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

arcOGEN Consortium

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2130-2136
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume73
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Hip Osteoarthritis
Genome-Wide Association Study
Meta-Analysis
Genes
Gene Frequency
Osteoarthritis
Nuclear Receptor Coactivator 3
Cartilage
Genetic Loci
Articular Cartilage
Computer Simulation
Arthritis
Single Nucleotide Polymorphism
Genome
Polymorphism
Nucleotides

Keywords

  • Epidemiology
  • Gene Polymorphism
  • Osteoarthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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

In: Annals of the Rheumatic Diseases, Vol. 73, No. 12, 01.12.2014, p. 2130-2136.

Research output: Contribution to journalArticle

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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.",
keywords = "Epidemiology, Gene Polymorphism, Osteoarthritis",
author = "{arcOGEN Consortium} and 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 Lane, {Nancy E}",
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TY - JOUR

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

AU - arcOGEN Consortium

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 - Lane, Nancy E

PY - 2014/12/1

Y1 - 2014/12/1

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.

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.

KW - Epidemiology

KW - Gene Polymorphism

KW - Osteoarthritis

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U2 - 10.1136/annrheumdis-2012-203114

DO - 10.1136/annrheumdis-2012-203114

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JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

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