Genomics of bone and body composition traits in children

儿童骨骼和身体成分特征的基因组学

• 批准号: 10441340
• 负责人: Struan F A Grant
• 金额: $ 67.63万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441340
• 关键词: 3-Dimensional; ATAC-seq; Address; Adipose tissue; Adult; Affect; Age; Aging; Body Composition; Bone Density; Bone Development; Bone Mineral Contents; CRISPR/Cas technology; Cell Line; Cell model; Child; Childhood; Chromatin; Chromosome Mapping; Cohort Studies; Complex; Computer software; Data; Development; Disease; Dual-Energy X-Ray Absorptiometry; Elements; Enhancers; Environmental Exposure; Epigenetic Process; Etiology; Failure; Fatty acid glycerol esters; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Determinism; Genetic study; Genomics; Genotype; Growth; Health; Heritability; Hip region structure; Human; Image; Knowledge; Laboratories; Life; Life Cycle Stages; Location; Measures; Mesenchymal Stem Cells; Methods; Muscle; Musculoskeletal; National Institute of Child Health and Human Development; Osteoblasts; Osteoporosis; Phase; Phenotype; Public Domains; Reporting; Resolution; Resources; Sentinel; Shapes; Signal Transduction; Skeletal Development; Skeleton; Small Interfering RNA; Techniques; Tissues; Trabecular Bone Score; Variant; base; bone; bone fragility; bone mass; bone quality; bone strength; cell immortalization; cell type; chromosome conformation capture; clinical development; clinically relevant; data quality; functional genomics; gene function; genetic architecture; genetic variant; genome wide association study; genome-wide; indexing; innovation; insight; knock-down; longitudinal design; novel; pediatric patients; prevent; progenitor; promoter; shape analysis; skeletal; trait; transcriptome sequencing

ABSTRACT Our objective is to identify genes that regulate development of bone density, quality and strength in childhood. Childhood is a critical window for lifelong musculoskeletal health. Failure to achieve optimal bone accrual during childhood results in suboptimal peak bone mass and bone fragility later in life. In excess of 50 million older US adults have osteoporosis or low bone mass. Osteoporosis has a strong heritable component, yet only 20% of adult bone mineral density (BMD) variability is explained by genetic variants discovered to date. Pediatric studies should be highly effective in distilling the genetics of this complex phenotype, given (a) the duration of environmental influences is shorter, and (b) the genetic determinants of growth, body composition and maturation also influence bone accrual. Uncovering the genetic architecture of childhood bone accrual is critical for understanding lifelong skeletal health and identifying targets for preventing and treating bone fragility. Dual energy x-ray absorptiometry (DXA) measures of areal BMD are widely used in genetic studies. With DXA software advances, elements of bone quality and structural strength can be extracted, along with body composition parameters known to influence bone accrual. These deeper DXA-derived phenotypes have great potential to shed further important, novel insights into genetic determinants of the developing skeleton. We have genome-wide genotyped the NICHD Bone Mineral Density in Childhood Study (BMDCS) cohort which is unique for its large size, broad age range, high data quality, diversity and longitudinal design. We will derive new phenotypes from existing DXA and radiograph images, and apply advanced multidimensional phenotyping and multivariate GWAS methods to identify new loci. GWAS only reports genomic signals associated with a given trait and not necessarily the precise location of culprit genes. Therefore, we will use high-resolution `variant to gene mapping' techniques established in our `Center for Spatial and Functional Genomics' to investigate both previously reported pediatric novel loci and our anticipated new loci. Our approach first prioritizes putative causal SNPs using open chromatin and enhancer epigenetic signatures, and then identifies 3D genomic contacts between these prioritized SNPs and their target gene promoters, using a high-resolution promoter-based chromatin conformation capture technique. To validate these target genes, we will use CRISPR/Cas9 to edit the putative regulatory SNPs and use siRNA to target genes and show an effect on bone-relevant phenotypes. We will apply our techniques in primary pediatric human mesenchymal progenitor cell (MSC)-derived osteoblasts, a very relevant bone cellular model for understanding pediatric bone mass accrual. Thus, our proposal is an unparalleled opportunity to interrogate novel phenotypes and functionally characterize the actual effector genes using high resolution chromatin conformation capture approaches at these new, as well as previously known bone-related loci.

抽象的 我们的目标是确定调节儿童时期骨密度、质量和强度发育的基因。 童年是终生肌肉骨骼健康的关键窗口。期间未能达到最佳骨增长 童年时期导致骨量峰值不理想，并且在以后的生活中骨脆性增加。美国有超过 5000 万老年人 成年人患有骨质疏松症或骨量低。骨质疏松症具有很强的遗传性，但只有 20% 成人骨密度 (BMD) 的变异性可以通过迄今为止发现的遗传变异来解释。儿科研究 考虑到（a）持续时间，应该非常有效地提取这种复杂表型的遗传学 环境影响较短，并且（b）生长、身体成分和的遗传决定因素 成熟也会影响骨生成。揭示儿童骨质增生的遗传结构至关重要 了解终生骨骼健康并确定预防和治疗骨脆性的目标。 面积 BMD 的双能 X 射线吸收测定法 (DXA) 测量广泛应用于遗传学研究。具有双能X线吸收分析仪 软件的进步，可以提取骨骼质量和结构强度的元素以及身体 已知影响骨生成的成分参数。这些更深层次的 DXA 衍生表型具有很大的 具有对骨骼发育的遗传决定因素提供进一步重要、新颖见解的潜力。我们有 对 NICHD 儿童骨矿物质密度研究 (BMDCS) 队列进行全基因组基因分型，该队列是独一无二的 其规模大、年龄范围广、数据质量高、多样性和纵向设计。我们将衍生出新的 从现有的 DXA 和放射线图像中分析表型，并应用先进的多维表型分析和 多变量 GWAS 方法来识别新基因座。 GWAS 仅报告与给定相关的基因组信号 性状，不一定是罪魁祸首基因的精确位置。因此，我们将使用高分辨率“变体 我们的“空间和功能基因组学中心”建立了基因图谱技术来研究这两个方面 先前报道的儿科新基因座和我们预期的新基因座。我们的方法首先优先考虑假定的因果关系 使用开放染色质和增强子表观遗传特征的 SNP，然后识别 3D 基因组接触 使用基于高分辨率启动子的方法，在这些优先的 SNP 及其目标基因启动子之间进行分析 染色质构象捕获技术。为了验证这些目标基因，我们将使用 CRISPR/Cas9 来编辑 推定的调节 SNP 并使用 siRNA 靶向基因并显示对骨相关表型的影响。我们 将把我们的技术应用于初级儿童人间充质祖细胞（MSC）衍生的成骨细胞， 对于了解儿童骨量增长非常相关的骨细胞模型。 因此，我们的建议是询问新表型和功能表征的无与伦比的机会 使用高分辨率染色质构象捕获方法在这些新的实际效应基因，如 以及先前已知的骨相关位点。