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Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.

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Authors
Zeggini, Eleftheria
Panoutsopoulou, Kalliope
Southam, Lorraine
Rayner, Nigel W
Day-Williams, Aaron G
Lopes, Margarida C
Boraska, Vesna
Esko, Tonu
Evangelou, Evangelos
Hoffman, Albert
Houwing-Duistermaat, Jeanine J
Ingvarsson, Thorvaldur
Jonsdottir, Ingileif
Jonnson, Helgi
Kerkhof, Hanneke J
Kloppenburg, Margreet
Bos, Steffan D
Mangino, Massimo
Metrustry, Sarah
Slagboom, P Eline
Thorleifsson, Gudmar
Raine, Emma V A
Ratnayake, Madhushika
Ricketts, Michelle
Beazley, Claude
Blackburn, Hannah
Bumpstead, Suzannah
Elliott, Katherine S
Hunt, Sarah E
Potter, Simon C
Shin, So-Youn
Yadav, Vijay K
Zhai, Guangju
Sherburn, Kate
Dixon, Kate
Arden, Elizabeth
Aslam, Nadim
Battley, Phillippa-kate
Carluke, Ian
Doherty, Sally
Gordon, Andrew
Joseph, John
Keen, Richard
Koller, Nicola C
Mitchell, Sheryl
O'Neill, Fiona
Paling, Ellen
Reed, Mike R
Rivadeneira, Fernando
Swift, Diane
Walker, Kirsten
Watkins, Bridget
Wheeler, Maggie
Birrell, Fraser
Ioannidis, John P A
Meulenbelt, Ingrid
Metspalu, Andres
Rai, Ashok
Salter, Donald
Stefansson, Kari
Stykarsdottir, Unnur
Uitterlinden, André G
van Meurs, Joyce B J
Chapman, Kay
Deloukas, Panos
Ollier, William E R
Wallis, Gillian A
Arden, Nigel
Carr, Andrew
Doherty, Michael
McCaskie, Andrew
Willkinson, J Mark
Ralston, Stuart H
Valdes, Ana M
Spector, Tim D
Loughlin, John
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Issue Date
2012-09-01

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Citation
Lancet 2012, 380(9844):815-23
Abstract
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. 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. We 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. Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.
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Additional Links
http://dx.doi.org/10.1016/S0140-6736(12)60681-3
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443899/
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ae974a485f413a2113503eed53cd6c53
10.1016/S0140-6736(12)60681-3
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