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: 10210189
• 负责人: MARCELLA Donovan WALKER
• 金额: $ 57.43万
• 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/10210189
• 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 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; Rod; Roentgen Rays; Role; Sample Size; Testing; Thick; Thinness; Variant; Washington; Woman; Work; X-Ray Computed Tomography; base; bone; bone health; bone strength; causal variant; cohort; design; endophenotype; exome; exome sequencing; experience; fracture risk; fragility fracture; genetic analysis; genetic approach; genetic association; genetic testing; genome wide association study; insight; multi-ethnic; new therapeutic target; next generation sequencing; novel; personalized medicine; population based; racial difference; rare variant; 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低骨矿物质密度（BMD）和微结构定义。尽管 BMD对与骨质疏松或断裂相关的变体具有较高的遗传力，基因检测 骨骼健康的临床评估。 BMD的大多数遗传差异尚未考虑。 使用的遗传方法和骨骼的遗传方法阻碍了解决这个问题的尝试 结果评估。全基因组关联研究（GWASS）无法识别稀有变体。如此罕见 可以通过整个外显子组测序（WES）来识别的变体通常具有很大的功能重要性 效果。此外，稀有变体与常见的多基因条件有关。一些“失踪 骨质疏松症的遗传力可能是由于身份不明的稀有变体所致。大多数GWASS都评估了 与“骨矿物质密度”（BMD）或“断裂”的遗传关联，这是异质性的两种结果 致病过程。为了克服这些局限性，我们将使用WES评估特定的骨骼特征，例如 作为微观结构或矩阵特性，易于骨折或保护裂缝。这样的特征很少 遗传上异质性，更适合遗传分析。那是除DXA以外的其他工具，例如高 分辨率外围定量计算机断层扫描（HRPQCT）和撞击显微标记（IMI）可以 测量导致骨折的特定骨骼元素对于鉴定骨质疏松基因很有用。和 HRPQCT，我们通过识别少数族裔，新颖的基于成像的骨表型取得了进步 DXA赋予更大的骨强度任务较低或类似的BMD。使用WES，我们已经开始学习 这些种族差异的遗传学。我们的数据表明这是一种识别通用的强大方法 微观结构的贡献者。该项目的目的是表型，一个大型，基于人群的多种族 使用HRPQCT和IMI与现有WES数据的队列，以确定调节骨微结构的基因 和矩阵属性。这样，我们可以评估因果变异等位基因频率的种族差异 决定这些特征的赛车差异。最后，我们将评估确定的变体是否与 断裂。这项研究的主要优势是WES数据的可用性，与GWA相比，该数据允许 识别常见和稀有编码变体。我们基于基因的统计方法是一种强大的 方法，使我们的样本量可行。这些方法已用于识别新的 引起疾病的基因（未发现GWA）调节脂质，高度，感染性易感性，癫痫 和其他条件。它才在骨质疏松症中才开始探索，但提供了一种识别新基因的方法 GWA未检测到重要的生物学效应。总体假设是骨骼 微结构和基质特性在遗传调节下，可以鉴定出其基因 使用Wes。最终，对此类基因的识别可能会增强对骨骼调节剂的理解，这些骨骼调节剂 可能导致基因检测的发展和鉴定新药物的骨质疏松症。