Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology1,2. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest2, we hypothesized that summation of risk-allele-associated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease3,4. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment.

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We are grateful to B. Zeng, D. Arafat, H. Somineni, S. Venkateswaran, and colleagues from the Gibson and Kugathasan laboratories for their support and helpful comments. We also would like to thank I. Mendizabal, J. Lachance and K. Jordan for comments on the manuscript. This research was supported by Project 3 (G.G., PI) of the NIH program project “Statistical and Quantitative Genetics” grant P01-GM0996568 (B. Weir, University of Washington, Director) as well as research grants from the Crohn's and Colitis Foundation of America (CCFA), New York, to the individual study institutions participating in the RISK study.

Author information

Author notes

    • Subra Kugathasan
    •  & Greg Gibson

    These authors jointly directed this work.


  1. Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, Georgia, USA.

    • Urko M Marigorta
    •  & Greg Gibson
  2. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Lee A Denson
  3. Division of Digestive Diseases, Hepatology and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut, USA.

    • Jeffrey S Hyams
  4. Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Kajari Mondal
    • , Jarod Prince
    •  & Subra Kugathasan
  5. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Thomas D Walters
    •  & Anne Griffiths
  6. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

    • Joshua D Noe
  7. Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio, USA.

    • Wallace V Crandall
  8. Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA.

    • Joel R Rosh
  9. Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ottawa, Ontario, Canada.

    • David R Mack
  10. Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.

    • Richard Kellermayer
  11. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.

    • Melvin B Heyman
  12. Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, New York, USA.

    • Susan S Baker
  13. Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.

    • Michael C Stephens
  14. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Robert N Baldassano
  15. Department of Pediatrics, Northwell Health, New York, New York, USA.

    • James F Markowitz
  16. Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Mi-Ok Kim
  17. Department of Pediatrics, Mount Sinai Hospital, New York, New York, USA.

    • Marla C Dubinsky
    •  & Judy Cho
  18. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Bruce J Aronow


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U.M.M. and G.G. conceived the theoretical framework for the TRSs. L.A.D., J.S.H. and S.K. participated in the conception and design of the RISK study. K.M., J.P., T.D.W., A.G., J.D.N., W.V.C., J.R.R., D.R.M., R.K., M.B.H., S.S.B., M.C.S., R.N.B., J.F.M., M.C.D., B.J.A., M.-O. K. and J.C. recruited subjects, collected the data, and worked on its curation and analysis. U.M.M. performed the TRS analyses. U.M.M. and G.G. interpreted the results and drafted the manuscript, while L.A.D., J.S.H. and S.K. assisted with results interpretation and writing.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Greg Gibson.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    eQTL association data in peripheral blood for 232 SNPs associated with IBD with genes <1 Mb away (7,389 SNP–gene pairs).

  2. 2.

    Supplementary Table 2

    Replicability of blood eQTL effects in ileal tissue from the RISK study.

  3. 3.

    Supplementary Table 3

    coloc results for 163 SNP–gene pairs selected from the Blood eQTL browser.

  4. 4.

    Supplementary Table 4

    SMR results for 163 SNP–gene pairs selected from the Blood eQTL browser.

  5. 5.

    Supplementary Table 5

    eQTL association and coloc results for 46 genes controlled by SNPs associated with IBD in the RISK ileal eQTL mapping study.

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