A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

作者：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; Engstrom Gunnar; Helgadottir Hafdis T; Hofman Albert

来源：Annals of the Rheumatic Diseases, 2014, 73(12): 2130-2136.

DOI：10.1136/annrheumdis-2012-203114

Objectives 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. %26lt;br%26gt;Methods 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 %26apos;in silico%26apos; or %26apos;de novo%26apos; 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. %26lt;br%26gt;Results 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=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-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=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). %26lt;br%26gt;Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

• 出版日期2014-12