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Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

Nature Genetics volume 45, pages 664–669 (2013)Cite this article

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Abstract

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor–negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10−8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10−6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10−6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

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Figure 1: Manhattan plot of association statistics for oligoarticular and RF-negative polyarticular juvenile idiopathic arthritis risk loci.
Figure 2: Association results for the HLA region (chromosome 6, 25–34 Mb).

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Acknowledgements

We thank P. Gilbert for preparing UK JIA case samples for genotyping and M. Ryan for preparing US JIA case samples and the Cincinnati local control samples. Genotyping of the US JIA, German JIA and respective control collections was supported by US National Institutes of Health (NIH) grants RC1-AR-058587 and U01-AI-067150S1. In addition, subject recruitment and DNA preparation in the United States was largely funded by US NIH grants N01-AR-42272, P01-AR-048929 and P30-AR-473639, with contributions from the Arthritis Foundation, The Val A. Browning Charitable Foundation in Salt Lake City, Utah, and the Marcus Foundation, Inc., in Atlanta, Georgia, as well as US NIH grants K23-AR-50177 and R01-AR-060893. The Federal Ministry of Education and Research, Germany (BMBF grants 01GM0907 and 01 ZZ 0403) supported subject recruitment and sample preparation in Germany. Genotyping of the UK JIA case samples was supported by Arthritis Research UK (grant 17552). Sparks Childhood Arthritis Response to Medication Study was funded by Sparks, UK (08ICH09) and the Big Lottery Fund, UK (RG/1/010135231). The study is on the UK Medicines for Children Research Network (MCRN) portfolio. We acknowledge support from the Wake Forest School of Medicine Center for Public Health Genomics and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; R01-AR-057106) for computing resources and data analysis.

Control sample recruitment and genotyping originating at the Oklahoma Medical Research Foundation (OMRF) was supported in part by NIH grants N01-AR-62277, P30-GM-103510, U19-AI-082714 and P30-AR-053483 from NIAMS, the National Institute of General Medicine Sciences (NIGMS) and the National Institute of Allergy and Infectious Diseases (NIAID). The contents are solely the responsibility of the authors and do not necessarily represent the official views of these institutes or the US NIH.

We thank J. Barrett and C. Wallace for the SNP selection. We thank the Wellcome Trust Sanger Institute Genotyping Facility and, in particular, E. Gray, S. Bumpstead, D. Simpkin and H. Blackburn for typing the UK samples. We acknowledge use of DNA from the UK Blood Services collection of common controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by a National Institute for Health Research program grant to National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort Collection, which is funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/01. Genotyping of control samples was supported, in part, by grants from Juvenile Diabetes Research Foundation International (JDRF) and the US NIH (U01 DK062418).

We thank P.K. Gregersen at the Feinstein Institute for providing US control genotyping from the Genotype and Phenotype Registry supported by US NIH grant RC2AR059092. We thank the National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease (NIDDK IBD) Genetics Consortium for providing North American control genotyping supported by US NIH grants DK062431, DK062422, DK062420, DK062432, DK062423, DK062413 and DK062429.

We gratefully acknowledge contributions from physicians at CCHMC and collaborating clinics. We also acknowledge the assistance of S. Kramer, B. Clifford and L. Ponder in subject recruitment and coordination of clinical information at Cincinnati Children's Hospital Medical Center, the University of Utah and Emory University, respectively. The Cincinnati normal control DNA collection was supported and made available by Cincinnati Children's Hospital Medical Center.

