Article | Published:

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Nature Genetics volume 43, pages 761767 (2011) | Download Citation

  • A Corrigendum to this article was published on 29 August 2011

This article has been updated


Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 11 August 2011

    In the version of this article initially published, the name of author Udo Oppermann was incorrectly spelled as Udo Opperman, and the name of author Loukas Moutsianas was incorrectly spelled as Loukas Moutsianis. The errors have been corrected in the HTML and PDF versions of the article.


  1. 1.

    et al. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand. J. Rheumatol. 37, 120–126 (2008).

  2. 2.

    et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 40, 1823–1828 (1997).

  3. 3.

    , , & Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 59, 883–886 (2000).

  4. 4.

    , , & Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheum. 26, 1460–1464 (1983).

  5. 5.

    , & The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Br. J. Rheumatol. 22, 18–19 (1983).

  6. 6.

    et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

  7. 7.

    Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  8. 8.

    et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PLoS Genet. 6, e1001195 (2010).

  9. 9.

    , & Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27, 361–368 (1984).

  10. 10.

    et al. Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes and Immunity 12, 319–320 (2011).

  11. 11.

    et al. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat. Immunol. 11, 257–264 (2010).

  12. 12.

    et al. Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. Am. J. Hum. Genet. 86, 88–92 (2010).

  13. 13.

    et al. Bayesian method for detecting and characterizing allelic heterogeneity and boosting signals in genome-wide association studies. Stat. Sci. 24, 430–450 (2009).

  14. 14.

    & Bayesian statistical methods for genetic association studies. Nat. Rev. Genet. 10, 681–690 (2009).

  15. 15.

    et al. Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism. Hum. Immunol. 66, 1057–1061 (2005).

  16. 16.

    et al. Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative Caucasian patients with ankylosing spondylitis. Hum. Immunol. 60, 83–86 (1999).

  17. 17.

    et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann. Rheum. Dis. 55, 268–270 (1996).

  18. 18.

    et al. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur. J. Immunol. 25, 3199–3201 (1995).

  19. 19.

    et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations. Tissue Antigens 45, 169–176 (1995).

  20. 20.

    et al. HLA Class I and II associations of ankylosing spondylitis. Arthritis Rheum. 60, S437 (2009).

  21. 21.

    et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol. 3, 1169–1176 (2002).

  22. 22.

    , , & The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl. Acad. Sci. USA 102, 17107–17112 (2005).

  23. 23.

    , , & Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J. Immunol. 171, 6814–6819 (2003).

  24. 24.

    , , & An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. J. Biol. Chem. 278, 28677–28685 (2003).

  25. 25.

    et al. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J. Clin. Invest. 110, 515–526 (2002).

  26. 26.

    , & A continuous fluorigenic assay for the measurement of the activity of endoplasmic reticulum aminopeptidase 1: competition kinetics as a tool for enzyme specificity investigation. Anal. Biochem. 395, 33–40 (2009).

  27. 27.

    et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).

  28. 28.

    The genetics and immunopathogenesis of inflammatory bowel disease. Nat. Rev. Immunol. 8, 458–466 (2008).

  29. 29.

    et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).

  30. 30.

    et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

  31. 31.

    et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

  32. 32.

    , & Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

  33. 33.

    et al. Endogenous PGE2 promotes the induction of human Th17 responses by fungal β-glucan. J. Leukoc. Biol. 88, 947–954 (2010).

  34. 34.

    et al. Fungal β-glucan triggers spondyloarthropathy and Crohn's disease in SKG mice. Arthritis Rheum. S1, 1446 (2010).

  35. 35.

    et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J. Exp. Med. 204, 41–47 (2007).

  36. 36.

    et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008).

  37. 37.

    Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. Hum. Genet. 40, 1–14 (1987).

  38. 38.

    Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46, 222–228 (1990).

  39. 39.

    et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

  40. 40.

    et al. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann. Rheum. Dis. 65, 775–780 (2006).

  41. 41.

    et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J. Rheumatol. 36, 801–808 (2009).

  42. 42.

    et al. The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD). Ann. Rheum. Dis. 69, 1243–1246 (2010).

