A Systems Genetics Approach to Identify BMD Genes

识别 BMD 基因的系统遗传学方法

基本信息

批准号：
10582131
负责人：
Charles R Farber
金额：
$ 11.98万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582131
关键词：
Address Affect Age Biomechanics Bone Density Bone Marrow Bone Tissue CRISPR/Cas technology Clinical Data Code Data Deterioration Development Disease Etiology Family Fracture Gene Expression Regulation Genes Genetic Genotype Heritability Heritable Quantitative Trait Hip Fractures Human In Vitro Individual Investigation Lead Link Measures Metabolic Diseases Morbidity - disease rate Mus Operative Surgical Procedures Osteoblasts Osteoclasts Osteocytes Osteoporosis Patients Persons Phenotype Population Prevention Property Quantitative Trait Loci Recording of previous events Risk Factors Sampling Specimen System Testing Time Tissues Variant bone bone cell bone fragility causal variant cell type cohort demographics density fracture risk gene discovery genetic analysis genetic approach genetic variant genome editing genome wide association study hip replacement arthroplasty in vivo innovation mechanical properties mineralization molecular phenotype mortality mutant mutant mouse model novel phenotypic data sex therapeutic target trait transcriptome sequencing transcriptomics

项目摘要

Osteoporosis is a sex-dependent, metabolic disease characterized by decreased bone mineral density (BMD), deterioration of bone microstructure, and increased risk of fracture. BMD is a strong predictor of fracture and a highly heritable quantitative trait. In recent years, genome-wide association studies (GWASs) have identified dozens of loci influencing variation in BMD; however, few of the underlying genes have been identified. One reason that gene discovery has been limited is a lack of transcriptomic data on human bone cells and tissues that can be used to link GWAS variants to alterations in the expression of causal genes. Here, we address this deficiency by generating population-scale transcriptomic profiles on the three primary cell types involved in determining BMD levels: osteoblasts, osteoclasts and osteocytes. These data will be generated from bone and marrow samples collected from individuals undergoing hip replacement surgery. In the same cohort, we will generate co-relatable tissue-level (microarchitecture, mineralization, and biomechanical properties) and in vitro cellular phenotypes (osteoblast and osteoclast activities). In Aim 1, RNA-seq data and high-density genotypes will be used to identify expression quantitative trait loci (eQTL) that colocalize with BMD GWAS loci. In Aim 2, we will prioritize genes and determine the mechanisms through which they impact BMD through association with tissue-level and cellular phenotypes and the investigation of co-expression networks. Genes will also be tested for association with a nearly identical set of phenotypes in a large outbred mouse population. In Aim 3, we will determine if SPTBN1, a gene identified in preliminary studies, is causal for a BMD GWAS locus on Chr. 2p16.2, and one additional candidate identified via the studies of Aims 1 and 2 will be tested for an effect on BMD and other bone traits in vivo. Our novel and innovative approach for informing GWAS will identify genes responsible for GWAS loci and lead to the discovery of putative therapeutic targets for the prevention and treatment of bone fragility.

骨质疏松症是一种性别依赖性代谢疾病，其特征是骨矿物质密度 (BMD) 降低，骨微结构恶化，骨折风险增加。 BMD 是骨折的有力预测因子高度遗传的数量性状。近年来，全基因组关联研究（GWAS）发现数十个影响 BMD 变异的基因座；然而，很少有潜在的基因被识别出来。一基因发现受到限制的原因是缺乏人类骨细胞和组织的转录组数据可用于将 GWAS 变异与因果基因表达的改变联系起来。在这里，我们解决这个问题通过在涉及的三种主要细胞类型上生成群体规模的转录组图谱来发现缺陷确定 BMD 水平：成骨细胞、破骨细胞和骨细胞。这些数据将从骨骼生成从接受髋关节置换手术的个体中采集的骨髓样本。在同一队列中，我们将产生相关的组织水平（微结构、矿化和生物力学特性）和体外细胞表型（成骨细胞和破骨细胞活性）。在目标 1 中，RNA-seq 数据和高密度基因型将用于识别与 BMD GWAS 基因座共定位的表达数量性状基因座 (eQTL)。在目标 2 中，我们将优先考虑基因并确定它们通过关联影响 BMD 的机制组织水平和细胞表型以及共表达网络的研究。基因也会在大型远交小鼠群体中测试了与一组几乎相同的表型的关联。在目标 3 中，我们将确定初步研究中确定的 SPTBN1 基因是否与 Chr. 上的 BMD GWAS 基因座有关。 2p16.2，并且通过目标 1 和 2 的研究确定的另一名候选者将测试其对 BMD 和其他体内骨骼特征。我们用于通知 GWAS 的新颖且创新的方法将识别基因负责 GWAS 位点并导致发现预防和预防的假定治疗靶点治疗骨质疏松。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dissecting the Genetics of Osteoporosis using Systems Approaches.

使用系统方法剖析骨质疏松症的遗传学。

DOI：
10.1016/j.tig.2018.10.004
发表时间：
2019-01
期刊：
Trends in genetics : TIG
影响因子：
0
作者：
Al-Barghouthi BM;Farber CR
通讯作者：
Farber CR

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts.

染色体 14q32.32 内的基因组变异通过成骨细胞中的 MARK3 信号调节骨量。

DOI：
10.1172/jci142580
发表时间：
2021
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Zhang,Qian;Mesner,LarryD;Calabrese,GinaM;Dirckx,Naomi;Li,Zhu;Verardo,Angela;Yang,Qian;Tower,RobertJ;Faugere,Marie-Claude;Farber,CharlesR;Clemens,ThomasL
通讯作者：
Clemens,ThomasL

Genetic variation influences the skeletal response to hindlimb unloading in the eight founder strains of the diversity outbred mouse population.

遗传变异影响多样性远交小鼠群体的八个创始品系对后肢卸载的骨骼反应。

DOI：
10.1002/jor.25646
发表时间：
2024
期刊：
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子：
0
作者：
Friedman,MichaelA;Buettmann,EvanG;Zeineddine,Yasmina;Abraham,LovellB;Hoppock,GabrielA;Meas,StevenJ;Zhang,Yue;Farber,CharlesR;Donahue,HenryJ
通讯作者：
Donahue,HenryJ