A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22†
Hanneke J. M. Kerkhof
Erasmus Medical Centre, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Search for more papers by this authorIngrid Meulenbelt
Leiden University Medical Centre, Leiden, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorIngileif Jonsdottir
deCODE Genetics and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorThorvaldur Ingvarsson
University of Akureyri, Akureyri, Iceland and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorHelgi Jonsson
Landspitali University Hospital and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorLisette Stolk
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorGudmar Thorleifsson
deCODE Genetics, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorYanyan Zhu
Boston University School of Public Health, Boston, Massachusetts
Search for more papers by this authorRuud van der Breggen
Leiden University Medical Centre, Leiden, The Netherlands
Search for more papers by this authorMichael Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorSally Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorDavid T. Felson
Boston University School of Medicine, Boston, Massachusetts
Search for more papers by this authorAntonio Gonzalez
Hospital Clinico Universitario Santiago, Santiago de Compostela, Spain
Search for more papers by this authorBjarni V. Halldorsson
deCODE Genetics and Reykjavik University, Reykjavik, Iceland
Search for more papers by this authorAlbert Hofman
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorJohn P. A. Ioannidis
University of Ioannina School of Medicine, Ioannina, Greece
Tufts University School of Medicine, Boston, Massachusetts
Search for more papers by this authorMargreet Kloppenburg
Leiden University Medical Centre, Leiden, The Netherlands
Search for more papers by this authorNancy E. Lane
University of California at San Francisco and University of California at Davis, Sacramento
Search for more papers by this authorFrank P. Luyten
Katholieke Universiteit Leuven, Leuven, Belgium
Search for more papers by this authorMichael C. Nevitt
University of California at San Francisco and University of California at Davis, Sacramento
Search for more papers by this authorNeeta Parimi
California Pacific Research Institute, San Francisco
Search for more papers by this authorHuibert A. P. Pols
Erasmus Medical Centre, Rotterdam, The Netherlands
Search for more papers by this authorFernando Rivadeneira
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorEline P. Slagboom
Leiden University Medical Centre, Leiden, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorTom van de Putte
TiGenix, Leuven, Belgium
Dr. van de Putte owns stock or stock options in TiGenix and is coholder of a patent on a transgenic animal with controllable hyperproliferation and a skin inflammation phenotype.
Search for more papers by this authorJoseph Zmuda
University of Pittsburgh, Pittsburgh, Pennsylvania
Search for more papers by this authorKari Stefansson
deCODE Genetics and University of Iceland, Reykjavik, Iceland
Search for more papers by this authorAndré G. Uitterlinden
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Search for more papers by this authorCorresponding Author
Joyce B. J. van Meurs
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Genetics Laboratory, Department of Internal Medicine, Room Ee571, Erasmus Medical Centre, PO Box 1738, 3000 DR Rotterdam, The NetherlandsSearch for more papers by this authorHanneke J. M. Kerkhof
Erasmus Medical Centre, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Search for more papers by this authorIngrid Meulenbelt
Leiden University Medical Centre, Leiden, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorIngileif Jonsdottir
deCODE Genetics and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorThorvaldur Ingvarsson
University of Akureyri, Akureyri, Iceland and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorHelgi Jonsson
Landspitali University Hospital and University of Iceland, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorLisette Stolk
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorGudmar Thorleifsson
deCODE Genetics, Reykjavik, Iceland
Drs. Jonsdottir, Ingvarsson, Thorleifsson, Halldorsson, Styrkársdóttir, and Stefansson own stock or stock options in deCODE Genetics.
Search for more papers by this authorYanyan Zhu
Boston University School of Public Health, Boston, Massachusetts
Search for more papers by this authorRuud van der Breggen
Leiden University Medical Centre, Leiden, The Netherlands
Search for more papers by this authorMichael Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorSally Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorDavid T. Felson
Boston University School of Medicine, Boston, Massachusetts
Search for more papers by this authorAntonio Gonzalez
Hospital Clinico Universitario Santiago, Santiago de Compostela, Spain
Search for more papers by this authorBjarni V. Halldorsson
deCODE Genetics and Reykjavik University, Reykjavik, Iceland
Search for more papers by this authorAlbert Hofman
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorJohn P. A. Ioannidis
University of Ioannina School of Medicine, Ioannina, Greece
Tufts University School of Medicine, Boston, Massachusetts
Search for more papers by this authorMargreet Kloppenburg
Leiden University Medical Centre, Leiden, The Netherlands
Search for more papers by this authorNancy E. Lane
University of California at San Francisco and University of California at Davis, Sacramento
Search for more papers by this authorFrank P. Luyten
Katholieke Universiteit Leuven, Leuven, Belgium
Search for more papers by this authorMichael C. Nevitt
University of California at San Francisco and University of California at Davis, Sacramento
Search for more papers by this authorNeeta Parimi
California Pacific Research Institute, San Francisco
Search for more papers by this authorHuibert A. P. Pols
Erasmus Medical Centre, Rotterdam, The Netherlands
Search for more papers by this authorFernando Rivadeneira
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorEline P. Slagboom
Leiden University Medical Centre, Leiden, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Search for more papers by this authorTom van de Putte
TiGenix, Leuven, Belgium
Dr. van de Putte owns stock or stock options in TiGenix and is coholder of a patent on a transgenic animal with controllable hyperproliferation and a skin inflammation phenotype.