Author information

Author notes

  1. Anne Hinks, Joanna Cobb, Miranda C Marion and Johannes Peter Haas: These authors contributed equally to this work.

  2. Wendy Thomson and Susan D Thompson: These authors jointly directed this work.

Authors and Affiliations

  1. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

    Anne Hinks, Joanna Cobb, John Bowes, Paul Martin, Stephen Eyre, Kathryn J A Steel & Wendy Thomson

  2. National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    Anne Hinks, Joanna Cobb, John Bowes, Paul Martin, Stephen Eyre, Kathryn J A Steel & Wendy Thomson

  3. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

    Miranda C Marion, Mary E Comeau, Satria Sajuthi & Carl D Langefeld

  4. Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

    Miranda C Marion, Mary E Comeau, Satria Sajuthi & Carl D Langefeld

  5. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

    Sampath Prahalad & Milton Brown

  6. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA

    Sampath Prahalad

  7. Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Marc Sudman, Mitchell L Onslow, David N Glass & Susan D Thompson

  8. The Wellcome Trust Sanger Institute, Cambridge, UK

    Robert Andrews, Panos Deloukas, Sarah Edkins & Sarah E Hunt

  9. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA

    Wei-Min Chen, Patrick Concannon, Suna Onengut-Gumuscu & Stephen S Rich

  10. Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

    Patrick M Gaffney, Joel M Guthridge, Judith A James & Kathy L Moser

  11. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Stephen L Guthery & John F Bohnsack

  12. School of Medicine, University of Utah, Salt Lake City, Utah, USA

    Stephen L Guthery & John F Bohnsack

  13. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Mehdi Keddache

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

    Peter A Nigrovic & Carlos D Rosé

  15. Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA

    Peter A Nigrovic & Carlos D Rosé

  16. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Edward K Wakeland

  17. Department of Pediatrics, Seattle Children's Hospital and Research Institute, Seattle, Washington, USA

    Carol A Wallace

  18. Rheumatology Unit, UCL Institute of Child Health, London, UK

    Lucy R Wedderburn

  19. Division of Infection and Immunity, University College London, London, UK

    Patricia Woo

  20. German Centre for Rheumatology in Children and Young People, Garmisch-Partenkirchen, Germany

    Johannes Peter Haas

Authors
  1. Anne Hinks
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  2. Joanna Cobb
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  3. Miranda C Marion
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  4. Sampath Prahalad
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  5. Marc Sudman
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  6. John Bowes
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  7. Paul Martin
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  8. Mary E Comeau
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  9. Satria Sajuthi
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  10. Robert Andrews
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  36. David N Glass
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  37. Carl D Langefeld
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  39. Susan D Thompson
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Consortia

Boston Children's JIA Registry

British Society of Paediatric and Adolescent Rheumatology (BSPAR) Study Group

Childhood Arthritis Prospective Study (CAPS)

Childhood Arthritis Response to Medication Study (CHARMS)

German Society for Pediatric Rheumatology (GKJR)

JIA Gene Expression Study

NIAMS JIA Genetic Registry

TREAT Study

United Kingdom Juvenile Idiopathic Arthritis Genetics Consortium (UKJIAGC)

Contributions

S.D.T., W.T., C.D.L., S.P., M.C.M., J.C. and A.H. led the study. A.H., J.C., M.C.M., C.D.L., S.P., W.T. and S.D.T. wrote the manuscript. A.H., J.C., C.D.L., M.C.M., M.S., S.P., J.B., M.E.C. and S.S. performed the data and statistical analyses. A.H. and P.M. performed the bioinformatics analysis. D.N.G., J.P.H., J.F.B., R.A., M.B., W.-M.C., P.C., P.D., S. Edkins, S. Eyre, P.M.G., S.L.G., J.M.G., S.E.H., J.A.J., M.K., K.L.M., P.A.N., S.O.-G., M.L.O., C.D.R., S.S.R., K.J.A.S., E.K.W., C.A.W., L.R.W. and P.W. contributed primarily to subject ascertainment, sample collection and/or genotyping. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Anne Hinks.

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The authors declare no competing financial interests.

Additional information

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

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Supplementary Note, Supplementary Tables 1–8 and Supplementary Figures 1–4 (PDF 3217 kb)

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Hinks, A., Cobb, J., Marion, M. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 45, 664–669 (2013). https://doi.org/10.1038/ng.2614

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