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

基本信息

批准号：
10451606
负责人：
Yi-Hsiang Hsu
金额：
$ 41.28万
依托单位：
HEBREW REHABILITATION CENTER FOR AGED
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451606
关键词：
Address 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 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 causal variant density drug development drug discovery genetic association genetic information genetic variant genome sequencing genome wide association study genome-wide individual variation new therapeutic target novel novel diagnostics novel strategies novel therapeutics osteoporosis with pathological fracture personalized approach personalized therapeutic programs rare variant reverse genetics side effect skeletal trait trend virtual whole genome

项目摘要

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.

项目概要/摘要骨质疏松症已成为全球日益严重的主要公共卫生负担。由于担心副作用，骨质疏松症药物的使用量下降了 50%。因此，开发新产品的需求尚未得到满足治疗骨质疏松症的药物；或开发个性化的治疗方法，并能够考虑到每个患者的个体差异。利用人类遗传学研究来识别新的药物靶点应该克服当前骨质疏松症的治疗危机。尽管 GWAS 已成功发现与复杂性状相关的遗传变异，超过 88% 的 GWAS 位点是非编码的，这使得识别因果变异及其目标基因是一项艰巨的挑战；因此，限制了人类的使用药物发现中的遗传学信息。为了克服这些挑战并更好地了解 GWAS 研究结果表明，我们建议在大型表型良好的人群中利用全基因组测序以及 CRISPR/Cas9 基因编辑斑马鱼模型，用于识别潜在的因果变异和影响的目标基因骨骼的完整性。我们的发现最终可能会带来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）通过现有的 WGS 精细绘制 10,000 个先前的 BMD GWAS 位点来自跨组学精准医学 (TOPMed) 计划的个人确定潜在的因果关系负责 GWAS 信号的序列变异（功能变异）； 2）识别新颖的结构通过使用以下方法进行全基因组扫描，与 BMD 相关的变异和新颖的罕见序列变异相同的 10,000 个 WGS 样本。我们将在另外 5,000 个从 GENOMOS/GEFOS 联盟； 3) 对从目标 1 和 2 中选择的多达 30 个基因进行功能表征通过 CRISPR/Cas9 基因编辑系统敲除斑马鱼。最先进的快速表型分析技术斑马鱼的研究将应用于广泛的生理学（骨骼发育、个体发生和再生）和特征（骨量增长、形态和矿物质密度）。我们的建议是至关重要，代表了骨骼遗传学研究中合乎逻辑的下一步。结果将导致急需的新药开发，以克服骨质疏松症日益扩大的治疗差距。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pleiotropic Genetic Effects between Multiple Sclerosis and Musculoskeletal Traits.

多发性硬化症和肌肉骨骼特征之间的多效性遗传效应。

DOI：
10.1101/2023.09.12.23295444
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Jeong,Sohyun;Tsai,Ming-Ju;Shen,Changbing;Hsu,Yi-Hsiang
通讯作者：
Hsu,Yi-Hsiang

Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.

DOI：
10.3389/fgene.2018.00267
发表时间：
2018
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Zhou X;Cheung CL;Karasugi T;Karppinen J;Samartzis D;Hsu YH;Mak TS;Song YQ;Chiba K;Kawaguchi Y;Li Y;Chan D;Cheung KM;Ikegawa S;Cheah KS;Sham PC
通讯作者：
Sham PC

Genetic basis of falling risk susceptibility in the UK Biobank Study.

DOI：
10.1038/s42003-020-01256-x
发表时间：
2020-09-30
期刊：
Communications biology
影响因子：
5.9
作者：
Trajanoska K;Seppala LJ;Medina-Gomez C;Hsu YH;Zhou S;van Schoor NM;de Groot LCPGM;Karasik D;Richards JB;Kiel DP;Uitterlinden AG;Perry JRB;van der Velde N;Day FR;Rivadeneira F
通讯作者：
Rivadeneira F

The 2020 FASEB virtual Catalyst Conference on Integrative Approach for Complex Diseases Prevention and Management and Beyond, December 16, 2020.

2020 年 FASEB 虚拟催化剂会议，讨论复杂疾病预防和管理及其他综合方法，2020 年 12 月 16 日。

DOI：
10.1096/fj.202100317
发表时间：
2021
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Chan,KeiHangKatie;Hsu,Yi-Hsiang;Yang,Xia;Goto,Atsushi;Chen,BrianH
通讯作者：
Chen,BrianH