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Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

Nature Genetics volume 42, pages 123–127 (2010)Cite this article

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Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

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Figure 1: SNP association plots for ankylosing spondylitis–associated regions.

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Acknowledgements

We would like to thank all participants, with and without ankylosing spondylitis, who provided the case and control DNA and clinical information necessary for this study. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in subject recruitment. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole Avon Longitudinal Study of Parents And Children (ALSPAC) team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This study was funded by US 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 Award grant UL1RR024188, Cedars-Sinai General Clinical Research Center grant MO1-RR00425, Intramural Research Program of NIAMS/National Institutes of Health, and Rebecca Cooper Foundation (Australia). This study was funded in part by the Arthritis Research Campaign (UK), by the Wellcome Trust (grant number 076113) and by the Oxford Radcliffe Hospital Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme code A91202). M.A.B. is funded by the National Health and Medical Research Council (Australia). The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC.

Author information

Authors and Affiliations

  1. Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA

    John D Reveille, Rui Jin, Xiaodong Zhou & Laura Diekman

  2. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia

    Anne-Marie Sims, Patrick Danoy, Paul Leo, Linda A Bradbury, Tracey Doan, Alison Dowling, Ran Duan, Emma L Duncan, Johanna Hadler, Karena Pryce, Jacqueline Taylor, Evgeny Glazov, Gethin P Thomas & Matthew A Brown

  3. Department of Social Medicine, Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK

    David M Evans & Sue M Ring

  4. Nuffield Department of Orthopaedics, Botnar Research Centre, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    Jennifer J Pointon, Louise H Appleton, Claire Farrar, David Harvey, Tugce Karaderi, B Paul Wordsworth & Matthew A Brown

  5. University of California, San Francisco, San Francisco, California, USA

    John C Davis

  6. Royal National Hospital for Rheumatic Diseases National Health Service Foundation Trust and University of Bath, Bath, UK

    Rebecca Mogg, Emma Pomeroy & Millicent A Stone

  7. The Spondylitis Association of America, Sherman Oaks, California, USA

    Laurie Savage

  8. Wellcome Trust Sanger Institute, Cambridge, UK

    Panos Deloukas, Vasudev Kumanduri, Leena Peltonen & Pamela Whittaker

  9. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Walter P Maksymowych

  10. University of Toronto, Toronto, Ontario, Canada

    Robert D Inman & Millicent A Stone

  11. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Michael M Ward

  12. Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Michael H Weisman

Consortia

The Australo-Anglo-American Spondyloarthritis Consortium (TASC)

  • John D Reveille
  • , Anne-Marie Sims
  • , Patrick Danoy
  • , David M Evans
  • , Paul Leo
  • , Jennifer J Pointon
  • , Rui Jin
  • , Xiaodong Zhou
  • , Linda A Bradbury
  • , Louise H Appleton
  • , John C Davis
  • , Laura Diekman
  • , Tracey Doan
  • , Alison Dowling
  • , Ran Duan
  • , Emma L Duncan
  • , Claire Farrar
  • , Johanna Hadler
  • , David Harvey
  • , Tugce Karaderi
  • , Rebecca Mogg
  • , Emma Pomeroy
  • , Karena Pryce
  • , Jacqueline Taylor
  • , Laurie Savage
  • , Panos Deloukas
  • , Vasudev Kumanduri
  • , Leena Peltonen
  • , Sue M Ring
  • , Pamela Whittaker
  • , Evgeny Glazov
  • , Gethin P Thomas
  • , Walter P Maksymowych
  • , Robert D Inman
  • , Michael M Ward
  • , Millicent A Stone
  • , Michael H Weisman
  • , B Paul Wordsworth
  •  & Matthew A Brown

Contributions

Case assessment and recruitment: L.A.B., M.A.B., J.C.D., L.D., C.F., R.D.I., W.P.M., R.M., E.P., J.D.R., L.S., M.A.S., M.M.W., M.H.W. and B.P.W. Sample processing and genotyping: L.H.A., P.D., T.D., A.D., E.L.D., J.H., D.H., R.J., T.K., R.M., J.J.P., E.P., K.P., A.-M.S., J.T. and X.Z. Gene expression studies: R.D., E.G. and G.P.T. Data analysis: M.A.B., P.D., D.M.E. and P.L. Study design and management committee: M.A.B., J.D.R., M.M.W., M.H.W. and B.P.W. Manuscript preparation: M.A.B., D.M.E., P.L., J.D.R., M.A.S., M.H.W. and B.P.W. ALSPAC control data: P.D., V.K., L.P., S.M.R. and P.W.

Corresponding authors

Correspondence to John D Reveille or Matthew A Brown.

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Competing interests

M.A.B. is an employee of the University of Queensland, which has applied for patents relating to genes discovered in this study.

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Supplementary Figures 1–5 and Supplementary Tables 1–3 (PDF 731 kb)

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The Australo-Anglo-American Spondyloarthritis Consortium (TASC). Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42, 123–127 (2010). https://doi.org/10.1038/ng.513

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