Informing Osteoporosis GWAS Using Networks

使用网络告知骨质疏松症 GWAS

基本信息

批准号：
10394372
负责人：
Charles R Farber
金额：
$ 56.26万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2026-04-30
项目状态：
未结题

项目摘要

Project Summary: Osteoporosis is a complex disease characterized by low bone mineral density (BMD), bone fragility, and an increased risk of fracture. Genome-wide association studies (GWASs) for BMD have identified over 1100 associations. This “treasure trove” of novel genetic information has the potential to revolutionize our understanding of bone biology and the treatment of bone diseases; however, few of the causal genes underlying associations have been identified. The long-term goal of my lab is to reduce this knowledge gap using innovative analytical and experimental strategies. A number of approaches exist to identify genes responsible for GWAS associations. However, most rely on population-based “-omics” data, which are scarce for human bone, to connect variants to molecular alterations. Furthermore, most approaches do not provide information on how causal genes impact “systems-level” function. To address these limitations, we recently used co-expression networks generated from mouse bone transcriptomic datasets to inform BMD GWAS. The idea is simple – genes that play a central role in the regulation of a complex trait are often functionally-related and functionally-related genes are often co-expressed. We demonstrated that by identifying modules of co-expressed genes in bone tissue that were enriched for genes implicated by GWAS, we were able to predict target genes and infer how they impact BMD. We have shown experimentally that several genes (MARK3, PPP6R3, etc.) identified using this approach are true regulators of BMD. However, to date our analyses have been based only on enrichment of genes implicated by GWAS in undirected networks generated from heterogenous bulk bone transcriptomic datasets of limited cellular diversity. Here, we address these limitations using an innovative analytical approach incorporating Bayesian networks and key driver analysis (KDA) and apply this strategy to transcriptomic data from primary bone cell cultures and osteoblast subtypes defined by single cell RNA-seq (scRNA-seq). We hypothesize that our approach of integrating GWAS with directed networks representing all major bone cell types will identify novel genes with direct and central roles in regulating BMD and elucidate how such genes impact network architecture. We will test this hypothesis through three specific aims. In Aim 1, we will discover novel BMD GWAS target genes through the integration of bone and bone cell networks and GWAS data. In Aim 2, we will discover novel BMD GWAS target genes through the integration of osteoblast cell-type specific networks and GWAS data. In Aim 3, we will define the impact of novel BMD GWAS target genes on BMD and bone network homeostasis. Our innovative approach for informing GWAS will identify causal BMD genes and lead to the discovery of putative therapeutic targets for the prevention and treatment of bone fragility.

项目概要：骨质疏松症是一种复杂的疾病，其特征是骨矿物质密度（BMD）低， BMD 的全基因组关联研究 (GWAS) 表明骨脆性和骨折风险增加。确定了 1100 多个关联，这个新遗传信息的“宝库”有潜力彻底改变我们对骨生物学和骨疾病治疗的理解；然而，其中很少有我的实验室的长期目标是减少这种现象。存在使用创新分析和实验策略来弥补知识差距的方法。识别负责 GWAS 关联的基因然而，大多数依赖于基于人群的“组学”数据，此外，大多数方法都将变异与分子改变联系起来。不提供有关因果基因如何影响“系统级”功能的信息。我们最近使用从小鼠骨转录组数据集生成的共表达网络来告知 BMD GWAS 的想法很简单——在复杂性状的调节中发挥核心作用的基因通常是我们通过鉴定证明了功能相关基因和功能相关基因通常是共表达的。骨组织中共表达基因的模块，这些模块富含 GWAS 涉及的基因，我们能够预测目标基因并推断它们如何影响 BMD 我们已经通过实验证明了一些。使用这种方法鉴定的基因（MARK3、PPP6R3 等）是 BMD 的真正调节因子。分析仅基于无向网络中 GWAS 涉及的基因富集从有限细胞多样性的异源骨转录组数据集中生成。这些限制使用结合贝叶斯网络和关键驱动因素的创新分析方法分析（KDA）并将该策略应用于来自原代骨细胞培养物和成骨细胞的转录组数据我们为整合 GWAS 的方法而苦苦挣扎。代表所有主要骨细胞类型的有向网络将识别具有直接和中心作用的新基因我们将测试这些基因在调节 BMD 中的作用并阐明这些基因如何影响网络架构。通过三个具体目标的假设在目标 1 中，我们将通过以下方式发现新的 BMD GWAS 靶基因。在目标 2 中，我们将发现新的 BMD GWAS 数据。在目标 3 中，我们将通过整合成骨细胞类型特定网络和 GWAS 数据来确定目标基因。定义新型 BMD GWAS 靶基因对 BMD 和骨网络稳态的影响。告知 GWAS 的方法将识别因果 BMD 基因并导致发现假定的治疗方法预防和治疗骨脆性的目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of Known and Novel Long Noncoding RNAs Potentially Responsible for the Effects of Bone Mineral Density (BMD) Genomewide Association Study (GWAS) Loci.

DOI：
10.1002/jbmr.4622
发表时间：
2022-08
期刊：
JOURNAL OF BONE AND MINERAL RESEARCH
影响因子：
6.2
作者：
Abood, Abdullah;Mesner, Larry;Rosenow, Will;Al-Barghouthi, Basel M.;Horowitz, Nina;Morgan, Elise F.;Gerstenfeld, Louis C.;Farber, Charles R.
通讯作者：
Farber, Charles R.

Using "-omics" Data to Inform Genome-wide Association Studies (GWASs) in the Osteoporosis Field.

DOI：
10.1007/s11914-021-00684-w
发表时间：
2021-08
期刊：
Current osteoporosis reports
影响因子：
4.3
作者：
Abood A;Farber CR
通讯作者：
Farber CR

Long-read proteogenomics to connect disease-associated sQTLs to the protein isoform effectors of disease.

长读蛋白质基因组学，将疾病相关 sQTL 与疾病的蛋白质亚型效应子联系起来。

DOI：
10.1101/2023.03.17.531557
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Abood,Abdullah;Mesner,LarryD;Jeffery,ErinD;Murali,Mayank;Lehe,Micah;Saquing,Jamie;Farber,CharlesR;Sheynkman,GloriaM
通讯作者：
Sheynkman,GloriaM

Intramembranous bone regeneration in diversity outbred mice is heritable.

DOI：
10.1016/j.bone.2022.116524
发表时间：
2022-11
期刊：
BONE
影响因子：
4.1
作者：
Moran, Meghan M.;Ko, Frank C.;Mesner, Larry D.;Calabrese, Gina M.;Al-Barghouthi, Basel M.;Farber, Charles R.;Sumner, D. Rick
通讯作者：
Sumner, D. Rick

Single-Cell Transcriptomics of Bone Marrow Stromal Cells in Diversity Outbred Mice: A Model for Population-Level scRNA-Seq Studies.

多样性远交小鼠骨髓基质细胞的单细胞转录组学：群体水平 scRNA 测序研究的模型。

DOI：
10.1002/jbmr.4882
发表时间：
2023
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
0
作者：
Dillard,LukeJ;Rosenow,WillT;Calabrese,GinaM;Mesner,LarryD;Al-Barghouthi,BaselM;Abood,Abdullah;Farber,EmilyA;Onengut-Gumuscu,Suna;Tommasini,StevenM;Horowitz,MarkA;Rosen,CliffordJ;Yao,Lutian;Qin,Ling;Farber,CharlesR
通讯作者：
Farber,CharlesR