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

被引：298

作者：

Zeggini, Eleftheria ^{[1
]}

Panoutsopoulou, Kalliope ^{[1
]}

Southam, Lorraine ^{[1
,2
]}

Rayner, Nigel W. ^{[2
,3
]}

Day-Williams, Aaron G. ^{[1
]}

Lopes, Margarida C. ^{[1
,2
]}

Boraska, Vesna ^{[1
,4
]}

Esko, Tonu ^{[5
,6
,7
,8
]}

Evangelou, Evangelos ^{[9
]}

Hofman, Albert ^{[10
]}

Houwing-Duistermaat, Jeanine J. ^{[11
]}

Ingvarsson, Thorvaldur ^{[12
,13
]}

Jonsdottir, Ingileif ^{[13
,14
]}

Jonsson, Helgi ^{[13
]}

Kerkhof, Hanneke J. M. ^{[10
]}

Kloppenburg, Margreet ^{[11
]}

Bos, Steffan D. ^{[11
]}

Mangino, Massimo ^{[15
]}

Metrustry, Sarah ^{[15
]}

Slagboom, P. Eline ^{[11
]}

Thorleifsson, Gudmar ^{[14
]}

Raine, Emma V. A. ^{[16
]}

Ratnayake, Madhushika ^{[16
]}

Ricketts, Michelle ^{[17
]}

Beazley, Claude ^{[1
]}

Blackburn, Hannah ^{[1
]}

Bumpstead, Suzannah ^{[1
]}

Elliott, Katherine S. ^{[2
]}

Hunt, Sarah E. ^{[1
]}

Potter, Simon C. ^{[1
]}

Shin, So-Youn ^{[1
]}

Yadav, Vijay K. ^{[1
]}

Zhai, Guangju ^{[15
,18
]}

Sherburn, Kate ^{[19
]}

Dixon, Kate ^{[19
]}

Arden, Elizabeth ^{[20
]}

Aslam, Nadim ^{[21
]}

Battley, Phillippa-Kate ^{[20
]}

Carluke, Ian ^{[22
]}

Doherty, Sally ^{[23
]}

Gordon, Andrew ^{[24
]}

Joseph, John ^{[21
]}

Keen, Richard ^{[25
]}

Koller, Nicola C. ^{[17
]}

Mitchell, Sheryl ^{[26
]}

O'Neill, Fiona ^{[15
]}

Paling, Ellen ^{[24
,27
]}

Reed, Mike R. ^{[22
]}

Rivadeneira, Fernando ^{[10
]}

Swift, Diane ^{[24
,27
]}

机构：

[1] Sanger Inst, Hinxton, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[4] Univ Split, Sch Med, Split, Croatia

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

[6] Univ Tartu, Ctr Translat Genom, EE-50090 Tartu, Estonia

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

[8] Estonian Bioctr, Tartu, Estonia

[9] Univ Ioannina, Sch Med, GR-45110 Ioannina, Greece

[10] Erasmus MC, Rotterdam, Netherlands

[11] Leiden Univ, Med Ctr, Leiden, Netherlands

[12] Univ Akureyri, Akureyri, Iceland

[13] Univ Iceland, Reykjavik, Iceland

[14] deCODE Genet, Reykjavik, Iceland

[15] Kings Coll London, London WC2R 2LS, England

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

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

[18] Mem Univ Newfoundland, St John, NF, Canada

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

[20] Southampton Gen Hosp, Wellcome Trust Clin Res Facil, Southampton SO9 4XY, Hants, England

[21] Worcestershire Acute Hosp NHS Trust, Worcester, England

[22] Wansbeck Gen Hosp, Ashington, England

[23] Univ Nottingham, Nottingham NG7 2RD, England

[24] Univ Sheffield, Dept Human Metab, Acad Unit Bone Metab, Sheffield, S Yorkshire, England

[25] Royal Natl Orthopaed Hosp, Stanmore HA7 4LP, Middx, England

[26] Freeman Rd Hosp, Newcastle Upon Tyne, Tyne & Wear, England

[27] No Gen Hosp, Sheffield Natl Inst Hlth Res, Musculoskeletal Biomed Res Unit, Sheffield S5 7AU, S Yorkshire, England

[28] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England

[29] Tufts Clin & Translat Sci Inst, Boston, MA USA

[30] Tufts Univ, Sch Med, Boston, MA 02111 USA

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

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

[33] Univ Southampton, Med Res Council, Epidemiol Resource Ctr, Southampton, Hants, England

来源：

LANCET | 2012年 / 380卷 / 9844期

关键词：

MESENCHYMAL STEM-CELLS; KNEE OSTEOARTHRITIS; BONE-MARROW; HIP; GENE; GDF5; NUCLEOSTEMIN; GROWTH; HAND; CHONDROITIN-4-SULFOTRANSFERASE-1;

D O I：

10.1016/S0140-6736(12)60681-3

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 <= 5.0x10(-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=7.24x10(-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.

引用

页码：815 / 823

页数：9

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