For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis)1,2,3. Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis4,5,6, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants7,8,9,10,11,12,13. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.

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We thank L. Hildyard, E. Gray and other members of the Wellcome Trust Sanger Institute DNA team for their help with sample coordination and A. Groff and C. Weiner for critical reading of the manuscript. This work was supported by NIHR Biomedical Research Centres in Cambridge and Guy's and St Thomas' (in particular, J. Todd and the NIHR Cambridge BRC Genomics Theme), Crohn's and Colitis UK (Medical Research Award M/14/2), the Evelyn Trust (17/07), and the Medical Research Council (programme grant MR/L019027/1). J.C.L. is supported by a Wellcome Trust Intermediate Clinical Fellowship (105920/Z/14/Z), and D.B. is supported by a Marie Curie PhD Fellowship (TranSVIR FP7-PEOPLE-ITN-2008 238756). N.J.P. is supported by a Wellcome Trust University Award (094491/Z/10/Z), and J.A.T. is supported by the European Research Council (695551). C.A.A. is supported by the Wellcome Trust (098051). K.G.C.S. is an NIHR Senior Investigator. This study makes use of data generated by the UK10K Consortium, derived from samples from the ALSPAC and DTR cohorts. A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust (WT091310).

Author information

Author notes

    • James C Lee
    •  & Daniele Biasci

    These authors contributed equally to this work.


  1. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
    • , Daniele Biasci
    • , Paul A Lyons
    • , Miles Parkes
    •  & Kenneth G C Smith
  2. Department of Medicine, University of Otago, Christchurch, New Zealand.

    • Rebecca Roberts
    •  & Richard B Gearry
  3. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

    • John C Mansfield
  4. University of Exeter Medical School, Exeter, UK.

    • Tariq Ahmad
  5. Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, London, UK.

    • Natalie J Prescott
  6. Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Jack Satsangi
  7. Paediatric Gastroenterology and Nutrition, Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Royal Hospital for Sick Children, Edinburgh, UK.

    • David C Wilson
  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

    • Luke Jostins
  9. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Carl A Anderson
  10. Department of Pathology, University of Cambridge, Cambridge, UK.

    • James A Traherne


  1. UK IBD Genetics Consortium

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


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The experiment was conceived by J.C.L., M.P., and K.G.C.S. J.C.L., D.B., and P.A.L. designed the analysis. D.B. performed the analysis with input from J.C.L., L.J., C.A.A., J.A.T., and P.A.L. Patient samples and phenotype data were provided by J.C.L., R.R., R.B.G., J.C.M., T.A., N.J.P., J.S., D.C.W., M.P., and other members of the UK IBD Genetics Consortium. J.C.L. and K.G.C.S. wrote the manuscript with input from D.B., P.A.L., and M.P. All authors reviewed and approved the manuscript prior to submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to James C Lee or Kenneth G C Smith.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1–6 and 9, and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 7

    SNPsea results for enrichment of prognosis-associated genes in known biological pathways (Gene Ontology).

  2. 2.

    Supplementary Table 8

    SNPsea results for enrichment of prognosis-associated genes in primary human cell types.

  3. 3.

    Supplementary Table 10

    Association statistics for 170 Crohn's disease susceptibility SNPs in GWAS of prognosis.

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