Review

. 2014 Dec;73(12):2130-6.

doi: 10.1136/annrheumdis-2012-203114. Epub 2013 Aug 29.

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

Evangelos Evangelou¹, Hanneke J Kerkhof², Unnur Styrkarsdottir³, Evangelia E Ntzani⁴, Steffan D Bos⁵, Tonu Esko⁶, Daniel S Evans⁷, Sarah Metrustry⁸, Kalliope Panoutsopoulou⁹, Yolande F M Ramos¹⁰, Gudmar Thorleifsson³, Konstantinos K Tsilidis⁴; arcOGEN Consortium; Nigel Arden¹¹, Nadim Aslam¹², Nicholas Bellamy¹³, Fraser Birrell¹⁴, Francisco J Blanco¹⁵, Andrew Carr¹⁶, Kay Chapman¹⁶, Aaron G Day-Williams⁹, Panos Deloukas⁹, Michael Doherty¹⁷, Gunnar Engström¹⁸, Hafdis T Helgadottir³, Albert Hofman¹⁹, Thorvaldur Ingvarsson²⁰, Helgi Jonsson²¹, Aime Keis²², J Christiaan Keurentjes²³, Margreet Kloppenburg²⁴, Penelope A Lind²⁵, Andrew McCaskie²⁶, Nicholas G Martin²⁷, Lili Milani²⁸, Grant W Montgomery²⁹, Rob G H H Nelissen²³, Michael C Nevitt³⁰, Peter M Nilsson¹⁸, William Er Ollier³¹, Neeta Parimi⁷, Ashok Rai³², Stuart H Ralston³³, Mike R Reed³⁴, Jose A Riancho³⁵, Fernando Rivadeneira³⁶, Cristina Rodriguez-Fontenla³⁷, Lorraine Southam⁹, Unnur Thorsteinsdottir³⁸, Aspasia Tsezou³⁹, Gillian A Wallis⁴⁰, J Mark Wilkinson⁴¹, Antonio Gonzalez³⁷, Nancy E Lane⁴², L Stefan Lohmander⁴³, John Loughlin²⁶, Andres Metspalu⁶, Andre G Uitterlinden³⁶, Ingileif Jonsdottir⁴⁴, Kari Stefansson⁴⁴, P Eline Slagboom⁵, Eleftheria Zeggini⁹, Ingrid Meulenbelt⁵, John Pa Ioannidis⁴⁵, Tim D Spector⁸, Joyce B J van Meurs², Ana M Valdes⁴⁶

Affiliations

¹ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland.
⁴ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁵ Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, The Netherlands.
⁶ Estonian Genome Center, University of Tartu, Tartu, Estonia Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
⁷ California Pacific Medical Center Research Institute, San Francisco, USA.
⁸ Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
⁹ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁰ Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ NIHR Biomedical Research Unit and ARUK Centre of excellence for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, UK MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK.
¹² Worcestershire Royal Hospital, Worcestershire Acute Hospitals NHS Trust, Worcester, UK.
¹³ Centre of National Research on Disability and Rehabilitation Medicine, The University of Queensland, Brisbane, Australia.
¹⁴ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK.
¹⁵ Rheumatology Division, Instituto de Investigación Biomédica-Hospital Universitario A Coruña, A Corunna, Spain.
¹⁶ NIHR Biomedical Research Unit and ARUK Centre of excellence for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, UK.
¹⁷ Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
¹⁸ Department of Clinical Sciences Malmo, Lund University, Malmo, Sweden.
¹⁹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland School of Health Sciences, University of Akureyri, Akureyri, Iceland.
²¹ Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
²² Department of Public Health, University of Tartu, Tartu, Estonia Orthopedic Surgeons, Elva Hospital, Elva, Estonia.
²³ Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands.
²⁴ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁶ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
²⁷ Department of Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁸ Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁹ Department of Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
³¹ Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
³² Worcestershire Acute Hospitals NHS Trust, Worcester, UK.
³³ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
³⁴ Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK.
³⁵ Department of Internal Medicine, Hospital U.M. Valdecilla-IFIMAV, University of Cantabria, Santander, Spain.
³⁶ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³⁷ Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
³⁸ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland.
³⁹ Department of Biology, University of Thessaly, Medical School, Larissa, Greece.
⁴⁰ Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
⁴¹ Department of Human Metabolism, University of Sheffield, Sheffield, UK.
⁴² Department of Medicine, University of California at Davis, Sacramento, USA.
⁴³ Research Unit for Musculoskeletal Function and Physiotherapy, and Department of Orthopedics and Traumatology, University of Southern Denmark, Odense, Denmark Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
⁴⁴ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁵ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA.
⁴⁶ Department of Twin Research & Genetic Epidemiology, King's College London, London, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.

