A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Evangelos Evangelou; Hanneke J. Kerkhof; Unnur Styrkarsdottir; Evangelia E. Ntzani; Steffan D. Bos; Tonu Esko; Daniel S. Evans; Sarah Metrustry; Kalliope Panoutsopoulou; Yolande F M Ramos; Gudmar Thorleifsson; Konstantinos K. Tsilidis; Nigel Arden; Nadim Aslam; Nicholas Bellamy; Fraser Birrell; Francisco J. Blanco; Andrew Carr; Kay Chapman; Aaron G. Day-Williams; Panos Deloukas; Michael Doherty; Gunnar Engström; Hafdis T. Helgadottir; Albert Hofman; Thorvaldur Ingvarsson; Helgi Jonsson; Aime Keis; J. Christiaan Keurentjes; Margreet Kloppenburg; Penelope A. Lind; Andrew McCaskie; Nicholas G. Martin; Lili Milani; Grant W. Montgomery; Rob G H H Nelissen; Michael C. Nevitt; Peter M. Nilsson; William E R Ollier; Neeta Parimi; Ashok Rai; Stuart H. Ralston; Mike R. Reed; Jose A. Riancho; Fernando Rivadeneira; Cristina Rodriguez-Fontenla; Lorraine Southam; Unnur Thorsteinsdottir; Aspasia Tsezou; Gillian A. Wallis; J. Mark Wilkinson; Antonio Gonzalez; Nancy E. Lane; L. Stefan Lohmander; John Loughlin; Andres Metspalu; Andre G. Uitterlinden; Ingileif Jonsdottir; Kari Stefansson; P. Eline Slagboom; Eleftheria Zeggini; Ingrid Meulenbelt; John P A Ioannidis; Tim D. Spector; Joyce B J van Meurs; Ana M. Valdes

doi:10.1136/annrheumdis-2012-203114

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Evangelos Evangelou, Hanneke J. Kerkhof, Unnur Styrkarsdottir, Evangelia E. Ntzani, Steffan D. Bos, Tonu Esko, Daniel S. Evans, Sarah Metrustry, Kalliope Panoutsopoulou, Yolande F M Ramos, Gudmar Thorleifsson, Konstantinos K. Tsilidis, Nigel Arden, Nadim Aslam, Nicholas Bellamy, Fraser Birrell, Francisco J. Blanco, Andrew Carr, Kay Chapman, Aaron G. Day-WilliamsPanos Deloukas, Michael Doherty, Gunnar Engström, Hafdis T. Helgadottir, Albert Hofman, Thorvaldur Ingvarsson, Helgi Jonsson, Aime Keis, J. Christiaan Keurentjes, Margreet Kloppenburg, Penelope A. Lind, Andrew McCaskie, Nicholas G. Martin, Lili Milani, Grant W. Montgomery, Rob G H H Nelissen, Michael C. Nevitt, Peter M. Nilsson, William E R Ollier, Neeta Parimi, Ashok Rai, Stuart H. Ralston, Mike R. Reed, Jose A. Riancho, Fernando Rivadeneira, Cristina Rodriguez-Fontenla, Lorraine Southam, Unnur Thorsteinsdottir, Aspasia Tsezou, Gillian A. Wallis, J. Mark Wilkinson, Antonio Gonzalez, Nancy E. Lane, L. Stefan Lohmander, John Loughlin, Andres Metspalu, Andre G. Uitterlinden, Ingileif Jonsdottir, Kari Stefansson, P. Eline Slagboom, Eleftheria Zeggini, Ingrid Meulenbelt, John P A Ioannidis, Tim D. Spector, Joyce B J van Meurs, Ana M. Valdes

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

Abstract

Objectives: 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. Methods: 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. Results: 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). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

Original language	English
Pages (from-to)	2130-2136
Number of pages	6
Journal	Annals of the rheumatic diseases
Volume	73
DOIs	https://doi.org/10.1136/annrheumdis-2012-203114
Publication status	Published - 29 Aug 2013

