Skeletal Microstructure - Racial Differences and Genetic Contributors

骨骼微观结构 - 种族差异和遗传因素

• 批准号: 9469037
• 负责人: MARCELLA Donovan WALKER
• 金额: $ 59.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469037
• 关键词: Address; African American; Aging; Asians; Bioinformatics; Biological; Biomedical Engineering; Bone Density; Bone Matrix; Bone structure; Caucasians; Clinical; Clinical assessments; Code; Cohort Studies; Communities; Complex; Data; Deterioration; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Elements; Endocrine; Epilepsy; Ethnic Origin; Fracture; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic screening method; Genetic study; Goals; Grant; Health; Height; Heritability; Hispanics; Image; Imaging Techniques; Individual; Lead; Lipids; Measures; Methods; Minority; Modality; Osteoporosis; Outcome; Pathogenicity; Patients; Peripheral; Phenotype; Play; Predisposition; Process; Property; Public Health; Publishing; Race; Regulation; Resolution; Roentgen Rays; Role; Sample Size; Testing; Thick; Thinness; Variant; Washington; Woman; Work; X-Ray Computed Tomography; base; bone; bone health; bone strength; cohort; design; endophenotype; exome; exome sequencing; experience; fracture risk; fragility fracture; genetic analysis; genetic approach; genetic association; genetic variant; genome wide association study; insight; new therapeutic target; next generation sequencing; novel; personalized medicine; population based; racial difference; rare variant; retinal rods; skeletal; skeletal disorder; tool; trait

Osteoporosis is characterized by low bone mineral density (BMD) and microstructural deterioration. While BMD has high heritability, genetic testing for variants associated with osteoporosis or fracture plays no role in the clinical assessment of bone health. Most of the genetic variance of BMD has yet to be accounted for. Attempts to address this issue have been impeded by the genetic approaches utilized and the skeletal outcomes assessed. Genome-wide association studies (GWASs) cannot identify rare variants. Such rare variants, which can be identified by whole exome sequencing (WES), often have large functionally important effects. Moreover, rare variants are relevant to common, polygenic conditions. Some of the “missing heritability” of osteoporosis is likely due to unidentified rare variants. Further most GWASs have assessed genetic associations with “bone mineral density” (BMD) or “fracture”, both outcomes of heterogeneous pathogenic processes. To overcome these limitations, we will use WES to assess specific skeletal traits, such as microstructure or matrix properties, that predispose to or protect from fracture. Such traits are less genetically heterogeneous and more amenable to genetic analysis. Thus, tools other than DXA, such as high resolution peripheral quantitative computed tomography (HRpQCT) and impact microindentation (IMI) that can measure specific skeletal elements contributing to fracture are useful to identify osteoporosis genes. With HRpQCT, we have made progress by identifying in minorities, novel imaging-based bone phenotypes conferring greater bone strength despite lower or similar BMD by DXA. Using WES, we have begun to study the genetics of these racial differences. Our data indicate this is a powerful approach to identify genetic contributors to microstructure. The goal of this project is to phenotype a large, population-based, multi-ethnic cohort with existing WES data using HRpQCT and IMI in order identify genes regulating bone microstructure and matrix properties. In doing so, we can assess how racial differences in causal variant allele frequencies dictate racial differences in these traits. Lastly, we will assess if identified variants are associated with fractures. A major strength of this study is the availability of WES data, which in contrast to GWAS, allows for the identification of both common and rare coding variants. Our gene-based statistical approach is a powerful method, making this approach feasible with our sample size. These methods have been used to identify new disease-causing genes (not found with GWAS) that regulate lipids, height, infectious susceptibility, epilepsy and other conditions. It has only begun to be explored in osteoporosis, but offers a way to identify novel genes with important biological effects not detected by GWAS. The overarching hypothesis is that skeletal microstructure and matrix properties are under genetic regulation and genes underlying them can be identified using WES. Ultimately, identification of such genes may enhance understanding of skeletal regulators, which may lead to the development of genetic tests and identification of new drug targets for osteoporosis.

骨质疏松症的特征是骨密度降低和微结构恶化。而当 BMD具有很高的遗传性，对与骨质疏松症或骨折相关的变异进行基因测试在 骨健康的临床评估。骨密度的大部分遗传变异尚未得到解释。 解决这一问题的努力受到了所使用的遗传方法和骨骼的阻碍 评估结果。全基因组关联研究(GWAS)无法识别罕见的变异。这样的稀有 变异体可以通过整个外显子组测序(WES)来识别，通常具有重要的功能 效果。此外，罕见的变异与常见的多基因疾病有关。一些“失踪的” 骨质疏松症的“遗传性”可能是由于未知的罕见变异。此外，大多数GWAS已经评估了 遗传与“骨密度”(BMD)或“骨折”的关系，这两种结果都是异质性的 致病过程。为了克服这些限制，我们将使用WES来评估特定的骨骼特征，如 如易于断裂或防止断裂的微观组织或基质性能。这样的特征就少了 遗传异质性的，更易于进行遗传分析。因此，DXA以外的工具，如高 分辨率外围定量计算机断层扫描(HRpQCT)和冲击微压痕(IMI)，可以 测量导致骨折的特定骨骼元素有助于识别骨质疏松症基因。使用 HRpQCT，我们在少数民族中识别基于成像的新型骨表型方面取得了进展 尽管DXA的骨密度较低或相似，但仍具有更高的骨强度。利用WES，我们已经开始研究 这些种族差异的遗传学。我们的数据表明，这是一种识别基因的有效方法 微观结构的贡献者。这个项目的目标是表现出一个庞大的，以人口为基础的，多种族的 利用HRpQCT和IMI与现有的WES数据进行队列分析，以确定调控骨微结构的基因 和矩阵性质。通过这样做，我们可以评估种族差异在因果变异等位基因频率上的差异 决定了这些特征的种族差异。最后，我们将评估识别出的变体是否与 骨折。这项研究的一个主要优势是WES数据的可用性，这与GWAS形成对比，允许 识别常见和罕见的编码变体。我们基于基因的统计方法是一种强大的 方法，使这种方法在我们的样本量下是可行的。这些方法已经被用来识别新的 调节血脂、身高、传染性易感性、癫痫的致病基因(GWAs未发现) 以及其他条件。它在骨质疏松症方面的探索才刚刚开始，但它提供了一种识别新基因的方法 其重要的生物学效应未被GWAS检测到。最重要的假设是骨骼 微结构和基质特性受遗传调控，其背后的基因可以被识别 使用韦斯。最终，识别这样的基因可能会加强对骨骼调节因子的理解，这是 可能导致开发基因测试和确定治疗骨质疏松症的新药靶点。