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

E Evangelou; HJ Kerkhof; U Styrkarsdottir; EE Ntzani; SD (Steffan Daniel) Bos; T Esko; DS Evans; S Metrustry; K Panoutsopoulou; YFM Ramos; G Thorleifsson; KK Tsilidis; N Arden; N Aslam; N Bellamy; F Birrell; FJ Blanco; A Carr; K Chapman; AG Day-Williams; P Deloukas; M Doherty; G Engstrom; HT Helgadottir; Bert Hofman; T Ingvarsson; H Jonsson; A Keis; JC Keurentjes; M Kloppenburg; PA Lind; A McCaskie; NG Martin; L Milani; GW Montgomery; RGHH Nelissen; MC Nevitt; PM Nilsson; WER Ollier; N Parimi; A Rai; SH Ralston; MR Reed; JA Riancho; Fernando Rivadeneira; C Rodriguez-Fontenla; L Southam; U Thorsteinsdottir; A Tsezou; G AWallis; JM Wilkinson; A Gonzalez; NE Lane; LS Lohmander; J Loughlin; A Metspalu; André Uitterlinden; I Jonsdottir; K Stefansson; PE (Eline) Slagboom; E Zeggini; I Meulenbelt; JPA Ioannidis; TD Spector; Joyce van Meurs; AM Valdes

doi:10.1136/annrheumdis-2012-203114

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

E Evangelou, HJ Kerkhof, U Styrkarsdottir, EE Ntzani, SD (Steffan Daniel) Bos, T Esko, DS Evans, S Metrustry, K Panoutsopoulou, YFM Ramos, G Thorleifsson, KK Tsilidis, N Arden, N Aslam, N Bellamy, F Birrell, FJ Blanco, A Carr, K Chapman, AG Day-WilliamsP Deloukas, M Doherty, G Engstrom, HT Helgadottir, Bert Hofman, T Ingvarsson, H Jonsson, A Keis, JC Keurentjes, M Kloppenburg, PA Lind, A McCaskie, NG Martin, L Milani, GW Montgomery, RGHH Nelissen, MC Nevitt, PM Nilsson, WER Ollier, N Parimi, A Rai, SH Ralston, MR Reed, JA Riancho, Fernando Rivadeneira, C Rodriguez-Fontenla, L Southam, U Thorsteinsdottir, A Tsezou, G AWallis, JM Wilkinson, A Gonzalez, NE Lane, LS Lohmander, J Loughlin, A Metspalu, André Uitterlinden, I Jonsdottir, K Stefansson, PE (Eline) Slagboom, E Zeggini, I Meulenbelt, JPA Ioannidis, TD Spector, Joyce van Meurs, AM Valdes

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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=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-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=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Original language	Undefined/Unknown
Pages (from-to)	2130-2136
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	73
Issue number	12
DOIs	https://doi.org/10.1136/annrheumdis-2012-203114
Publication status	Published - 2014

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-02

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10.1136/annrheumdis-2012-203114

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Cite this

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., ... Valdes, AM. (2014). A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. Annals of the Rheumatic Diseases, 73(12), 2130-2136. https://doi.org/10.1136/annrheumdis-2012-203114

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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=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-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=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.",

author = "E Evangelou and HJ Kerkhof and U Styrkarsdottir and EE Ntzani and Bos, {SD (Steffan Daniel)} and T Esko and DS Evans and S Metrustry and K Panoutsopoulou and YFM Ramos and G Thorleifsson and KK Tsilidis and N Arden and N Aslam and N Bellamy and F Birrell and FJ Blanco and A Carr and K Chapman and AG Day-Williams and P Deloukas and M Doherty and G Engstrom and HT Helgadottir and Bert Hofman and T Ingvarsson and H Jonsson and A Keis and JC Keurentjes and M Kloppenburg and PA Lind and A McCaskie and NG Martin and L Milani and GW Montgomery and RGHH Nelissen and MC Nevitt and PM Nilsson and WER Ollier and N Parimi and A Rai and SH Ralston and MR Reed and JA Riancho and Fernando Rivadeneira and C Rodriguez-Fontenla and L Southam and U Thorsteinsdottir and A Tsezou and G AWallis and JM Wilkinson and A Gonzalez and NE Lane and LS Lohmander and J Loughlin and A Metspalu and Andr{\'e} Uitterlinden and I Jonsdottir and K Stefansson and Slagboom, {PE (Eline)} and E Zeggini and I Meulenbelt and JPA Ioannidis and TD Spector and {van Meurs}, Joyce and AM Valdes",

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

language = "Undefined/Unknown",

volume = "73",

pages = "2130--2136",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

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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, Engstrom, G, Helgadottir, HT, Hofman, B, 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, AWallis, G, Wilkinson, JM, Gonzalez, A, Lane, NE, Lohmander, LS, Loughlin, J, Metspalu, A, Uitterlinden, A, Jonsdottir, I, Stefansson, K, Slagboom, PE, Zeggini, E, Meulenbelt, I, Ioannidis, JPA, Spector, TD, van Meurs, J & Valdes, AM 2014, 'A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip', Annals of the Rheumatic Diseases, vol. 73, no. 12, 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, E

AU - Kerkhof, HJ

AU - Styrkarsdottir, U

AU - Ntzani, EE

AU - Bos, SD (Steffan Daniel)

AU - Esko, T

AU - Evans, DS

AU - Metrustry, S

AU - Panoutsopoulou, K

AU - Ramos, YFM

AU - Thorleifsson, G

AU - Tsilidis, KK

AU - Arden, N

AU - Aslam, N

AU - Bellamy, N

AU - Birrell, F

AU - Blanco, FJ

AU - Carr, A

AU - Chapman, K

AU - Day-Williams, AG

AU - Deloukas, P

AU - Doherty, M

AU - Engstrom, G

AU - Helgadottir, HT

AU - Hofman, Bert

AU - Ingvarsson, T

AU - Jonsson, H

AU - Keis, A

AU - Keurentjes, JC

AU - Kloppenburg, M

AU - Lind, PA

AU - McCaskie, A

AU - Martin, NG

AU - Milani, L

AU - Montgomery, GW

AU - Nelissen, RGHH

AU - Nevitt, MC

AU - Nilsson, PM

AU - Ollier, WER

AU - Parimi, N

AU - Rai, A

AU - Ralston, SH

AU - Reed, MR

AU - Riancho, JA

AU - Rivadeneira, Fernando

AU - Rodriguez-Fontenla, C

AU - Southam, L

AU - Thorsteinsdottir, U

AU - Tsezou, A

AU - AWallis, G

AU - Wilkinson, JM

AU - Gonzalez, A

AU - Lane, NE

AU - Lohmander, LS

AU - Loughlin, J

AU - Metspalu, A

AU - Uitterlinden, André

AU - Jonsdottir, I

AU - Stefansson, K

AU - Slagboom, PE (Eline)

AU - Zeggini, E

AU - Meulenbelt, I

AU - Ioannidis, JPA

AU - Spector, TD

AU - van Meurs, Joyce

AU - Valdes, AM

PY - 2014

Y1 - 2014

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=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-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=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

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=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-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=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

U2 - 10.1136/annrheumdis-2012-203114

DO - 10.1136/annrheumdis-2012-203114

M3 - Article

C2 - 23989986

SN - 0003-4967

VL - 73

SP - 2130

EP - 2136

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 12

ER -