Evangelou Evangelos, Kerkhof Hanneke J, Styrkarsdottir Unnur, Ntzani Evangelia E, Bos Steffan D, Esko Tonu, Evans Daniel S, Metrustry Sarah, Panoutsopoulou Kalliope, Ramos Yolande F M, Thorleifsson Gudmar, Tsilidis Konstantinos K, Arden Nigel, Aslam Nadim, Bellamy Nicholas, Birrell Fraser, Blanco Francisco J, Carr Andrew, Chapman Kay, Day-Williams Aaron G, Deloukas Panos, Doherty Michael, Engström Gunnar, Helgadottir Hafdis T, Hofman Albert, Ingvarsson Thorvaldur, Jonsson Helgi, Keis Aime, Keurentjes J Christiaan, Kloppenburg Margreet, Lind Penelope A, McCaskie Andrew, Martin Nicholas G, Milani Lili, Montgomery Grant W, Nelissen Rob G H H, Nevitt Michael C, Nilsson Peter M, Ollier William Er, Parimi Neeta, Rai Ashok, Ralston Stuart H, Reed Mike R, Riancho Jose A, Rivadeneira Fernando, Rodriguez-Fontenla Cristina, Southam Lorraine, Thorsteinsdottir Unnur, Tsezou Aspasia, Wallis Gillian A, Wilkinson J Mark, Gonzalez Antonio, Lane Nancy E, Lohmander L Stefan, Loughlin John, Metspalu Andres, Uitterlinden Andre G, Jonsdottir Ingileif, Stefansson Kari, Slagboom P Eline, Zeggini Eleftheria, Meulenbelt Ingrid, Ioannidis John Pa, Spector Tim D, van Meurs Joyce B J, Valdes Ana M
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Ann Rheum Dis. 2014 Dec;73(12):2130-6. doi: 10.1136/annrheumdis-2012-203114. Epub 2013 Aug 29.
Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.
We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.
We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).
Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
骨关节炎（OA）是最常见的关节炎形式，具有明确的遗传成分。为了确定与髋关节OA相关的新基因座，我们对欧洲受试者的全基因组关联研究（GWAS）进行了荟萃分析。
我们对超过78,000名参与者进行了两阶段荟萃分析。在第一阶段，我们综合了来自八项GWAS的数据，而来自10个中心的数据用于“电子”或“从头”复制。除了主要分析外，还进行了按性别分层分析以检测可能的性别特异性信号。使用逆方差固定效应模型进行荟萃分析。还使用了随机效应方法。
我们积累了11,277例影像学和有症状的髋关节OA病例。我们在发现阶段（4349例OA病例）对八个单核苷酸多态性（SNP）进行了后续研究的优先排序；五个来自联合分析，两个为男性特异性，一个为女性特异性。一个位于20q13的基因座，由NCOA3（核受体共激活因子3）基因附近的rs6094710（次要等位基因频率（MAF）4%）代表，在发现阶段（p=5.6×10(-8)）和后续研究（p=7.3×10(-4)）的联合分析中达到全基因组显著性水平，p=7.9×10(-9)，OR=1.28（95%CI 1.18至1.39）。我们表明该基因在关节软骨中表达，并且其表达在OA影响的软骨中显著降低。此外，两个基因座仍显示出提示性关联；7q31处的rs5009270（MAF 30%，p=9.9×10(-7)，OR=1.10）和7p13处的rs3757837（MAF 6%，在男性特异性分析中p=2.2×10(-6)，OR=1.27）。
在这项GWAS荟萃分析中发现了髋关节OA的新遗传基因座。
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