Search for more papers by this authorJoseph Zmuda
University of Pittsburgh, Pittsburgh, Pennsylvania
Search for more papers by this authorKari Stefansson
deCODE Genetics and University of Iceland, Reykjavik, Iceland
Search for more papers by this authorAndré G. Uitterlinden
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Search for more papers by this authorCorresponding Author
Joyce B. J. van Meurs
Erasmus Medical Centre, Rotterdam, The Netherlands and The Netherlands Genomics Initiative–Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
Ms Kerkhof and Drs. Uitterlinden and van Meurs have a patent pending in the field of disease diagnostics, including classification and prognosis of osteoarthritis by use of genetic markers.
Genetics Laboratory, Department of Internal Medicine, Room Ee571, Erasmus Medical Centre, PO Box 1738, 3000 DR Rotterdam, The NetherlandsSearch for more papers by this authorPoints of view or opinions in this paper are those of the authors and do not necessarily represent the official position or policies of the Tufts Clinical and Translational Science Institute.
Abstract
Objective
To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study.
Methods
We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and ∼39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 × 10−7 considered genome-wide significant.
Results
The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09–1.19) of knee and/or hand OA (P = 8 × 10−8) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03–1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 × 10−12). Immunohistochemistry experiments revealed that G protein–coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.
Conclusion
Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein–coupled receptor, this is potentially an interesting therapeutic target.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ART_27184_sm_Supplementarytextandtables.doc135.5 KB | Supplementary Data |
| ART_27184_sm_Supplementaryfigure1.TIF470.4 KB | Supplementary Supplementary Figure 1 |
| ART_27184_sm_Supplementaryfigure2.TIF3.6 MB | Supplementary Supplementary Figure 2 |
| ART_27184_sm_Supplementaryfigure3.TIF1.5 MB | Supplementary Supplementary Figure 3 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage 2004; 12: Suppl A: S39–44.
- 2 Chapman K, Takahashi A, Meulenbelt I, Watson C, Rodriguez-Lopez J, Egli R, et al. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5′ UTR of GDF5 with osteoarthritis susceptibility. Hum Mol Genet 2008; 17: 1497–504.
- 3 Meulenbelt I, Min JL, Bos S, Riyazi N, Houwing-Duistermaat JJ, van der Wijk HJ, et al. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum Mol Genet 2008; 17: 1867–75.
- 4 Valdes AM, Loughlin J, Timms KM, van Meurs JJ, Southam L, Wilson SG, et al. Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis. Am J Hum Genet 2008; 82: 1231–40.
- 5 Miyamoto Y, Shi D, Nakajima M, Ozaki K, Sudo A, Kotani A, et al. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nat Genet 2008; 40: 994–8.
- 6 Meulenbelt I, Chapman K, Dieguez-Gonzalez R, Shi D, Tsezou A, Dai J, et al. Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations. Hum Mol Genet 2009; 18: 1518–23.
- 7 Valdes AM, Spector TD, Doherty S, Wheeler M, Hart DJ, Doherty M. Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations. Ann Rheum Dis 2008. E-pub ahead of print.
- 8 Hofman A, Breteler MM, van Duijn CM, Krestin GP, Pols HA, Stricker BH, et al. The Rotterdam Study: objectives and design update. Eur J Epidemiol 2007; 22: 819–29.
- 9 Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957; 16: 494–502.
- 10 Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1990; 33: 1601–10.
- 11 Ingvarsson T. Prevalence and inheritance of hip osteoarthritis in Iceland. Acta Orthop Scand Suppl 2000; 298: 1–46.
- 12 Stefansson SE, Jonsson H, Ingvarsson T, Manolescu I, Jonsson HH, Olafsdottir G, et al. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet 2003; 72: 1448–59.
- 13 Hart DJ, Spector TD. Cigarette smoking and risk of osteoarthritis in women in the general population: the Chingford study. Ann Rheum Dis 1993; 52: 93–6.
