Letter | Published:

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

Nature Genetics volume 42, pages 508514 (2010) | Download Citation

Abstract

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 × 10−8) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

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Acknowledgements

R.M.P. is supported by grants from the US National Institutes of Health (NIH) (R01-AR057108, R01-AR056768 and U54 RR020278), a private donation from the Fox Trot Fund, the William Randolph Hearst Fund of Harvard University, the American College of Rheumatology 'Within Our Reach' campaign and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. S.R. is supported by an NIH Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. F.A.S.K. is supported by an EMBO-UNESCO L'Oreal Fellowship. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The BRASS Registry is supported by a grant from Crescendo and Biogen-Idec. EIRA is supported by grants from the Swedish Medical Research council, the Swedish Council for Working Life and Social Research, King Gustaf V's 80-year foundation, the Swedish Rheumatism Foundation, Stockholm County Council, from Vinnova and the insurance company AFA. NARAC is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). L.A.C. is supported by the NIH (R01 AI065841 and 5-M01-RR-00079). The Nurses Health Study is supported by NIH grants P01 CA87969, CA49449, CA67262, CA50385, AR049880-06 and AR47782. This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the US National Institutes of Health. This research was also supported in part by grants to K.A.S. from the Canadian Institutes for Health Research (MOP79321 and IIN-84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. Genotyping of United Kingdom Rheumatoid Arthritis Genetics samples was supported by the Arthritis Research campaign arc grant reference number 17552 and by the Manchester Biomedical Research Centre and Manchester Academy of Health Sciences. C.W. was funded by the Netherlands Organization for Scientific Research (VICI grant 918.66.620). We acknowledge the help of B.A.C. Dijkmans, D. van Schaardenburg, A. Salvador Peña, P.L. Klarenbeek, Z. Zhang, M.T. Nurmohamed, W.F. Lems, R.R. J. van de Stadt, W.H. Bos, J. Ursum, M.G.M. Bartelds, D.M. Gerlag, M.G.H. van der Sande, C.A. Wijbrandts and M.M.J. Herenius in gathering Genetics Network Rheumatology Amsterdam subject samples and data. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of genotype data from their healthy controls in our study. The MIGen study was funded by the US National Institutes of Health and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiological Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank J. Seddon, Progression of AMD Study, Age-Related Macular Degeneration (AMD) Registry Study, Family Study of AMD, The US Twin Study of AMD and the Age-Related Eye Disease Study (AREDS) for use of genotype data from their healthy controls in our study. We thank D. Hafler and the Multiple Sclerosis Collaborative for use of genotype data from their healthy controls recruited at Brigham and Women's Hospital.

Author information

Author notes

    • Jane Worthington
    • , Katherine A Siminovitch
    • , Peter K Gregersen
    •  & Lars Klareskog

    These authors contributed equally to this work.

Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Eli A Stahl
    • , Soumya Raychaudhuri
    • , Fina A S Kurreeman
    • , Robert Chen
    • , Jonathan Coblyn
    • , Karen H Costenbader
    • , Jing Cui
    • , Nancy A Shadick
    • , Michael E Weinblatt
    • , Elizabeth W Karlson
    •  & Robert M Plenge
  2. Broad Institute, Cambridge, Massachusetts, USA.

    • Eli A Stahl
    • , Soumya Raychaudhuri
    • , Brian P Thomson
    • , Fina A S Kurreeman
    • , Candace Guiducci
    • , Kristin G Ardlie
    • , Noel P Burtt
    • , Paul I W de Bakker
    • , Philip L De Jager
    •  & Robert M Plenge
  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  4. Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA.

    • Elaine F Remmers
    •  & Daniel L Kastner
  5. Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada.

    • Gang Xie
    • , Xiangdong Liu
    •  & Katherine A Siminovitch
  6. Arthritis Research UK Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK.

    • Stephen Eyre
    • , Anne Hinks
    • , Anne Barton
    • , John Bowes
    • , Edward Flynn
    • , Xiayi Ke
    • , Paul Martin
    • , Wendy Thomson
    •  & Jane Worthington
  7. Celera, Alameda, California, USA.

    • Yonghong Li
    • , Joseph J Catanese
    •  & Ann B Begovich
  8. Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Fina A S Kurreeman
    • , Tom W J Huizinga
    • , Annette H M van der Helm-van Mil
    •  & Rene E M Toes
  9. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Alexandra Zhernakova
    •  & Cisca Wijmenga
  10. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Lars Alfredsson
    •  & Bo Ding
  11. University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Christopher I Amos
  12. Department of Rheumatology and Clinical Immunology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Elisabeth Brouwer
    •  & Marcel D Posthumus
  13. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Marieke J H Coenen
  14. Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California at San Francisco, San Francisco, California, USA.

