1. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
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William E R Ollier, Gillian A. Wallis, Unnur Styrkarsdottir, Nicholas G. Martin, P. Eline Slagboom, Mike R. Reed, Helgi Jonsson, J. Mark Wilkinson, John P. A. Ioannidis, Aime Keis, Yolande F. M. Ramos, Daniel S. Evans, Penelope A. Lind, Stuart H. Ralston, Thorvaldur Ingvarsson, Andrew McCaskie, Konstantinos K. Tsilidis, Evangelos Evangelou, Kay Chapman, Tim D. Spector, Aaron G. Day-Williams, L. Stefan Lohmander, Aspasia Tsezou, Ashok Rai, Rob G H H Nelissen, Kari Stefansson, Cristina Rodriguez-Fontenla, Sarah Metrustry, Andres Metspalu, Kalliope Panoutsopoulou, Albert Hofman, Hanneke J. M. Kerkhof, John Loughlin, Panos Deloukas, Joyce B. J. van Meurs, Ana M. Valdes, Evangelia E. Ntzani, Lorraine Southam, José A. Riancho, J. Christiaan Keurentjes, Francisco J. Blanco, Gudmar Thorleifsson, Peter M. Nilsson, Ingrid Meulenbelt, Lili Milani, Fernando Rivadeneira, Michael C. Nevitt, Nicholas Bellamy, Nancy E Lane, Unnur Thorsteinsdottir, Grant W. Montgomery, Michael Doherty, Tõnu Esko, Ingileif Jonsdottir, Nigel K Arden, Hafdis T. Helgadottir, André G. Uitterlinden, Antonio Gonzalez, Steffan D. Bos, Margreet Kloppenburg, Andrew Carr, Eleftheria Zeggini, Gunnar Engström, N Aslam, Fraser Birrell, Neeta Parimi, Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 3Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland. 4Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 5Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, The Netherlands. 6Estonian Genome Center, University of Tartu, Tartu, Estonia Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 7California Pacific Medical Center Research Institute, San Francisco, USA. 8Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. 9Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. 10Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 11NIHR 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. 12Worcestershire Royal Hospital, Worcestershire Acute Hospitals NHS Trust, Worcester, UK. 13Centre of National Research on Disability and Rehabilitation Medicine, The University of Queensland, Brisbane, Australia. 14Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK. 15Rheumatology Division, Instituto de Investigación Biomédica-Hospital Universitario A Coruña, A Corunna, Spain. 16NIHR Biomedical Research Unit and ARUK Centre of excellence for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, UK. 17Department of Academic Rheumatology, University of Nottingham, Nottingham, UK. 18Department of Clinical Sciences Malmo, Lund University, Malmo, Sweden. 19Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 20Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland School of Health Sciences, University of Akureyri, Akureyri, Iceland. 21Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 22Department of Public Health, University of Tartu, Tartu, Estonia Orthopedic Surgeons, Elva Hospital, Elva, Estonia. 23Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands. 24Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 25Department of Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 26Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. 27Department of Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 28Estonian Genome Center, University of Tartu, Tartu, Estonia. 29Department of Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 30Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. 31Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK. 32Worcestershire Acute Hospitals NHS Trust, Worcester, UK. 33Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. 34Wansbeck General Hospital, Northumbria Healthcare NHS Foundation Trust, Ashington, UK. 35Department of Internal Medicine, Hospital U.M. Valdecilla-IFIMAV, University of Cantabria, Santander, Spain. 36Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 37Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. 38Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Department of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland. 39Department of Biology, University of Thessaly, Medical School, Larissa, Greece. 40Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK. 41Department of Human Metabolism, University of Sheffield, Sheffield, UK. 42Department of Medicine, University of California at Davis, Sacramento, USA. 43Research 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. 44Department of Population Genetics, deCODE Genetics, Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 45Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA. 46Department of Twin Research & Genetic Epidemiology, King's College London, London, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK., arcOGEN Consortium, Universidad de Cantabria, Medical Oncology, Epidemiology, and Internal Medicine
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Male ,Aging ,Epidemiology ,Genome-wide association study ,Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ,Bioinformatics ,Osteoarthritis, Hip ,Nuclear Receptor Coactivator 3 ,Gene Frequency ,Grupo de Ascendencia Continental Europea ,Immunology and Allergy ,Medicine ,2.1 Biological and endogenous factors ,Osteoarthritis, Hip/genetics ,Aetiology ,European Continental Ancestry Group/genetics ,Gene polymorphism ,Single Nucleotide ,Protein-Tyrosine Kinases ,Protein-Serine-Threonine Kinases ,3. Good health ,Slitgigt ,1117 Public Health And Health Services ,1107 Immunology ,Nuclear Receptor Coactivator 3/genetics ,Female ,arcOGEN Consortium ,Frecuencia de los Genes ,Protein-Serine-Threonine Kinases/genetics ,Clinical Sciences ,Immunology ,European Continental Ancestry Group ,Predisposición Genética a la Enfermedad ,Single-nucleotide polymorphism ,Locus (genetics) ,Protein Serine-Threonine Kinases ,Public Health And Health Services ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Immediate early protein ,White People ,Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina ,Estudio de Asociación del Genoma Completo ,Immediate-Early Proteins ,Sex Factors ,Rheumatology ,Gene Polymorphism ,Osteoarthritis ,Genetics ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Allele frequency ,Genetic association ,Rheumatology and Autoimmunity ,Homeodomain Proteins ,Hip ,Protein-Tyrosine Kinases/genetics ,business.industry ,Whites ,Arthritis ,Prevention ,Human Genome ,1103 Clinical Sciences ,Clinical and Epidemiological Research ,Arfgengi ,Immediate-Early Proteins/genetics ,Arthritis & Rheumatology ,Minor allele frequency ,Musculoskeletal ,Mjaðmir ,HMGN Proteins ,Osteoartritis de la Cadera ,Homeodomain Proteins/genetics ,business ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,HMGN Proteins/genetics ,Genome-Wide Association Study - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. 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. info:eu-repo/grantAgreement/EC/FP7/200800 info:eu-repo/grantAgreement/EC/FP7/286213
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- 2014