  43. 43.

    et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

  44. 44.

    et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007).

  45. 45.

    et al. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum. Mol. Genet. 20, 345–353 (2011).

  46. 46.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  47. 47.

    , , & Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

  48. 48.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  49. 49.

    R Core Development Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2009).

  50. 50.

    , & lumi: a pipeline for processing Illumina microarray. Bioinformatics 24, 1547–1548 (2008).

  51. 51.

    et al. Analysis of gene expression data using BRB-array tools. Cancer Inform. 3, 11–17 (2007).

Download references


We would like to thank all participating subjects with ankylosing spondylitis and healthy individuals who provided the DNA and clinical information necessary for this study. The Wellcome Trust Case Control Consortium 2 project is funded by the Wellcome Trust (083948/Z/07/Z). We also thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. The TASC study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and R01-AR046208. Funding was also received from the University of Texas at Houston Clinical and Translational Science Awards grant UL1RR024188, Cedars-Sinai General Clinical Research Centre grant MO1-RR00425, Intramural Research Program, NIAMS/US National Institutes of Health and Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (grant number 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme code: A91202). The Spondyloarthritis Research Consortium of Canada (SPARCC) was funded by a National Research Initiative Award from the Arthritis Society (Canada). G.P.T. was funded by a Lions Medical Research Foundation fellowship. M.A.B. is funded by a National Health and Medical Research Council (Australia) Principal Research Fellowship, and support for this study was received from a National Health and Medical Research Council (Australia) program grant (566938) and project grant (569829) and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for subject recruitment was provided by the National Institute for Health Research (NIHR), Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research Network. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02, and we thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We would like to thank A. Mathieu (Cagliari University) and S. Brown (Cedars-Sinai Hospital) for providing samples. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust.

Author information

Author notes

    • David M Evans
    •  & Chris C A Spencer

    These authors contributed equally to this work.

    • Matthew A Brown
    •  & Peter Donnelly

    These authors jointly directed this work.


  1. Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • David M Evans
    • , Alexander Dilthey
    • , Matti Pirinen
    •  & Tetyana Zayats
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Chris C A Spencer
    • , Zhan Su
    • , Gavin Band
    • , Céline Bellenguez
    • , Colin Freeman
    • , Amy Strange
    • , Gilean McVean
    •  & Peter Donnelly
  3. National Institute for Health Research Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK.

    • Jennifer J Pointon
    • , David Harvey
    • , Louise Appleton
    • , Tom Wordsworth
    • , Tugce Karaderi
    • , Claire Farrar
    • , Paul Bowness
    •  & B Paul Wordsworth
  4. Structural Genomics Consortium, University of Oxford, Oxford, UK.

    • Grazyna Kochan
    •  & Udo Oppermann
  5. University of Bath, Bath, UK.

    • Millicent A Stone
  6. Department of Statistics, University of Oxford, Oxford, UK.

    • Loukas Moutsianas
  7. Department of Clinical Pharmacology, University of Oxford, Oxford, UK.

    • Stephen Leslie
  8. University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia.

    • Tony J Kenna
    • , Gethin P Thomas
    • , Linda A Bradbury
    • , Patrick Danoy
    •  & Matthew A Brown
  9. National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Michael M Ward
  10. Department of Medicine/Rheumatology, Cedars-Sinai Medical Centre, Los Angeles, California, USA.

    • Michael H Weisman
  11. University of Toronto, Toronto, Ontario, Canada.

    • Robert D Inman
    •  & Dafna Gladman
  12. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

    • Walter Maksymowych
  13. Memorial University, St. John's, Newfoundland, Canada.

    • Proton Rahman
  14. National Institute for Health Research (NIHR)–Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, UK.

    • Ann Morgan
    •  & Helena Marzo-Ortega
  15. Department of Rheumatology, Norfolk & Norwich University Hospital, Norfolk, UK.

    • Karl Gaffney
  16. Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.

    • J S Hill Gaston
  17. Repatriation General Hospital, Adelaide, Australia.

