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

被引：89

作者：

Evangelou, Evangelos ^{[1
,2
]}

Kerkhof, Hanneke J. ^{[3
]}

Styrkarsdottir, Unnur ^{[4
]}

Ntzani, Evangelia E. ^{[1
]}

Bos, Steffan D. ^{[5
,6
]}

Esko, Tonu ^{[7
,8
]}

Evans, Daniel S. ^{[9
]}

Metrustry, Sarah ^{[2
]}

Panoutsopoulou, Kalliope ^{[10
]}

Ramos, Yolande F. M. ^{[5
]}

Thorleifsson, Gudmar ^{[4
]}

Tsilidis, Konstantinos K. ^{[1
]}

Arden, Nigel ^{[11
,12
,13
]}

Aslam, Nadim ^{[14
]}

Bellamy, Nicholas ^{[15
]}

Birrell, Fraser ^{[16
,17
]}

Blanco, Francisco J. ^{[18
]}

Carr, Andrew ^{[11
,12
]}

Chapman, Kay ^{[11
,12
]}

Day-Williams, Aaron G. ^{[10
]}

Deloukas, Panos ^{[10
]}

Doherty, Michael ^{[19
]}

Engstrom, Gunnar ^{[20
]}

Helgadottir, Hafdis T. ^{[4
]}

Hofman, Albert ^{[21
]}

Ingvarsson, Thorvaldur ^{[22
,23
]}

Jonsson, Helgi ^{[24
,25
]}

Keis, Aime ^{[26
,27
]}

Keurentjes, J. Christiaan ^{[28
]}

Kloppenburg, Margreet ^{[29
]}

Lind, Penelope A. ^{[30
]}

McCaskie, Andrew ^{[16
]}

Martin, Nicholas G. ^{[31
]}

Milani, Lili ^{[7
]}

Montgomery, Grant W. ^{[32
]}

Nelissen, Rob G. H. H. ^{[28
]}

Nevitt, Michael C. ^{[33
]}

Nilsson, Peter M. ^{[20
]}

Ollier, William E. R. ^{[34
]}

Parimi, Neeta ^{[9
]}

Rai, Ashok ^{[35
]}

Ralston, Stuart H. ^{[36
]}

Reed, Mike R. ^{[17
]}

Riancho, Jose A. ^{[37
]}

Rivadeneira, Fernando ^{[3
,21
]}

Rodriguez-Fontenla, Cristina ^{[38
,39
]}

Southam, Lorraine ^{[10
]}

Thorsteinsdottir, Unnur ^{[4
,24
]}

Tsezou, Aspasia ^{[40
]}

AWallis, Gillian ^{[41
]}

机构：

[1] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece

[2] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[3] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[4] deCODE Genet, Dept Populat Genet, Reykjavik, Iceland

[5] Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands

[6] Netherlands Consortium Hlth Ageing, Leiden, Netherlands

[7] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[8] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[9] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA

[10] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England

[11] Univ Oxford, NIHR Biomed Res Unit, Oxford, England

[12] Univ Oxford, ARUK Ctr Excellence Sport Exercise & Osteoarthrit, Oxford, England

[13] Univ Southampton, MRC Epidemiol Resource Ctr, Southampton, Hants, England

[14] Worcestershire Acute Hosp NHS Trust, Worcestershire Royal Hosp, Worcester, Worcs, England

[15] Univ Queensland, Ctr Natl Res Disabil & Rehabil Med, Brisbane, Qld, Australia

[16] Newcastle Univ, Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[17] Northumbria Healthcare NHS Fdn Trust, Wansbeck Gen Hosp, Ashington, England

[18] Hosp Univ A Coruna, Rheumatol Div, Inst Invest Biomed, A Corunna, Spain

[19] Univ Nottingham, Dept Acad Rheumatol, Nottingham NG5 1PB, England

[20] Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden

[21] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[22] Akureyri Hosp, Dept Orthoped Surg, Akureyri, Iceland

[23] Univ Akureyri, Sch Hlth Sci, Akureyri, Iceland

[24] Natl Univ Hosp Iceland, Dept Med, Reykjavik, Iceland

[25] Univ Iceland, Fac Med, Reykjavik, Iceland

[26] Univ Tartu, Dept Publ Hlth, EE-50090 Tartu, Estonia

[27] Elva Hosp, Elva, Estonia

[28] Leiden Univ, Med Ctr, Dept Orthoped, Leiden, Netherlands

[29] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

[30] QIMR Berghofer Med Res Inst, Dept Quantitat Genet, Brisbane, Qld, Australia

[31] QIMR Berghofer Med Res Inst, Dept Genet Epidemiol, Brisbane, Qld, Australia

[32] QIMR Berghofer Med Res Inst, Dept Mol Epidemiol, Brisbane, Qld, Australia

[33] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[34] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[35] Worcestershire Acute Hosp NHS Trust, Worcester, Worcs, England

[36] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[37] Univ Cantabria, Dept Internal Med, Hosp UM Valdecilla IFIMAV, E-39005 Santander, Spain

[38] Hosp Clin Univ de Santiago, Lab Invest 10, Inst Invest Sanitaria, Santiago De Compostela, Spain

[39] Hosp Clin Univ de Santiago, Rheumatol Unit, Inst Invest Sanitaria, Santiago De Compostela, Spain

[40] Univ Thessaly, Sch Med, Dept Biol, Larisa, Greece

[41] Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England

[42] Univ Sheffield, Dept Human Metab, Sheffield, S Yorkshire, England

[43] Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA

[44] Univ Southern Denmark, Res Unit Musculoskeletal Funct & Physiotherapy, Odense, Denmark

[45] Univ Southern Denmark, Dept Orthoped & Traumatol, Odense, Denmark

[46] Lund Univ, Dept Clin Sci Lund, Lund, Sweden

[47] Stanford Univ, Stanford Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2014年 / 73卷 / 12期

关键词：

TRANSCRIPTIONAL ACTIVATION; SUSCEPTIBILITY LOCUS; POLYMORPHISM; PATHWAYS; RECEPTOR; REVEAL; GENES;

D O I：

10.1136/annrheumdis-2012-203114

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2130 / 2136

页数：7

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