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Skeletal Microstructure - Racial Differences and Genetic Contributors

骨骼微观结构 - 种族差异和遗传因素

基本信息

批准号：
10456808
负责人：
MARCELLA Donovan WALKER
金额：
$ 58.61万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456808
关键词：
Address African American Aging Asian Asian population Bioinformatics Biological Biomedical Engineering Bone Density Bone Matrix Bone structure Caucasians Clinical Clinical assessments Code Cohort Studies Communities Complex Data Deterioration Development Diagnosis Diagnostic tests Disease Elements Endocrine Epilepsy Ethnic Origin Fracture Gene Frequency Genes Genetic Genetic Determinism Genetic study Goals Grant Health Height Heritability Hispanic 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 diagnostic strategy 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 determinant racial difference rare variant skeletal skeletal disorder tool trait

项目摘要

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.

骨质疏松症以低骨密度（BMD）和显微结构恶化为特征。而