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Evangelou, E., Kerkhof, H. J., Styrkarsdottir, U., Ntzani, E. E., Bos, S. D., Esko, T., Evans, D. S., Metrustry, S., Panoutsopoulou, K., Ramos, Y. F. M., Thorleifsson, G., Tsilidis, K. K., Arden, N., Aslam, N., Bellamy, N., Birrell, F., Blanco, F. J., Carr, A., Chapman, K., ... Valdes, A. M. (2013). A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. Annals of the rheumatic diseases, 73, 2130-2136. https://doi.org/10.1136/annrheumdis-2012-203114

@article{659ef62d2d0e4d71bc1c13cc749e57d6,

title = "A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip",

abstract = "Objectives: 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. Methods: 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. Results: 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). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. {\textcopyright} 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.",

author = "Evangelos Evangelou and Kerkhof, {Hanneke J.} and Unnur Styrkarsdottir and Ntzani, {Evangelia E.} and Bos, {Steffan D.} and Tonu Esko and Evans, {Daniel S.} and Sarah Metrustry and Kalliope Panoutsopoulou and Ramos, {Yolande F M} and Gudmar Thorleifsson and Tsilidis, {Konstantinos K.} and Nigel Arden and Nadim Aslam and Nicholas Bellamy and Fraser Birrell and Blanco, {Francisco J.} and Andrew Carr and Kay Chapman and Day-Williams, {Aaron G.} and Panos Deloukas and Michael Doherty and Gunnar Engstr{\"o}m and Helgadottir, {Hafdis T.} and Albert Hofman and Thorvaldur Ingvarsson and Helgi Jonsson and Aime Keis and Keurentjes, {J. Christiaan} and Margreet Kloppenburg and Lind, {Penelope A.} and Andrew McCaskie and Martin, {Nicholas G.} and Lili Milani and Montgomery, {Grant W.} and Nelissen, {Rob G H H} and Nevitt, {Michael C.} and Nilsson, {Peter M.} and Ollier, {William E R} and Neeta Parimi and Ashok Rai and Ralston, {Stuart H.} and Reed, {Mike R.} and Riancho, {Jose A.} and Fernando Rivadeneira and Cristina Rodriguez-Fontenla and Lorraine Southam and Unnur Thorsteinsdottir and Aspasia Tsezou and Wallis, {Gillian A.} and Wilkinson, {J. Mark} and Antonio Gonzalez and Lane, {Nancy E.} and Lohmander, {L. Stefan} and John Loughlin and Andres Metspalu and Uitterlinden, {Andre G.} and Ingileif Jonsdottir and Kari Stefansson and Slagboom, {P. Eline} and Eleftheria Zeggini and Ingrid Meulenbelt and Ioannidis, {John P A} and Spector, {Tim D.} and {van Meurs}, {Joyce B J} and Valdes, {Ana M.}",

note = "all access done through the resource described in the paper at http://www.ebi.ac.uk/chebi",

