Causal Genes at BMD Loci

项目摘要/摘要 骨质疏松症是一种常见的慢性病，有着巨大的健康负担。迫切需要 新的合成代谢疗法。这个项目的长期目标是了解骨质疏松的遗传风险因素。 以确定新的药物靶点，以减轻这一巨大的健康负担。全基因组关联研究 已经确定了数百个与骨密度(BMD)相关的基因座。然而，致病基因在 这些基因座仍有待发现。这个项目的基本原理是，定义BMD基因座的原因基因是 目前，这是一个表型受限的问题。更具体地说，大多数致病基因位于基因组区域。 两侧的骨密度基因座。因此，每个基因座都包含位于这些侧翼区域的多个候选基因。 然而，有100个这样的候选基因的骨骼功能是未知的，并且在体内 有足够的吞吐量来填补这一表型差距的方法实际上是不存在的。有一件急事 科学需要了解BMD基因座的基因功能，因为它们构成了 了解遗传变异如何影响骨密度，进而将这些基因座转化为临床的能力 目标。这个项目的目标是利用斑马鱼的快速吞吐生物学来促进我们的 了解影响骨量和骨质的BMD基因及其机制 行动起来。我们的中心假设是，遗传变异通过调节BMD相关基因来影响BMD， 它们协同作用，影响骨骼的质量和质量。在特定目标1(SA1)中，我们将在 反向遗传筛查中具有成人功能丧失骨骼表型的BMD基因座。我们的团队已经确定 一项大规模的GWAMeta分析中的56个BMD基因座。一种新的表型策略将被用来 从功能上注释位于这56个BMD基因座中80kb内的候选基因。人类基因分析将 以探索在我们的屏幕中识别的每个基因是如何影响BMD的。在具体目标2(SA2)中， 我们将进行多水平的检查，以确定基因在 7q31.31影响骨量和骨质。SA2将作为在SA1中发现新基因的模型， 以及它们之间的相互作用，将被机械地评估。这个项目具有创新性，因为它 与BMD基因座因果基因功能测试的现状有很大不同--使用小鼠 表型鉴定联盟-并利用我们团队开发的方法来执行最重要的 到目前为止，对骨密度基因的全面功能分析。该项目意义重大，因为它将：1) 为探索人类骨质疏松相关性状的基因组学建立一个有效的模型 有迫切的需要；2)在BMD基因座上识别新的骨骼基因，这是一个富含 已知的骨质疏松症药物靶点，并已被证明产生了可能在临床上可行的药物靶点；3) 定义7q31.31上的基因影响骨量和质量的机制，作为不同之处的模型 遗传变异和它们的致病基因可以协同作用，影响BMD。

PROJECT SUMMARY/ABSTRACT Osteoporosis is a common, chronic disease with an enormous health burden. There is an urgent need for new anabolic therapies. The long-term goal of this project is to understand genetic risk factors for osteoporosis to identify new drug targets to reduce this massive health burden. Genome wide association studies (GWAS) have identified hundreds of loci associated with bone mineral density (BMD). However, the causal genes at these loci remain to be discovered. The rationale for this project is that defining causal genes at BMD loci is, at present, a phenotype-limited problem. More specifically, most causal genes reside in the genomic regions flanking BMD loci. Thus, each locus implicates multiple candidate genes residing in these flanking regions. However, there are 100s of such candidate genes whose skeletal functions are unknown, and in vivo approaches with sufficient throughput to fill this phenotype gap are virtually non-existent. There is an urgent scientific need to understand the functions of genes at BMD loci, because they form the basis for understanding how genetic variants influence BMD, and in turn, the ability to translate these loci into clinical targets. The objective of this project is to leverage rapid-throughput biology in zebrafish to advance our understanding of genes at BMD loci that influence bone mass and quality, and the mechanisms by which they act. Our central hypothesis is that genetic variants influence BMD by regulating genes at BMD-associated loci, which work in concert to influence bone mass and quality. In specific aim 1 (SA1), we will identify genes at BMD loci with adult loss-of-function skeletal phenotypes in a reverse genetic screen. Our team has identified 56 BMD loci in a large-scale GWAS meta-analysis. A novel phenotyping strategy will be employed to functionally annotate candidate genes residing within 80kb of these 56 BMD loci. Human genetic analyses will be performed to explore how each gene identified in our screen contributes to BMD. In specific aim 2 (SA2), we will perform a multi-level examination to determine cellular and molecular mechanisms by which genes at 7q31.31 influence bone mass and quality. SA2 will serve as a model by which new genes discovered in SA1, and their interactions with each other, will be mechanistically evaluated. This project is innovative because it substantially differs from the status quo for functional testing for causal genes at BMD loci—the use of mouse phenotyping consortiums—and harnesses approaches developed by our team to perform one of the most comprehensive functional analyses of genes at BMD loci to date. This project is significant because it will: 1) establish an efficient model for exploration of human genomics underlying osteoporosis-related traits, for which there is an urgent need; 2) identify new skeletal genes at BMD loci, a genetic territory that is enriched with known osteoporosis drug targets, and which has proven to yield drug targets likely to be clinically viable; 3) define mechanisms by which genes at 7q31.31 influence bone mass and quality, as a model of how different genetic variants and their causal genes can act in concert to affect BMD.