• arcOGEN Consortium, arcOGEN Collaborators, Eleftheria Zeggini, Kalliope Panoutsopoulou, Lorraine Southam, Nigel W Rayner, Aaron G Day-Williams, Margarida C Lopes, Vesna Boraska, Tonu Esko, Evangelos Evangelou, Albert Hoffman, Jeanine J Houwing-Duistermaat, Thorvaldur Ingvarsson, Ingileif Jonsdottir, Helgi Jonnson, Hanneke J Kerkhof, Margreet Kloppenburg, Steffan D Bos, Massimo Mangino, Sarah Metrustry, P Eline Slagboom, Gudmar Thorleifsson, Emma V A Raine, Madhushika Ratnayake, Michelle Ricketts, Claude Beazley, Hannah Blackburn, Suzannah Bumpstead, Katherine S Elliott, Sarah E Hunt, Simon C Potter, So-Youn Shin, Vijay K Yadav, Guangju Zhai, Kate Sherburn, Kate Dixon, Elizabeth Arden, Nadim Aslam, Phillippa-kate Battley, Ian Carluke, Sally Doherty, Andrew Gordon, John Joseph, Richard Keen, Nicola C Koller, Sheryl Mitchell, Fiona O'Neill, Ellen Paling, Mike R Reed, Fernando Rivadeneira, Diane Swift, Kirsten Walker, Bridget Watkins, Maggie Wheeler, Fraser Birrell, John P A Ioannidis, Ingrid Meulenbelt, Andres Metspalu, Ashok Rai, Donald Salter, Kari Stefansson, Unnur Stykarsdottir, André G Uitterlinden, Joyce B J van Meurs, Kay Chapman, Panos Deloukas, William E R Ollier, Gillian A Wallis, Nigel Arden, Andrew Carr, Michael Doherty, Andrew McCaskie, J Mark Willkinson, Stuart H Ralston, Ana M Valdes, Tim D Spector, and John Loughlin.
• Wellcome Trust Sanger Institute, Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK. eleftheria@sanger.ac.uk
• Lancet. 2012 Sep 1;380(9844):815-23.

BackgroundOsteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.MethodsWe undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.FindingsWe identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.InterpretationOur findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.FundingarcOGEN was funded by a special purpose grant from Arthritis Research UK.Copyright © 2012 Elsevier Ltd. All rights reserved.

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