Abstract

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls1. We used Gene Relationships Across Implicated Loci (GRAIL)2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3,4,5,6,7,8,9,10,11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 × 10−6 replication, P = 1 × 10−9 overall), CD28 (rs1980422, P = 5 × 10−6 replication, P = 1 × 10−9 overall) and PRDM1 (rs548234, P = 1 × 10−5 replication, P = 2 × 10−8 overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 × 10−7 overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 × 10−7 overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 × 10−6 overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 × 10−5 overall). Many of these loci are also associated to other immunologic diseases.

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Acknowledgements

S.R. is supported by a US National Institutes of Health (NIH) Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. R.M.P. is supported by a K08 grant from the NIH (AI55314-3), 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 holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M.J.D. is supported by NIH grants through the U01 (HG004171, DK62432) and R01 (DK083756-1, DK64869) mechanisms. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. The North American Rheumatoid Arthritis Consortium (NARAC) is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH. This research was also supported in part by grants to KAS from the Canadian Institutes for Health Research (MOP79321 and IIN - 84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. We acknowledge the help of C.E. van der Schoot for healthy control samples for the Genetics Network Rheumatology Amsterdam (GENRA) and the help of B.A.C. Dijkmans, D. van Schaardenburg, A.S. Peña, P.L. Klarenbeek, Z. Zhang, M.T. Nurmohammed, 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 GENRA patient 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 NIH and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank the Johanna Seddon Progression of AMD Study, 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

Affiliations

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

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

    • Soumya Raychaudhuri
    • , Brian P Thomson
    • , Candace Guiducci
    • , Kristin G Ardlie
    • , Noel P Burtt
    • , Phillip L De Jager
    • , David Altshuler
    • , Mark J Daly
    •  & Robert M Plenge
  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
    • , David Altshuler
    •  & Mark J Daly
  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. Arthritis Research Campaign (arc)–Epidemiology Unit, The University of Manchester, Manchester, United Kingdom.

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

    • Joseph J Catanese
    • , Monica Chang
    • , Yonghong Li
    •  & Ann B Begovich
  7. Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada.

    • Gang Xie
    • , Xiangdong Liu
    •  & Katherine A Siminovitch
  8. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

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

    • Christopher I Amos
  10. Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, California, USA.

    • Lindsey A Criswell
  11. Laboratory of Immunogenetics, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.

    • J Bart A Crusius
  12. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Phillip L De Jager
  13. National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.

    • Paul Emery
    •  & Ann W Morgan
  14. University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford, United Kingdom.

    • Pille Harrison
    •  & Paul Wordsworth
  15. Musculoskeletal and Genetics Section, Division of Applied Medicine, University of Aberdeen, United Kingdom.

    • Lynne J Hocking
    •  & David M Reid
  16. Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Tom W J Huizinga
    • , Fina A S Kurreeman
    • , Annette H M van der Helm-van Mil
    •  & Rene E M Toes
  17. The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.

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

    • Leonid Padyukov
    •  & Lars Klareskog
  19. Genome Institute of Singapore, Singapore.

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

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

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

    • Paul P Tak
    •  & Niek de Vries
  23. Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.

    • Irene E van der Horst-Bruinsma
  24. School of Medicine and Biomedical Sciences, Sheffield University, Sheffield, United Kingdom.

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

    • Gert Jan Wolbink
  26. Sanquin Research Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Gert Jan Wolbink
  27. 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

S.R., M.J.D., D.A. and R.M.P. designed the study, conducted the statistical analysis, interpreted the primary data and wrote the initial manuscript. All authors contributed to the final manuscript. B.P.T., E.F.R., S.E., A.H., C.G., J.J.C., G.X., E.A.S., R.C., N.P.B. and M.S. were involved directly in genotyping samples or extracting genotypes for this study. The BRASS genetic study was coordinated by E.A.S., P.L.d.J., J.C., S.R. and R.M.P. under the direction of M.E.W. and N.A.S. The CANADA genetic study was coordinated by C.I.A., X.L. and G.X. under the direction of K.A.S. The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) genetic study was coordinated by L.A., B.D., L.P. and M.S. under the direction of L.K. The Genomics Collaborative Initiative (GCI) genetic study was coordinated by K.G.A., J.J.C., M.C. and Y.L. under the direction of A.B.B. The GENRA genetic study was coordinated by J.B.A.C., P.P.T., I.E.v.d.H.-B. and G.J.W. under the direction of N.d.V. The Leiden University Medical Center (LUMC) genetic study was coordinated by T.W.J.H., F.A.S.K., Y.L. and A.H.M.v.d.H.-v.M. under the direction of R.E.M.T. The NARAC genetic study was coordinated by E.F.R., C.I.A., M.C., L.A.C., D.L.K., A.T.L. and M.F.S. under the direction of P.K.G. The NHS genetic study was coordinated by K.H.C. and J.C. under the direction of E.W.K. The UK Rheumatoid Arthritis Genetics (UKRAG) genetic study was coordinated by S.E., B.I.R.A.C., A.B., J.B., P.E., E.F., P.H., A.H., L.J.H., X.K., P.M., A.W.M., D.M.R., S.S., W.T., A.G.W., P.W. and Y.E.A.R. under the direction of J.W.

Corresponding authors

Correspondence to Soumya Raychaudhuri or Robert M Plenge.

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    Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–5.

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DOI

https://doi.org/10.1038/ng.479

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