Katsoula Georgia, Lawrence John E G, Arruda Ana Luiza, Tutino Mauro, Balogh Petra, Southam Lorraine, Swift Diane, Behjati Sam, Teichmann Sarah A, Wilkinson J Mark, Zeggini Eleftheria
Technical University of Munich (TUM), School of Medicine and Health, Graduate School of Experimental Medicine, 81675 Munich, Germany; Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine and Health, 81675 Munich, Germany.
Department of Trauma and Orthopaedics, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Box 37, Hills Road, Cambridge CB2 0QQ, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Am J Hum Genet. 2024 Dec 5;111(12):2735-2755. doi: 10.1016/j.ajhg.2024.10.019. Epub 2024 Nov 22.
Translational efforts in osteoarthritis are hampered by a gap in our understanding of disease processes at the molecular level. Here, we present evidence of pronounced transcriptional changes in high- and low-disease-grade cartilage tissue, pointing to embryonic processes involved in disease progression. We identify shared transcriptional programs between osteoarthritis cartilage and cell populations in the human embryonic and fetal limb, pointing to increases in pre-hypertrophic chondrocytes' transcriptional programs in low-grade cartilage and increases in osteoblastic signatures in high-grade disease tissue. We find that osteoarthritis genetic risk signals are enriched in six gene co-expression modules and show that these transcriptional signatures reflect cell-type-specific expression along the endochondral ossification developmental trajectory. Using this network approach in combination with causal inference analysis, we present evidence of a causal effect on osteoarthritis risk for variants associated with the expression of ten genes that have not been previously reported as effector genes in genome-wide association studies in osteoarthritis. Our findings point to key molecular pathways as drivers of cartilage degeneration and identify high-value drug targets and repurposing opportunities.
骨关节炎的转化研究因我们在分子水平上对疾病过程的理解存在差距而受阻。在此，我们展示了高疾病分级和低疾病分级软骨组织中明显的转录变化证据，表明胚胎过程参与了疾病进展。我们确定了骨关节炎软骨与人类胚胎和胎儿肢体中的细胞群体之间共享的转录程序，表明低分级软骨中前肥大软骨细胞转录程序增加，高分级疾病组织中成骨细胞特征增加。我们发现骨关节炎遗传风险信号在六个基因共表达模块中富集，并表明这些转录特征反映了沿软骨内骨化发育轨迹的细胞类型特异性表达。通过将这种网络方法与因果推断分析相结合，我们提供了证据，证明在全基因组关联研究中尚未被报道为骨关节炎效应基因的十个基因的表达相关变体对骨关节炎风险有因果影响。我们的研究结果指出了关键分子途径是软骨退化的驱动因素，并确定了高价值的药物靶点和重新利用的机会。
