Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish

通过全基因组测序和功能验证鉴定斑马鱼骨质疏松症基因

• 批准号: 9367512
• 负责人: Yi-Hsiang Hsu
• 金额: $ 59.2万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9367512
• 关键词: Address; Adverse effects; Affect; Alleles; Animal Model; Area; Bioinformatics; Biological; Biological Process; Biology; Bone Density; CRISPR/Cas technology; Characteristics; Code; Complex; Databases; Detection; Disease; Dual-Energy X-Ray Absorptiometry; Elderly; Etiology; Fracture; Fright; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Research; Genetic Screening; Genetic study; Genome; Genome Scan; Genotype; Goals; Heritability; Hip Fractures; Human Genetics; Incidence; Individual; Knock-out; Lead; Link; Maps; Mediating; Meta-Analysis; Minerals; Modeling; Morphology; Mutation; Natural regeneration; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiology; Population; Privatization; Public Health; Reporting; Research; Sampling; Signal Transduction; Skeletal Development; Skeleton; System; Technology; Time; Trans-Omics for Precision Medicine; Untranslated RNA; Validation; Variant; Zebrafish; base; bone mass; bone metabolism; density; drug development; drug discovery; genetic association; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide; new therapeutic target; novel; novel diagnostics; novel strategies; novel therapeutics; osteoporosis with pathological fracture; personalized approach; personalized therapeutic; programs; rare variant; reverse genetics; skeletal; trait; trend; virtual; whole genome

Project Summary/Abstract Osteoporosis has become a major and growing worldwide public health burden. Due to fears of side effects, the use of osteoporosis drugs has fallen by as much as 50%. Thus, there is an unmet need to develop new drugs for osteoporosis; or to develop personalized therapeutic approaches with the ability to takes into account individual variability for each patient. Using human genetic studies to identify new druggable targets should overcome the current treatment crisis in osteoporosis. Although GWAS have been successful in discovering associated genetic variants with complex traits, more than 88% of GWAS loci are non-coding, which makes the identification of causal variants and their targeted genes a difficult challenge; thus, limits the use of human genetics information in drug discovery. To overcome these challenges and get better understanding of GWAS findings, we proposed to utilize whole genome sequencing in large well-phenotyped populations as well as the CRISPR/Cas9 gene-editing zebrafish model to identify potential causal variants and targeted genes influencing skeletal integrity. Our findings may eventually lead to new diagnostics and therapeutics of osteoporosis. We proposed three specific aims, including: 1) Fine-map previous BMD GWAS loci by existing WGS in 10,000 individuals from the Trans-Omics for Precision Medicine (TOPMed) Program to identify potential causal sequence variants (functional variants) that are responsible for GWAS signals; 2) Identify novel structural variation and novel rare sequence variants associated with BMD by performing a whole genome scan using the same 10,000 WGS samples. We will replicate findings in an additional 5,000 samples selected from the GENOMOS/GEFOS consortium; 3) Functionally characterize up to 30 genes selected from aims 1 and 2 in knockout zebrafish by CRISPR/Cas9 gene-editing systems. State-of-the-art technologies for rapid phenotyping in zebrafish will be applied to a broad range of physiologies (skeletal development, ontogenesis, and regeneration) and characteristics (bone mass accrual, morphology, and mineral density). Our proposal is fundamentally important and represents the logical next step in skeletal genetics research. The results will lead to much needed new drug development to overcome the growing treatment gap in osteoporosis.

项目摘要/摘要 骨质疏松症已成为全球范围内日益严重的公共卫生负担。由于担心副作用， 骨质疏松症药物的使用量下降了多达50%。因此，有一种尚未得到满足的需求，即开发新的 治疗骨质疏松症的药物；或开发个性化治疗方法，能够考虑到 每个患者的个体差异。利用人类基因研究来识别新的可用药靶点应该 克服当前骨质疏松症的治疗危机。尽管地球科学院已经成功地发现了 与复杂性状相关的遗传变异，超过88%的GWA基因座是非编码的，这使得 鉴定因果变异及其靶基因是一项艰巨的挑战；因此，限制了人类基因的使用 药物发现中的遗传学信息。要克服这些挑战，更好地了解全球气候变化 我们建议在大量表型良好的群体中利用全基因组测序，以及 CRISPR/Cas9基因编辑斑马鱼模型识别潜在的原因变异和影响的靶基因 骨骼的完整性。我们的发现可能最终导致骨质疏松症的新诊断和治疗方法。我们 提出了三个具体目标，包括：1)精细映射现有WGS在10,000人中以前的BMD Gwas基因座 精准医学(TOPMed)计划中的个人，以确定潜在的原因 负责GWAS信号的序列变体(功能变体)；2)识别新的结构 通过执行全基因组扫描获得与BMD相关的变异和新的罕见序列变体 同样的10,000个WGS样本。我们将在另外5,000个样本中复制发现，这些样本是从 GENOMOS/GEFOS联盟；3)从功能上表征从目标1和2中选择的多达30个基因 利用CRISPR/Cas9基因编辑系统敲除斑马鱼。最新的快速表型鉴定技术 斑马鱼的基因将应用于广泛的生理学(骨骼发育、个体发育和 再生)和特征(骨量增加、形态和矿物质密度)。我们的建议是 从根本上来说很重要，代表着骨骼遗传学研究的合乎逻辑的下一步。结果将领先 到亟需的新药开发，以克服骨质疏松症日益增长的治疗缺口。