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Lookup NU author(s): Dr Madhushika Ratnayake, Sheryl Mitchell, Michael Reed, Professor Andrew McCaskie, Professor John LoughlinORCiD
Background Osteoarthritis 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. Methods We 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. Findings We identified five genome-wide significant loci (binomial test p <= 5.0x10(-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=7.24x10(-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. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.
Author(s): Zeggini E, Panoutsopoulou K, Southam L, Rayner NW, Day-Williams AG, Lopes MC, Boraska V, Esko T, Evangelou E, Hofman A, Houwing-Duistermaat JJ, Ingvarsson T, Jonsdottir I, Jonsson H, Kerkhof HJM, Kloppenburg M, Bos SD, Mangino M, Metrustry S, Slagboom PE, Thorleifsson G, Raine EVA, Ratnayake M, Ricketts M, Beazley C, Blackburn H, Bumpstead S, Elliott KS, Hunt SE, Potter SC, Shin SY, Yadav VK, Zhai GJ, Sherburn K, Dixon K, Arden E, Aslam N, Battley PK, Carluke I, Doherty S, Gordon A, Joseph J, Keen R, Koller NC, Mitchell S, O'Neill F, Paling E, Reed MR, Rivadeneira F, Swift D, Walker K, Watkins B, Wheeler M, Birrell F, Ioannidis JPA, Meulenbelt I, Metspalu A, Rai A, Salter D, Stefansson K, Styrkarsdottir U, Uitterlinden AG, van Meurs JBJ, Chapman K, Deloukas P, Ollier WER, Wallis GA, Arden N, Carr A, Doherty M, McCaskie A, Wilkinson JM, Ralston SH, Valdes AM, Spector TD, Loughlin J
Publication type: Article
Publication status: Published
Journal: Lancet
Year: 2012
Volume: 380
Issue: 9844
Pages: 815-823
Print publication date: 01/09/2012
Date deposited: 07/11/2012
ISSN (print): 0140-6736
ISSN (electronic): 1474-547X
Publisher: Lancet Publishing Group
URL: http://dx.doi.org/10.1016/S0140-6736(12)60681-3
DOI: 10.1016/S0140-6736(12)60681-3
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