A Systems Genetics Approach to Identify BMD Genes

摘要 骨质疏松症是一种性别依赖性代谢性疾病，其特征是骨矿物质密度（BMD）降低， 骨骼微观结构的恶化和骨折风险的增加。BMD是骨折的强预测因子， 高度可遗传数量性状。近年来，全基因组关联研究（GWASs）发现， 几十个位点影响BMD的变化;然而，很少有潜在的基因已被确定。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学数据 可以用来将GWAS变异体与致病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学谱来检测缺陷。 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收集的骨髓样本。在同一个队列中，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 将用于鉴定与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。基因也将 在一个大的远系小鼠群体中测试与几乎相同的一组表型的关联。在目标3中， 我们将确定SPTBN 1，一个在初步研究中鉴定的基因，是否是导致染色体上BMD GWAS基因座的原因。 2p16.2，以及通过目标1和2的研究确定的另外一种候选物，将测试其对 体内BMD和其他骨特征。我们为GWAS提供信息的新颖创新方法将识别基因 负责GWAS基因座，并导致发现推定的治疗靶点，用于预防和 治疗骨质疏松。

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.