    • Lindsey A Criswell
  15. Laboratory of Immunogenetics, Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

    • J Bart A Crusius
  16. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Paul I W de Bakker
  17. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Philip L De Jager
  18. National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.

    • Paul Emery
    •  & Ann W Morgan
  19. University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford, UK.

    • Pille Harrison
    •  & B Paul Wordsworth
  20. Musculoskeletal and Genetics Section, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.

    • Lynne J Hocking
    •  & David M Reid
  21. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA.

    • Annette T Lee
    •  & Peter K Gregersen
  22. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.

    • Leonid Padyukov
    •  & Lars Klareskog
  23. Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Timothy R D J Radstake
    •  & Piet L C M van Riel
  24. Genome Institute of Singapore, Singapore.

    • Mark Seielstad
  25. Rowe Program in Genetics, University of California at Davis, Davis, California, USA.

    • Michael F Seldin
  26. Clinical and Academic Rheumatology, Kings College Hospital National Health Service Foundation Trust, Denmark Hill, London, UK.

    • Sophia Steer
  27. Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Paul P Tak
    •  & Niek de Vries
  28. Department of Rheumatology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.

    • Irene E van der Horst-Bruinsma
  29. Sanquin Research Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • C Ellen van der Schoot
    •  & Gert Jan Wolbink
  30. School of Medicine and Biomedical Sciences, Sheffield University, Sheffield, UK.

    • Anthony G Wilson
  31. Jan van Breemen Institute, Amsterdam, The Netherlands.

    • Gert Jan Wolbink
  32. Roche Diagnostics, Pleasanton, California, USA.

    • Ann B Begovich

Consortia

  1. BIRAC Consortium

    A full list of members is provided in the Supplementary Note.

  2. YEAR Consortium

    A full list of members is provided in the Supplementary Note.

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Contributions

Study design: R.M.P., S.R., E.A.S. Analysis: E.A.S. (lead), S.R., F.A.S.K., R.C. Sample procurement and data generation: J.W., K.A.S., P.K.G., L.K., N.A.S., M.E.W., C.W., M.J.H.C., N.d.V., P.P.T., E.W.K., R.E.M.T., T.W.J.H., A.B.B. (leads); E.F.R., G.X., S.E., B.P.T., Y.L., A.Z., A.H., C.G., L.A., C.I.A., K.G.A., A.B., J.B., E.B., N.P.B., J.J.C., J. Coblyn, K.H.C., L.A.C., J.B.A.C., J. Cui, P.I.W.d.B., P.L.D.J., B.D., P.E., E.F., P.H., L.J.H., D.L.K., X.K., A.T.L., X.L., P.M., A.W.M., L.P., M.D.P., T.R.D.J.R., D.M.R., M.S., M.F.S., S.S., W.T., A.H.M.v.d.H.-v.M., I.E.v.d.H.-B., C.E.v.d.S., P.L.C.M.v.R., A.G.W., G.J.W., B.P.W., BIRAC and YEAR consortia. Writing: R.M.P., E.A.S. (leads); S.R., F.A.S.K. (primary contributors); J.W., K.A.S., P.K.G., L.K., N.A.S., M.E.W., C.W., M.J.H.C., N.d.V., P.P.T., E.W.K., R.E.M.T., T.W.J.H., A.B.B., E.F.R., G.X., S.E., B.P.T., Y.L., A.Z., A.H., C.G., L.A., C.I.A., K.G.A., A.B., J.B., E.B., N.P.B., J.J.C., J. Coblyn, K.H.C., L.A.C., J.B.A.C., J. Cui, P.I.W.d.B., P.L.D.J., B.D., P.E., E.F., P.H., L.J.H., D.L.K., X.K., A.T.L., X.L., P.M., A.W.M., L.P., M.D.P., T.R.D.J.R., D.M.R., M.S., M.F.S., S.S., W.T., A.H.M.v.d.H.-v.M., I.E.v.d.H.-B., C.E.v.d.S., P.L.C.M.v.R., A.G.W., G.J.W., B.P.W.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert M Plenge.

Supplementary information

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    Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–7

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https://doi.org/10.1038/ng.582

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