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

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  • External authors:
  • Evangelos Evangelou
  • Hanneke J. Kerkhof
  • Unnur Styrkarsdottir
  • Evangelia E. Ntzani
  • Steffan D. Bos
  • Tonu Esko
  • Daniel S. Evans
  • Sarah Metrustry
  • Kalliope Panoutsopoulou
  • Yolande F M Ramos
  • Gudmar Thorleifsson
  • Konstantinos K. Tsilidis
  • Nigel Arden
  • Nadim Aslam
  • Nicholas Bellamy
  • Fraser Birrell
  • Francisco J. Blanco
  • Andrew Carr
  • Kay Chapman
  • Aaron G. Day-Williams
  • Panos Deloukas
  • Michael Doherty
  • Gunnar Engström
  • Hafdis T. Helgadottir
  • Albert Hofman
  • Thorvaldur Ingvarsson
  • Helgi Jonsson
  • Aime Keis
  • J. Christiaan Keurentjes
  • Margreet Kloppenburg
  • Penelope A. Lind
  • Andrew McCaskie
  • Nicholas G. Martin
  • Lili Milani
  • Grant W. Montgomery
  • Rob G H H Nelissen
  • Michael C. Nevitt
  • Peter M. Nilsson
  • Neeta Parimi
  • Ashok Rai
  • Stuart H. Ralston
  • Mike R. Reed
  • Jose A. Riancho
  • Fernando Rivadeneira
  • Cristina Rodriguez-Fontenla
  • Lorraine Southam
  • Unnur Thorsteinsdottir
  • Aspasia Tsezou
  • J. Mark Wilkinson
  • Antonio Gonzalez
  • Nancy E. Lane
  • L. Stefan Lohmander
  • John Loughlin
  • Andres Metspalu
  • Andre G. Uitterlinden
  • Ingileif Jonsdottir
  • Kari Stefansson
  • P. Eline Slagboom
  • Eleftheria Zeggini
  • Ingrid Meulenbelt
  • John P A Ioannidis
  • Tim D. Spector
  • Joyce B J van Meurs
  • Ana M. Valdes

Abstract

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. 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 '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. 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=7.9×10-9 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). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

Bibliographical metadata

Original languageEnglish
Pages (from-to)2130-2136
Number of pages6
JournalAnnals of the rheumatic diseases
Volume73
DOIs
Publication statusPublished - 29 Aug 2013

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