year = "2013",

month = aug,

day = "29",

doi = "10.1136/annrheumdis-2012-203114",

language = "English",

volume = "73",

pages = "2130--2136",

journal = "Annals of the rheumatic diseases",

issn = "0003-4967",

publisher = "Elsevier BV",

}

Evangelou, E, Kerkhof, HJ, Styrkarsdottir, U, Ntzani, EE, Bos, SD, Esko, T, Evans, DS, Metrustry, S, Panoutsopoulou, K, Ramos, YFM, Thorleifsson, G, Tsilidis, KK, Arden, N, Aslam, N, Bellamy, N, Birrell, F, Blanco, FJ, Carr, A, Chapman, K, Day-Williams, AG, Deloukas, P, Doherty, M, Engström, G, Helgadottir, HT, Hofman, A, Ingvarsson, T, Jonsson, H, Keis, A, Keurentjes, JC, Kloppenburg, M, Lind, PA, McCaskie, A, Martin, NG, Milani, L, Montgomery, GW, Nelissen, RGHH, Nevitt, MC, Nilsson, PM, Ollier, WER, Parimi, N, Rai, A, Ralston, SH, Reed, MR, Riancho, JA, Rivadeneira, F, Rodriguez-Fontenla, C, Southam, L, Thorsteinsdottir, U, Tsezou, A, Wallis, GA, Wilkinson, JM, Gonzalez, A, Lane, NE, Lohmander, LS, Loughlin, J, Metspalu, A, Uitterlinden, AG, Jonsdottir, I, Stefansson, K, Slagboom, PE, Zeggini, E, Meulenbelt, I, Ioannidis, JPA, Spector, TD, van Meurs, JBJ & Valdes, AM 2013, 'A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip', Annals of the rheumatic diseases, vol. 73, pp. 2130-2136. https://doi.org/10.1136/annrheumdis-2012-203114

TY - JOUR

T1 - A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

AU - Evangelou, Evangelos

AU - Kerkhof, Hanneke J.

AU - Styrkarsdottir, Unnur

AU - Ntzani, Evangelia E.

AU - Bos, Steffan D.

AU - Esko, Tonu

AU - Evans, Daniel S.

AU - Metrustry, Sarah

AU - Panoutsopoulou, Kalliope

AU - Ramos, Yolande F M

AU - Thorleifsson, Gudmar

AU - Tsilidis, Konstantinos K.

AU - Arden, Nigel

AU - Aslam, Nadim

AU - Bellamy, Nicholas

AU - Birrell, Fraser

AU - Blanco, Francisco J.

AU - Carr, Andrew

AU - Chapman, Kay

AU - Day-Williams, Aaron G.

AU - Deloukas, Panos

AU - Doherty, Michael

AU - Engström, Gunnar

AU - Helgadottir, Hafdis T.

AU - Hofman, Albert

AU - Ingvarsson, Thorvaldur

AU - Jonsson, Helgi

AU - Keis, Aime

AU - Keurentjes, J. Christiaan

AU - Kloppenburg, Margreet

AU - Lind, Penelope A.

AU - McCaskie, Andrew

AU - Martin, Nicholas G.

AU - Milani, Lili

AU - Montgomery, Grant W.

AU - Nelissen, Rob G H H

AU - Nevitt, Michael C.

AU - Nilsson, Peter M.

AU - Ollier, William E R

AU - Parimi, Neeta

AU - Rai, Ashok

AU - Ralston, Stuart H.

AU - Reed, Mike R.

AU - Riancho, Jose A.

AU - Rivadeneira, Fernando

AU - Rodriguez-Fontenla, Cristina

AU - Southam, Lorraine

AU - Thorsteinsdottir, Unnur

AU - Tsezou, Aspasia

AU - Wallis, Gillian A.

AU - Wilkinson, J. Mark

AU - Gonzalez, Antonio

AU - Lane, Nancy E.

AU - Lohmander, L. Stefan

AU - Loughlin, John

AU - Metspalu, Andres

AU - Uitterlinden, Andre G.

AU - Jonsdottir, Ingileif

AU - Stefansson, Kari

AU - Slagboom, P. Eline

AU - Zeggini, Eleftheria

AU - Meulenbelt, Ingrid

AU - Ioannidis, John P A

AU - Spector, Tim D.

AU - van Meurs, Joyce B J

AU - Valdes, Ana M.

N1 - all access done through the resource described in the paper at http://www.ebi.ac.uk/chebi

PY - 2013/8/29

Y1 - 2013/8/29

N2 - Objectives: 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. Methods: 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. Results: 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). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

AB - Objectives: 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. Methods: 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. Results: 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). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

U2 - 10.1136/annrheumdis-2012-203114

DO - 10.1136/annrheumdis-2012-203114

M3 - Article

SN - 0003-4967

VL - 73

SP - 2130

EP - 2136

JO - Annals of the rheumatic diseases

JF - Annals of the rheumatic diseases

ER -

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

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