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.

项目摘要/摘要 骨质疏松症已成为全球范围内的重大公共卫生负担。由于担心副作用， 使用骨质疏松药物的使用已下降多达50％。因此，有未满足的需要开发新的 骨质疏松症的药物；或开发个性化的治疗方法，并能够考虑 每个患者的个体变异性。使用人类遗传研究鉴定新的可毒靶应该 克服骨质疏松症的当前治疗危机。尽管GWAS已成功发现 相关的具有复杂性状的遗传变异，超过88％的GWAS基因座是非编码的，这使得这使得 鉴定因果变异及其靶向基因是一个困难的挑战；因此，限制了人类的使用 药物发现中的遗传信息。克服这些挑战并更好地了解GWAS 调查结果，我们提议在大型良好的人群中利用整个基因组测序以及 CRISPR/CAS9基因编辑斑马鱼模型，以鉴定潜在的因果变异和靶向基因 骨骼完整性。我们的发现最终可能导致骨质疏松症的新诊断和疗法。我们 拟议的三个特定目标，包括：1）现有WGS中的BMD GWAS Loci上的精细图。 精密医学跨词的个人（TOPMED）计划，以识别潜在的因果关系 负责GWAS信号的序列变体（功能变体）； 2）确定新颖的结构 通过使用使用整个基因组扫描与BMD相关的变异和新型稀有序列变体 相同的10,000个WGS样品。我们将在从中选择的另外5,000个样本中复制发现 Genomos/GEFOS联盟； 3）在功能上最多表征了从目标1和2中选择的30个基因 CRISPR/CAS9基因编辑系统的敲除斑马鱼。快速表型的最先进技术 在斑马鱼中，将应用于广泛的生理（骨骼发育，个体发生和 再生）和特征（骨质量应计，形态和矿物质密度）。我们的建议是 从根本上重要，代表了骨骼遗传学研究的逻辑下一步。结果将领导 急需的新药物开发以克服骨质疏松症的不断增长的治疗差距。

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