PMID: 23989986
PMCID: PMC4251181
DOI: 10.1136/annrheumdis-2012-203114

Free PMC article

Review

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

Evangelos Evangelou et al. Ann Rheum Dis. 2014 Dec.

Free PMC article

. 2014 Dec;73(12):2130-6.

doi: 10.1136/annrheumdis-2012-203114. Epub 2013 Aug 29.

Authors

Affiliations

¹ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland.
⁴ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁵ Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, The Netherlands.
⁶ Estonian Genome Center, University of Tartu, Tartu, Estonia Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
⁷ California Pacific Medical Center Research Institute, San Francisco, USA.
⁸ Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
⁹ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁰ Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ NIHR Biomedical Research Unit and ARUK Centre of excellence for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, UK MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK.
¹² Worcestershire Royal Hospital, Worcestershire Acute Hospitals NHS Trust, Worcester, UK.
¹³ Centre of National Research on Disability and Rehabilitation Medicine, The University of Queensland, Brisbane, Australia.
¹⁴ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK.
¹⁵ Rheumatology Division, Instituto de Investigación Biomédica-Hospital Universitario A Coruña, A Corunna, Spain.
¹⁶ NIHR Biomedical Research Unit and ARUK Centre of excellence for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, UK.
¹⁷ Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
¹⁸ Department of Clinical Sciences Malmo, Lund University, Malmo, Sweden.
¹⁹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland School of Health Sciences, University of Akureyri, Akureyri, Iceland.
²¹ Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
²² Department of Public Health, University of Tartu, Tartu, Estonia Orthopedic Surgeons, Elva Hospital, Elva, Estonia.
²³ Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands.
²⁴ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁶ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
²⁷ Department of Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁸ Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁹ Department of Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
³¹ Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
³² Worcestershire Acute Hospitals NHS Trust, Worcester, UK.
³³ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
³⁴ Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK.
³⁵ Department of Internal Medicine, Hospital U.M. Valdecilla-IFIMAV, University of Cantabria, Santander, Spain.
³⁶ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³⁷ Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
³⁸ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland.
³⁹ Department of Biology, University of Thessaly, Medical School, Larissa, Greece.
⁴⁰ Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
⁴¹ Department of Human Metabolism, University of Sheffield, Sheffield, UK.
⁴² Department of Medicine, University of California at Davis, Sacramento, USA.
⁴³ Research Unit for Musculoskeletal Function and Physiotherapy, and Department of Orthopedics and Traumatology, University of Southern Denmark, Odense, Denmark Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
⁴⁴ Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁵ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA.
⁴⁶ Department of Twin Research & Genetic Epidemiology, King's College London, London, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.

PMID: 23989986
PMCID: PMC4251181
DOI: 10.1136/annrheumdis-2012-203114

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.

Keywords: Epidemiology; Gene Polymorphism; Osteoarthritis.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Figures

**Figure 1**
(A) Forest plot for meta-analysis of rs6094710. The blue diamond in the forest plot denotes the summary effect size and its edges the respective 95% CIs. Studies shaded in blue were included in the replication stage. *Discovery and replication estimate combined; and (B) regional plot for rs6094710 comprising directly genotyped and imputed SNPs. Case-control association results (−log10 P) in the discovery set are plotted against genomic position (National Center for Biotechnology Information build 36) for the stratum where the most significant meta-analysis p was observed. The colour reflects the correlation coefficients (r²) of each genotyped SNP with the index SNP estimated using the CEU HapMap II panel.

See this image and copyright information in PMC

References

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

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

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