Background/Aims Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in 3D space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel effector genes for the disease. Methods Primary chondrocytes collected from eight knee osteoarthritis patients underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results to identify variants involved in gene regulation via enhancer-promoter interactions. Results We identified 36 genetic variants residing within chromatin loop anchors that are associated with 13 osteoarthritis GWAS signals. Five of these variants reside directly in enhancer regions of 3 enhancer-promoter loops newly described in chondrocytes, pointing to high-confidence effector genes: PAPPA, NSD2 and NCOA6. PAPPA is directly associated with the turnover of IGF-1 transport proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes. Conclusion We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D-genomics with large-scale genetic association data, we identify high-confidence osteoarthritis effector genes which enhance our understanding of disease and can serve as putative high-value novel targets. Disclosure N. Bittner: None. C. Shi: None. D. Zhao: None. J. Ding: None. L. Southam: None. D. Swift: None. P. Kreitmaier: None. M. Tutino: None. J. Hankinson: None. M. Wilkinson: None. G. Orozco: None. E. Zeggini: None.

中文翻译：

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OA30原发性骨关节炎软骨细胞染色质构象图揭示了新的效应基因

背景/目标 骨关节炎是一种复杂的疾病，给公众健康带来巨大负担。全基因组关联研究（GWAS）已经识别出数百种与骨关节炎相关的序列变异，但支撑这些信号的效应基因在很大程度上仍然难以捉摸。了解 3D 空间中的染色体组织对于以组织特异性方式识别遥远基因组特征之间（例如，基因和调控元件之间）的远程接触至关重要。在这里，我们生成了第一个原发性骨关节炎软骨细胞的全基因组染色体构象分析（Hi-C）图谱，并鉴定了该疾病的新效应基因。方法 对从 8 名膝骨关节炎患者采集的原代软骨细胞进行 Hi-C 分析，将染色体结构与基因组序列联系起来。然后将识别出的环与骨关节炎 GWAS 结果相结合，以识别通过增强子-启动子相互作用参与基因调控的变异体。结果我们确定了染色质环锚内的 36 个遗传变异，这些变异与 13 个骨关节炎 GWAS 信号相关。其中五个变体直接位于软骨细胞中新描述的 3 个增强子-启动子环的增强子区域，指向高可信度效应基因：PAPPA、NSD2 和 NCOA6。 PAPPA与IGF-1转运蛋白的周转直接相关，而IGF-1是受损软骨细胞修复的重要因素。结论 我们构建了第一个人类原代软骨细胞的 Hi-C 图谱，并将其作为科学界的资源。通过将 3D 基因组学与大规模遗传关联数据相结合，我们确定了高可信度的骨关节炎效应基因，这增强了我们对疾病的理解，并可以作为假定的高价值新靶点。披露 N. Bittner：无。 C.施：没有。赵东：没有。丁俊晖：没有。 L.索瑟姆：没有。 D. 斯威夫特：没有。 P. Kreitmaier：没有。 M. 图蒂诺：没有。 J.汉金森：没有。 M.威尔金森：没有。 G.奥罗斯科：没有。 E.泽吉尼：没有。