Osteoarthritis is a complex degenerative joint disease. Here, we investigate matched genotype and methylation profiles of primary chondrocytes from macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage and from synoviocytes collected from 98 osteoarthritis-affected individuals undergoing knee replacement surgery. We perform an epigenome-wide association study of knee cartilage degeneration and report robustly replicating methylation markers, which reveal an etiologic mechanism linked to the migration of epithelial cells. Using machine learning, we derive methylation models of cartilage degeneration, which we validate with 82% accuracy in independent data. We report a genome-wide methylation quantitative trait locus (mQTL) map of articular cartilage and synovium and identify 18 disease-grade-specific mQTLs in osteoarthritis cartilage. We resolve osteoarthritis GWAS loci through causal inference and colocalization analyses and decipher the epigenetic mechanisms that mediate the effect of genotype on disease risk. Together, our findings provide enhanced insights into epigenetic mechanisms underlying osteoarthritis in primary tissues.

骨关节炎是一种复杂的退行性关节疾病。在这里，我们研究了来自宏观完整（低级）和退化（高级）骨关节炎软骨以及从 98 名接受膝关节置换手术的骨关节炎患者收集的滑膜细胞的原代软骨细胞的匹配基因型和甲基化谱。我们对膝关节软骨退化进行了全表观基因组关联研究，并报告了稳健复制的甲基化标记，揭示了与上皮细胞迁移相关的病因机制。利用机器学习，我们推导出软骨退化的甲基化模型，并在独立数据中以 82% 的准确度进行验证。我们报告了关节软骨和滑膜的全基因组甲基化数量性状位点（mQTL）图谱，并鉴定了骨关节炎软骨中的 18 个疾病级别特异性 mQTL。我们通过因果推理和共定位分析解决骨关节炎 GWAS 位点，并破译介导基因型对疾病风险影响的表观遗传机制。总之，我们的研究结果增强了对原发组织中骨关节炎的表观遗传机制的认识。