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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  1. 1.

    et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

  2. 2.

    et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).

  3. 3.

    , & The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

  4. 4.

    et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

  5. 5.

    et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

  6. 6.

    et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).

  7. 7.

    et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).

  8. 8.

    et al. Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat. Genet. 40, 1224–1229 (2008).

  9. 9.

    et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat. Genet. 40, 1156–1159 (2008).

  10. 10.

    et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am. J. Hum. Genet. 81, 1284–1288 (2007).

  11. 11.

    et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77, 1044–1060 (2005).

  12. 12.

    Oxford Textbook of Rheumatology (Oxford University Press, Oxford, UK, and New York, 2004).

  13. 13.

    et al. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat. Genet. 41, 820–823 (2009).

  14. 14.

    Computational Text Analysis for Functional Genomics and Bioinformatics (Oxford University Press, Oxford, 2006).

  15. 15.

    et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

  16. 16.

    , & A general overview of Mantel-Haenszel methods: applications and recent developments. Annu. Rev. Public Health 9, 123–160 (1988).

  17. 17.

    et al. Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum. 38, 1832–1836 (1995).

  18. 18.

    et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

  19. 19.

    et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

  20. 20.

    et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

  21. 21.

    et al. The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans. J. Immunol. 166, 6144–6148 (2001).

  22. 22.

    et al. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nat. Genet. 29, 23–24 (2001).

  23. 23.

    et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat. Genet. 26, 495–499 (2000).

  24. 24.

    et al. Does 77C→G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nat. Genet. 29, 22–23 (2001).

  25. 25.

    et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

  26. 26.

    et al. The role of the CD58 locus in multiple sclerosis. Proc. Natl. Acad. Sci. USA 106, 5264–5269 (2009).

  27. 27.

    et al. Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians. Genes Immun. 9, 624–630 (2008).

  28. 28.

    , , & Association of CD2 and CD45 on human T lymphocytes. Nature 345, 71–74 (1990).

  29. 29.

    et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J. Biol. Chem. 271, 28745–28748 (1996).

  30. 30.

    Activation-dependent induction of Blimp-1. Curr. Opin. Immunol. 20, 259–264 (2008).

  31. 31.

    et al. The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28. Arthritis Res. Ther. 8, R57 (2006).

  32. 32.

    et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 41, 776–782 (2009).

  33. 33.

    et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

  34. 34.

    et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet. 40, 616–622 (2008).

  35. 35.

    et al. TRAF1–C5 as a risk locus for rheumatoid arthritis–a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).

  36. 36.

    et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann. Rheum. Dis. 64, 1199–1204 (2005).

  37. 37.

    et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pre-treatment TNFα expression in the synovium. Ann. Rheum. Dis. (2007).

  38. 38.

    et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 4, e278 (2007).

  39. 39.

    et al. Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. Arthritis Rheum. 52, 2948–2950 (2005).

  40. 40.

    et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 5, 911–916 (2006).

  41. 41.

    , , , & Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking. Arthritis Res. Ther. 10, R52 (2008).

  42. 42.

    , & High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res. 10, 258–266 (2000).

  43. 43.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

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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


  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


  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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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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