    • Malcolm Smith
  18. Serviço Especializado De Epidemiologia E Biologia Molecular, Hospital de Santo Espírito, Angra do Heroísmo, Terceira, The Azores, Portugal.

    • Jacome Bruges-Armas
    •  & Ana-Rita Couto
  19. Genetics and Arthritis Research Group, Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.

    • Jacome Bruges-Armas
  20. Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy.

    • Rosa Sorrentino
    •  & Fabiana Paladini
  21. Queensland Institute of Medical Research, Brisbane, Australia.

    • Manuel A Ferreira
  22. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University Hospital, Shanghai, China.

    • Huji Xu
    • , Yu Liu
    •  & Lei Jiang
  23. Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.

    • Carlos Lopez-Larrea
    • , Roberto Díaz-Peña
    • , Antonio López-Vázquez
    •  & Hannah Blackburn
  24. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Elvira Bramon
    • , Suzannah J Bumpstead
    • , Panos Deloukas
    • , Serge Dronov
    • , Sarah Edkins
    • , Matthew Gillman
    • , Emma Gray
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Sarah E Hunt
    • , Alagurevathi Jayakumar
    • , Cordelia Langford
    • , Jennifer Liddle
    • , Owen T McCann
    • , Leena Peltonen
    • , Simon C Potter
    • , Anna Rautanen
    • , Radhi Ravindrarajah
    • , Michelle Ricketts
    • , Matthew Waller
    • , Paul Weston
    • , Pamela Whittaker
    •  & Sara Widaa
  25. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia.

    • Jenefer M Blackwell
  26. Genetics and Infection Laboratory, Cambridge Institute of Medical Research, Addenbrooke's Hospital, Cambridge, UK.

    • Jenefer M Blackwell
  27. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  28. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  29. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, Wales.

    • Nicholas Craddock
  30. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  31. Centre for Gastroenterology, Bart's and the London School of Medicine and Dentistry, London, UK.

    • Janusz Jankowski
  32. Clinical Neurosciences, St. George's University of London, London, UK.

    • Hugh S Markus
  33. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Christopher G Mathew
    •  & Richard C Trembath
  34. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  35. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  36. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK.

    • Robert Plomin
  37. Department of Cardiovascular Science, University of Leicester, Glenfield General Hospital, Leicester, UK.

    • Nilesh Samani
  38. University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  39. Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

    • Ananth C Viswanathan
  40. Department of Genetics, University College London Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  41. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.

    • Nicholas W Wood
  42. Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • John D Reveille


  1. The Australo-Anglo-American Spondyloarthritis Consortium (TASC)

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

  2. the Wellcome Trust Case Control Consortium 2 (WTCCC2)