- 14 Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol 1993; 20: 331–5.
- 15 Hart DJ, Mootoosamy I, Doyle DV, Spector TD. The relationship between osteoarthritis and osteoporosis in the general population: the Chingford Study. Ann Rheum Dis 1994; 53: 158–62.
- 16 Spector TD, Williams FM. The UK Adult Twin Registry (TwinsUK). Twin Res Hum Genet 2006; 9: 899–906.
- 17 Dawber TR, Meadors GF, Moore FE Jr. Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951; 41: 279–81.
- 18 Hunter DJ, Demissie S, Cupples LA, Aliabadi P, Felson DT. A genome scan for joint-specific hand osteoarthritis susceptibility: The Framingham Study. Arthritis Rheum 2004; 50: 2489–96.
- 19 Fytili P, Giannatou E, Papanikolaou V, Stripeli F, Karachalios T, Malizos K, et al. Association of repeat polymorphisms in the estrogen receptors alpha, beta, and androgen receptor genes with knee osteoarthritis. Clin Genet 2005; 68: 268–77.
- 20 Rodriguez-Lopez J, Pombo-Suarez M, Liz M, Gomez-Reino JJ, Gonzalez A. Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians. Arthritis Res Ther 2006; 8: R55.
- 21 Riyazi N, Meulenbelt I, Kroon HM, Ronday KH, Hellio le Graverand MP, Rosendaal FR, et al. Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study. Ann Rheum Dis 2005; 64: 438–43.
- 22 Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al, Study of Osteoporotic Fractures Research Group. Risk factors for hip fracture in white women. N Engl J Med 1995; 332: 767–73.
- 23 Orwoll E, Blank JB, Barrett-Connor E, Cauley J, Cummings S, Ensrud K, et al. Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study—a large observational study of the determinants of fracture in older men. Contemp Clin Trials 2005; 26: 569–85.
- 24 Blank JB, Cawthon PM, Carrion-Petersen ML, Harper L, Johnson JP, Mitson E, et al. Overview of recruitment for the osteoporotic fractures in men study (MrOS). Contemp Clin Trials 2005; 26: 557–68.
- 25 Reijman M, Hazes JM, Bierma-Zeinstra SM, Koes BW, Christgau S, Christiansen C, et al. A new marker for osteoarthritis: cross-sectional and longitudinal approach. Arthritis Rheum 2004; 50: 2471–8.
- 26 Christgau S, Garnero P, Fledelius C, Moniz C, Ensig M, Gineyts E, et al. Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 2001; 29: 209–15.
- 27 Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008; 371: 1505–12.
- 28 Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–75.
- 29 Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003; 35: 131–8.
- 30 Devlin B, Roeder K. Genomic control for association studies. Biometrics 1999; 55: 997–1004.
- 31 Lories RJ, Derese I, De Bari C, Luyten FP. In vitro growth rate of fibroblast-like synovial cells is reduced by methotrexate treatment. Ann Rheum Dis 2003; 62: 568–71.
- 32 Dell'Accio F, De Bari C, Luyten FP. Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. Arthritis Rheum 2001; 44: 1608–19.
- 33 Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 2007; 15: 1061–9.
- 34 Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 2007; 56: 4095–103.
- 35 Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2008; 24: 2938–9.
- 36 Cummings DE, Brandon EP, Planas JV, Motamed K, Idzerda RL, McKnight GS. Genetically lean mice result from targeted disruption of the RII β subunit of protein kinase A. Nature 1996; 382: 622–6.
- 37 Newhall KJ, Cummings DE, Nolan MA, McKnight GS. Deletion of the RIIβ-subunit of protein kinase A decreases body weight and increases energy expenditure in the obese, leptin-deficient ob/ob mouse. Mol Endocrinol 2005; 19: 982–91.
- 38 Adams JW, Wang J, Davis JR, Liaw C, Gaidarov I, Gatlin J, et al. Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor. Am J Physiol Heart Circ Physiol 2008; 295: H509–21.
- 39 Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, et al. A genome-wide association study of global gene expression. Nat Genet 2007; 39: 1202–7.
- 40 Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, et al. A survey of genetic human cortical gene expression. Nat Genet 2007; 39: 1494–9.
- 41 Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori Y, Saito S, et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 2007; 39: 529–33.
- 42 Vaes RB, Rivadeneira F, Kerkhof JM, Hofman A, Pols HA, Uitterlinden AG, et al. Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study. Ann Rheum Dis 2009; 68: 1754–60.
- 43 Evangelou E, Chapman K, Meulenbelt I, Karassa FB, Loughlin J, Carr A, et al. Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. Arthritis Rheum 2009; 60: 1710–21.
