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

Eleftheria Zeggini; Kalliope Panoutsopoulou; Lorraine Southam; Nigel W. Rayner; Aaron G. Day-Williams; Margarida C. Lopes; Vesna Boraska; Tonu Esko; Evangelos Evangelou; Albert Hofman; Jeanine J. Houwing-Duistermaat; Thorvaldur Ingvarsson; Ingileif Jonsdottir; Helgi Jonsson; Hanneke J M 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 Styrkarsdottir; 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 Wilkinson; Stuart H. Ralston; Ana M. Valdes; Tim D. Spector; John Loughlin

doi:10.1016/S0140-6736(12)60681-3

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

Eleftheria Zeggini, Kalliope Panoutsopoulou, Lorraine Southam, Nigel W. Rayner, Aaron G. Day-Williams, Margarida C. Lopes, Vesna Boraska, Tonu Esko, Evangelos Evangelou, Albert Hofman, Jeanine J. Houwing-Duistermaat, Thorvaldur Ingvarsson, Ingileif Jonsdottir, Helgi Jonsson, Hanneke J M Kerkhof, Margreet Kloppenburg, Steffan D. Bos, Massimo Mangino, Sarah Metrustry, P. Eline SlagboomGudmar 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 Styrkarsdottir, 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 Wilkinson, Stuart H. Ralston, Ana M. Valdes, Tim D. Spector, John Loughlin

Research output: Contribution to journal › Article › peer-review

Abstract

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=5.0×10 -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. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Original language	English
Pages (from-to)	815-823
Number of pages	8
Journal	The Lancet
Volume	380
Issue number	9844
DOIs	https://doi.org/10.1016/S0140-6736(12)60681-3
Publication status	Published - Sept 2012

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10.1016/S0140-6736(12)60681-3

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Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N. W., Day-Williams, A. G., Lopes, M. C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J. J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H. J. M., Kloppenburg, M., Bos, S. D., Mangino, M., Metrustry, S., ... Loughlin, J. (2012). Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study. The Lancet, 380(9844), 815-823. https://doi.org/10.1016/S0140-6736(12)60681-3

@article{485820e4523041789700c64f5c74050a,

title = "Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study",

abstract = "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=5.0×10 -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. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.",

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

note = "18030, Arthritis Research UK, United Kingdom",

year = "2012",

month = sep,

doi = "10.1016/S0140-6736(12)60681-3",

language = "English",

volume = "380",

pages = "815--823",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier BV",

number = "9844",

}

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, G, 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 2012, 'Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study', The Lancet, vol. 380, no. 9844, pp. 815-823. https://doi.org/10.1016/S0140-6736(12)60681-3

TY - JOUR

T1 - Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study

AU - Zeggini, Eleftheria

AU - Panoutsopoulou, Kalliope

AU - Southam, Lorraine

AU - Rayner, Nigel W.

AU - Day-Williams, Aaron G.

AU - Lopes, Margarida C.

AU - Boraska, Vesna

AU - Esko, Tonu

AU - Evangelou, Evangelos

AU - Hofman, Albert

AU - Houwing-Duistermaat, Jeanine J.

AU - Ingvarsson, Thorvaldur

AU - Jonsdottir, Ingileif

AU - Jonsson, Helgi

AU - Kerkhof, Hanneke J M

AU - Kloppenburg, Margreet

AU - Bos, Steffan D.

AU - Mangino, Massimo

AU - Metrustry, Sarah

AU - Slagboom, P. Eline

AU - Thorleifsson, Gudmar

AU - Raine, Emma V A

AU - Ratnayake, Madhushika

AU - Ricketts, Michelle

AU - Beazley, Claude

AU - Blackburn, Hannah

AU - Bumpstead, Suzannah

AU - Elliott, Katherine S.

AU - Hunt, Sarah E.

AU - Potter, Simon C.

AU - Shin, So Youn

AU - Yadav, Vijay K.

AU - Zhai, Guangju

AU - Sherburn, Kate

AU - Dixon, Kate

AU - Arden, Elizabeth

AU - Aslam, Nadim

AU - Battley, Phillippa Kate

AU - Carluke, Ian

AU - Doherty, Sally

AU - Gordon, Andrew

AU - Joseph, John

AU - Keen, Richard

AU - Koller, Nicola C.

AU - Mitchell, Sheryl

AU - O'Neill, Fiona

AU - Paling, Ellen

AU - Reed, Mike R.

AU - Rivadeneira, Fernando

AU - Swift, Diane

AU - Walker, Kirsten

AU - Watkins, Bridget

AU - Wheeler, Maggie

AU - Birrell, Fraser

AU - Ioannidis, John P A

AU - Meulenbelt, Ingrid

AU - Metspalu, Andres

AU - Rai, Ashok

AU - Salter, Donald

AU - Stefansson, Kari

AU - Styrkarsdottir, Unnur

AU - Uitterlinden, André G.

AU - Van Meurs, Joyce B J

AU - Chapman, Kay

AU - Deloukas, Panos

AU - Ollier, William E R

AU - Wallis, Gillian A.

AU - Arden, Nigel

AU - Carr, Andrew

AU - Doherty, Michael

AU - McCaskie, Andrew

AU - Wilkinson, J. Mark

AU - Ralston, Stuart H.

AU - Valdes, Ana M.

AU - Spector, Tim D.

AU - Loughlin, John

N1 - 18030, Arthritis Research UK, United Kingdom

PY - 2012/9

Y1 - 2012/9

N2 - 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=5.0×10 -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. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.

AB - 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=5.0×10 -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. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.

UR - https://www.scopus.com/pages/publications/84865595151

U2 - 10.1016/S0140-6736(12)60681-3

DO - 10.1016/S0140-6736(12)60681-3

M3 - Article

C2 - 22763110

SN - 0140-6736

VL - 380

SP - 815

EP - 823

JO - The Lancet

JF - The Lancet

IS - 9844

ER -

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

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