A Systems Genetics Approach to Identify BMD Genes

摘要 骨质疏松症是一种性别依赖的代谢性疾病，其特征是骨密度(BMD)降低， 骨骼微结构恶化，骨折风险增加。骨密度是骨折的一个强有力的预测因子， 高度可遗传的数量性状。近年来，全基因组关联研究(GWASs)已经确定 影响骨密度变异的基因有几十个；然而，很少有潜在基因被识别出来。一 基因发现受到限制的原因是缺乏关于人类骨细胞和组织的转录数据 这可以用来将GwA变异与因果基因表达的变化联系起来。在这里，我们解决这个问题 通过在涉及到的三种主要细胞类型上生成种群规模的转录转录图谱而导致的缺乏症 骨密度测定：成骨细胞、破骨细胞和骨细胞。这些数据将从骨骼和 从接受髋关节置换手术的个人身上采集的骨髓样本。在同一批人中，我们将 在体外产生相互关联的组织水平(微结构、矿化和生物力学特性) 细胞表型(成骨细胞和破骨细胞活性)。在目标1中，RNA-seq数据和高密度基因类型 将用于确定与BMD GWAs基因座共定位的表达数量性状基因座(EQTL)。在目标2中， 我们将确定基因的优先顺序，并确定它们通过关联影响BMD的机制 具有组织水平和细胞表型的共表达网络的研究。基因也将是 测试与一组几乎相同的表型在一个大的近亲交配的小鼠群体中的关联。在《目标3》中， 我们将确定SPTBN1，一个在初步研究中发现的基因，是否与Chr上的BMD GWA基因座有关。 2p16.2，通过研究AIMS 1和AIMS 2确定的另外一个候选者将被测试对 活体内的骨密度和其他骨骼特征。我们的新的和创新的方法来通知GWA将识别基因 负责GWAS基因座，并领导发现可能的治疗靶点，以预防和 治疗骨质疏松症。

ABSTRACT 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.