Identifying novel osteoarthritis risk genes using GWAS, chondrocyte genomics, and genome editing

项目摘要 尽管膝关节骨关节炎（OA）的全球患病率很高，但治疗选择仅限于症状 治疗和全关节置换术在很大程度上是因为驱动膝关节OA的机制仍然很差 明白全基因组关联研究（GWAS）表明，非编码遗传变异是一个主要的基因组。 然而，人类基因组的LD结构， 转录调控，以及缺乏基因组可编辑和生物学上准确的系统来研究 OA造成了一个瓶颈，阻碍了我们将GWAS的发现转化为新的治疗方法的能力。的 该提案的总体目标是识别假定的膝关节OA因果风险变体，将其映射到其目标 基因，并量化它们在软骨细胞中的表型影响。我们将确定激活的监管区域 响应软骨降解（目标1），将调控基因座和GWAS变体映射到其靶基因 (Aim 2），并使用离体模型量化膝关节OA相关变异的表型影响。 软骨细胞OA表型（Aim 3）。这项工作将打破膝关节OA遗传学的现有障碍，改善 为进一步研究和治疗膝关节OA提供新的危险基因 发展

Project Abstract Despite the high global prevalence of knee osteoarthritis (OA), treatment options have been limited to symptom management and total joint replacement in large part because the mechanisms driving knee OA remain poorly understood. Genome-wide association studies (GWAS) suggest that non-coding genetic variation is a major contributor to knee OA disease-risk; however, the LD structure of human genomes, the long-range nature of transcriptional regulation, and the lack of genome-editable and biologically accurate systems in which to study OA have created a bottleneck that hinders our ability to translate GWAS findings into new treatments. The overall objective of this proposal is to identify putative causal knee OA risk variants, map them to their target genes, and quantify their phenotypic impact in chondrocytes. We will identify regulatory regions activated in response to cartilage degradation (Aim 1), map regulatory loci and GWAS variants to their target genes (Aim 2), and quantify the phenotypic impacts of knee OA-associated variants using an ex vivo model of the chondrocyte OA phenotype (Aim 3). This work will break down existing barriers in knee OA genetics, improve our mechanistic understanding of knee OA, and provide new risk genes for further study and therapeutic development.