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: 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
• 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

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.

项目总结/摘要 骨质疏松症已成为一个主要的和日益增长的全球公共卫生负担。由于担心副作用， 骨质疏松症药物的使用下降了50%。因此，存在开发新的 治疗骨质疏松症的药物;或开发个性化的治疗方法， 每个患者的个体差异。利用人类遗传学研究来确定新的药物靶点， 克服目前骨质疏松症的治疗危机。尽管GWAS已经成功地发现了 与复杂性状相关的遗传变异，超过88%的GWAS基因座是非编码的，这使得 鉴定致病性变体及其靶基因是一个困难的挑战;因此，限制了人类免疫缺陷病毒的使用。 药物发现中的遗传学信息。为了克服这些挑战并更好地理解GWAS， 研究结果，我们建议利用全基因组测序在大型良好的表型人群以及 CRISPR/Cas9基因编辑斑马鱼模型，以确定潜在的致病变异和影响的靶基因 骨骼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。我们 提出了三个具体目标，包括：1）通过现有的WGS在10，000个 来自Trans-Omics for Precision Medicine（TOPMed）计划的个人，以确定潜在的因果关系 负责GWAS信号的序列变体（功能变体）; 2）鉴定新的结构变体 变异和与BMD相关的新的罕见序列变异， 同样的一万个WGS样本我们将在另外5，000个样本中复制研究结果， GENOMOS/GEFOS联合体; 3）在功能上表征从目标1和2中选择的多达30个基因， 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 将应用于广泛的生理学（骨骼发育，个体发育， 再生）和特征（骨量增加、形态学和矿物质密度）。我们的建议是 这是非常重要的，代表了骨骼遗传学研究的下一步。结果将导致 急需的新药开发，以克服骨质疏松症日益增长的治疗差距。

项目成果

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
• 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
• 作者: Chan,KeiHangKatie;Hsu,Yi-Hsiang;Yang,Xia;Goto,Atsushi;Chen,BrianH
• 通讯作者: Chen,BrianH