Objectives Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. Methods We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. Results We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. Conclusions We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.

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GLIS3 的新变异与骨关节炎相关

目的 骨关节炎 (OA) 是一种复杂的疾病，但其遗传病因学仍知之甚少。为了确定 OA 的新易感位点，我们对迄今为止英国最大的 OA 收集中的个体进行了全基因组关联研究 (GWAS)。方法 我们对 5414 名接受膝关节和/或髋关节全关节置换术 (TJR) 的 OA 个体和 9939 名基于人群的对照组进行了发现 GWAS。我们跟踪了英国生物库资源临时发布的 OA 受试者中的优先变异（最多 12 658 例病例和 50 898 例对照），以及英国生物库全面发布的手术 OA 受试者中的主要发现（17 894 例病例和 89 例对照）。 470 控制）。我们研究了其对来自接受 TJR 的患者的 12 对完整和退化软骨样本的原代软骨细胞的甲基化、基因表达和蛋白质组学数据的功能影响。结果我们检测到 rs10116772 与 TJR 存在全基因组显着关联（P=3.7×10−8；对于等位基因 A：OR (95% CI) 0.97（0.96 至 0.98）），TJR 是 GLIS3 中的一个内含子变体，在软骨。与 rs10116772 密切相关的变异与血浆葡萄糖水平升高和糖尿病有关。结论 我们确定了一个新的 OA 易感位点，该位点之前已被认为与糖尿病和血糖特征有关。