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

Evangelou, Evangelos; Kerkhof, Hanneke J.; Styrkarsdottir, Unnur; Ntzani, Evangelia E.; Bos, Steffan D.; Esko, Tonu; Evans, Daniel S.; Metrustry, Sarah; Panoutsopoulou, Kalliope and Ramos, Yolande F. M., et al. (2014) In Annals of the Rheumatic Diseases 73(12). p.2130-2136
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.... (More)
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=7.9x10(-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). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS. (Less)
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Annals of the Rheumatic Diseases
volume
73
issue
12
pages
2130 - 2136
publisher
British Medical Association
external identifiers
  • wos:000344783900016
  • scopus:84883445177
ISSN
1468-2060
DOI
10.1136/annrheumdis-2012-203114
language
English
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yes
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23d39cc8-7e16-4aca-8c12-1d5ed3c127bf (old id 4982802)
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2015-02-03 07:11:45
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@article{23d39cc8-7e16-4aca-8c12-1d5ed3c127bf,
  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=7.9x10(-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). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.},
  author       = {Evangelou, Evangelos and Kerkhof, Hanneke J. and Styrkarsdottir, Unnur and Ntzani, Evangelia E. and Bos, Steffan D. and Esko, Tonu and Evans, Daniel S. and Metrustry, Sarah and Panoutsopoulou, Kalliope and Ramos, Yolande F. M. and Thorleifsson, Gudmar and Tsilidis, Konstantinos K. and Arden, Nigel and Aslam, Nadim and Bellamy, Nicholas and Birrell, Fraser and Blanco, Francisco J. and Carr, Andrew and Chapman, Kay and Day-Williams, Aaron G. and Deloukas, Panos and Doherty, Michael and Engström, Gunnar and Helgadottir, Hafdis T. and Hofman, Albert and Ingvarsson, Thorvaldur and Jonsson, Helgi and Keis, Aime and Keurentjes, J. Christiaan and Kloppenburg, Margreet and Lind, Penelope A. and McCaskie, Andrew and Martin, Nicholas G. and Milani, Lili and Montgomery, Grant W. and Nelissen, Rob G. H. H. and Nevitt, Michael C. and Nilsson, Peter and Ollier, William E. R. and Parimi, Neeta and Rai, Ashok and Ralston, Stuart H. and Reed, Mike R. and Riancho, Jose A. and Rivadeneira, Fernando and Rodriguez-Fontenla, Cristina and Southam, Lorraine and Thorsteinsdottir, Unnur and Tsezou, Aspasia and AWallis, Gillian and Wilkinson, J. Mark and Gonzalez, Antonio and Lane, Nancy E. and Lohmander, Stefan and Loughlin, John and Metspalu, Andres and Uitterlinden, Andre G. and Jonsdottir, Ingileif and Stefansson, Kari and Slagboom, P. Eline and Zeggini, Eleftheria and Meulenbelt, Ingrid and Ioannidis, John P. A. and Spector, Tim D. and van Meurs, Joyce B. J. and Valdes, Ana M.},
  issn         = {1468-2060},
  language     = {eng},
  number       = {12},
  pages        = {2130--2136},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2012-203114},
  volume       = {73},
  year         = {2014},
}