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

  3. Spondyloarthritis Research Consortium of Canada (SPARCC)


  1. Search for David M Evans in:

  2. Search for Chris C A Spencer in:

  3. Search for Jennifer J Pointon in:

  4. Search for Zhan Su in:

  5. Search for David Harvey in:

  6. Search for Grazyna Kochan in:

  7. Search for Udo Oppermann in:

  8. Search for Alexander Dilthey in:

  9. Search for Matti Pirinen in:

  10. Search for Millicent A Stone in:

  11. Search for Louise Appleton in:

  12. Search for Loukas Moutsianas in:

  13. Search for Stephen Leslie in:

  14. Search for Tom Wordsworth in:

  15. Search for Tony J Kenna in:

  16. Search for Tugce Karaderi in:

  17. Search for Gethin P Thomas in:

  18. Search for Michael M Ward in:

  19. Search for Michael H Weisman in:

  20. Search for Claire Farrar in:

  21. Search for Linda A Bradbury in:

  22. Search for Patrick Danoy in:

  23. Search for Robert D Inman in:

  24. Search for Walter Maksymowych in:

  25. Search for Dafna Gladman in:

  26. Search for Proton Rahman in:

  27. Search for Ann Morgan in:

  28. Search for Helena Marzo-Ortega in:

  29. Search for Paul Bowness in:

  30. Search for Karl Gaffney in:

  31. Search for J S Hill Gaston in:

  32. Search for Malcolm Smith in:

  33. Search for Jacome Bruges-Armas in:

  34. Search for Ana-Rita Couto in:

  35. Search for Rosa Sorrentino in:

  36. Search for Fabiana Paladini in:

  37. Search for Manuel A Ferreira in:

  38. Search for Huji Xu in:

  39. Search for Yu Liu in:

  40. Search for Lei Jiang in:

  41. Search for Carlos Lopez-Larrea in:

  42. Search for Roberto Díaz-Peña in:

  43. Search for Antonio López-Vázquez in:

  44. Search for Tetyana Zayats in:

  45. Search for Gavin Band in:

  46. Search for Céline Bellenguez in:

  47. Search for Hannah Blackburn in:

  48. Search for Jenefer M Blackwell in:

  49. Search for Elvira Bramon in:

  50. Search for Suzannah J Bumpstead in:

  51. Search for Juan P Casas in:

  52. Search for Aiden Corvin in:

  53. Search for Nicholas Craddock in:

  54. Search for Panos Deloukas in:

  55. Search for Serge Dronov in:

  56. Search for Audrey Duncanson in:

  57. Search for Sarah Edkins in:

  58. Search for Colin Freeman in:

  59. Search for Matthew Gillman in:

  60. Search for Emma Gray in:

  61. Search for Rhian Gwilliam in:

  62. Search for Naomi Hammond in:

  63. Search for Sarah E Hunt in:

  64. Search for Janusz Jankowski in:

  65. Search for Alagurevathi Jayakumar in:

  66. Search for Cordelia Langford in:

  67. Search for Jennifer Liddle in:

  68. Search for Hugh S Markus in:

  69. Search for Christopher G Mathew in:

  70. Search for Owen T McCann in:

  71. Search for Mark I McCarthy in:

  72. Search for Colin N A Palmer in:

  73. Search for Leena Peltonen in:

  74. Search for Robert Plomin in:

  75. Search for Simon C Potter in:

  76. Search for Anna Rautanen in:

  77. Search for Radhi Ravindrarajah in:

  78. Search for Michelle Ricketts in:

  79. Search for Nilesh Samani in:

  80. Search for Stephen J Sawcer in:

  81. Search for Amy Strange in:

  82. Search for Richard C Trembath in:

  83. Search for Ananth C Viswanathan in:

  84. Search for Matthew Waller in:

  85. Search for Paul Weston in:

  86. Search for Pamela Whittaker in:

  87. Search for Sara Widaa in:

  88. Search for Nicholas W Wood in:

  89. Search for Gilean McVean in:

  90. Search for John D Reveille in:

  91. Search for B Paul Wordsworth in:

  92. Search for Matthew A Brown in:

  93. Search for Peter Donnelly in:


M.A.B., L.A.B., C. Farrar, J.D.R., J.J.P., B.P.W., D.G., W.M. and P.R. oversaw cohort collection for the discovery and replication datasets. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.J.B., S.D., S.E., E.G., C.L. and L.P.) executed GWAS sample handling, genotyping and quality control. The WTCCC2 data and analysis group (A.S., C.C.A.S., G.B., C.B., C. Freeman and P. Donnelly), D.M.E. and M.A.B. performed statistical analyses. M.A.B., D.M.E., C.C.A.S. and P. Donnelly contributed to writing the manuscript. The WTCCC2 management committee (J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, P. Donnelly (chairperson), A. Duncanson, J.J., J.L., H.S.M., C.G.M., C.N.A.P., L.P., R.P., A.R., S.J.S., R.C.T., A.C.V. and N.W.W.) monitored the execution of the GWAS. D.H., G.K. and U.O. performed analyses of recombinant ERAP1 function. T.J.K. and G.P.T. performed gene expression, cell count and ERAP1 sheddase functional studies. Other authors contributed variously to sample collection and all other aspects of the study. All authors reviewed the final manuscript.

Competing interests

The University of Queensland has applied for patents relating to material presented in this manuscript in Australia, Europe and the United States.

Corresponding authors

Correspondence to Matthew A Brown or Peter Donnelly.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1–6.

About this article

Publication history





Further reading