort; deep sequencing; exome; exome sequencing; genetic variant; genome sequencing; genome wide association study; genome-wide; histone modification; interest; lifestyle factors; male; novel; offspring; parent grant; population based; public health relevance; retiree; tibia; tool; transcription factor

This supplement ("Revision") to our currently funded grant entitled, "Bone Microarchitecture: The Framingham Osteoporosis Study," expands the scope of the genetics work of the parent grant. It will extend the genome- wide association study (GWAS) of the parent grant to the realm of potentially more functional, less common variants that will provide important data on the contribution of these variants to bone microarchitecture measured by high resolution peripheral quantitative computed tomography (HR-pQCT). Ideally, the best way to identify potentially functional genetic variants associated with bone microarchitecture is to have sequencing data from as much of the genome as possible. Although deep sequencing represents a powerful approach for the discovery of the complete spectrum of variants that cause diseases, the cost of obtaining and analyzing whole genome or even exome-sequences on a large human sample remains prohibitive. Therefore, this study will make use of exome chip data along with dense genome wide genotyping data in several cohorts with HR- pQCT phenotypes to impute less common and potentially functional variants across the whole genome. The imputation will make use of a growing reference panel of whole genome sequencing that has emerged from several international efforts. To accomplish our aim, we have assembled all the cohorts from around the world who currently have HR-pQCT phenotypes and DNA available. The approach to be taken in this project will involve the following steps: 1) Use existing GWAS genotyping and exome chip genotyping from the family- based Framingham Study to impute variants with minor allele frequency as low as 0.5%; 2) Obtain the same GWAS and exome chip genotyping in three other cohorts with the identical HR-pQCT-derived bone microarchitecture phenotypes; 3) Perform the whole genome imputation in those population-based cohorts using an integrated reference panel consisting of 10,000 publicly available whole genome sequences; 4) Meta-analyze results from cohort specific association analyses using the imputed genotypes; 5) Prioritize the most significant findings in the meta-analyses, using statistical significance levels as well as bioinformatic tools to predict functional potential (e.g. ENCODE, eQTL analysis); 6) Validate the accuracy of the imputed variants having the most significant association with bone microarchitecture by performing de-novo genotyping in the Framingham Study; 7) Replicate the most significant associations for variants with confirmed accurate genotype in five other HR-pQCT cohorts using de-novo genotyping. Our strategy of identifying both common and less common, potentially causal variants in protein-coding regions and non-coding regulatory regions represents a robust conceptual paradigm for the study of bone microarchitectural deterioration that characterizes the disease, osteoporosis.

本补充（“修订”）是对我们目前资助的赠款，题为“骨骼微架构：弗雷明汉 骨质疏松症研究”扩大了父母资助的遗传学工作范围。它将扩展基因组- 家长的广泛关联研究 (GWAS) 授予潜在更实用、不太常见的领域 变体将提供有关这些变体对骨微结构的贡献的重要数据 通过高分辨率外周定量计算机断层扫描 (HR-pQCT) 进行测量。理想情况下，最好的方法 识别与骨微结构相关的潜在功能性遗传变异的方法是进行测序 来自尽可能多的基因组的数据。尽管深度测序代表了一种强大的方法 导致疾病的完整变异谱的发现、获取和分析的成本 大型人类样本的整个基因组甚至外显子组序列仍然令人望而却步。因此，本研究 将在几个 HR 队列中利用外显子组芯片数据以及密集的全基因组基因分型数据 pQCT 表型可估算整个基因组中不太常见且具有潜在功能的变异。这 插补将利用越来越多的全基因组测序参考面板，这些参考面板已经出现在 多项国际努力。为了实现我们的目标，我们聚集了来自世界各地的所有队伍 目前拥有 HR-pQCT 表型和 DNA 的人。该项目将采取的方法 涉及以下步骤： 1) 使用该家族现有的 GWAS 基因分型和外显子组芯片基因分型 - 基于 Framingham 研究，估算次要等位基因频率低至 0.5% 的变异； 2）获得相同的 对具有相同 HR-pQCT 衍生骨的其他三个队列进行 GWAS 和外显子组芯片基因分型 微结构表型； 3) 在基于人群的队列中进行全基因组插补 使用由 10,000 个公开可用的全基因组序列组成的综合参考组； 4） 使用估算基因型对队列特定关联分析的结果进行荟萃分析； 5）优先考虑 使用统计显着性水平和生物信息学工具进行荟萃分析中最重要的发现 预测功能潜力（例如 ENCODE、eQTL 分析）； 6) 验证估算变量的准确性 通过在骨中进行从头基因分型，与骨微结构具有最显着的关联 弗雷明汉研究； 7) 复制最显着的变异关联并确认准确 使用从头基因分型对其他五个 HR-pQCT 队列进行基因分型。我们的策略是识别两者的共同点 以及蛋白质编码区和非编码调控区中不太常见的潜在因果变异 代表了骨微结构退化研究的一个强大的概念范式 该疾病的特征是骨质疏松症。