A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.

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We acknowledge P. Chinnasamy for backcrossing of Aif1−/− mice; E. Esplugues; K. Saulnier from Charles River Laboratories; S. Graham, J. Mena, and G. Lyng from Biomodels; K. Amin from Qiagen; E. Venturini and the New York Genome Center; M. Mahajan, Y. Kasai, and the Genome Core at Mount Sinai; H. Thomas; R. Ng; the Pathology Department and the Histology core at MSH; and Sinai Innovations. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. This work was funded by the Schadt laboratory at the Icahn Institute for Genomics and Multi-scale Biology, Icahn School of Medicine at Mount Sinai (NewYork). This work was partially funded by NIH/NIA grant R01AG046170 (to E.E.S. and B.Z.), a component of the AMP-AD Target Discovery and Preclinical Validation Project, the Rheumatology Research Foundation (to T.K.T.), the Leading Advanced Projects for Medical Innovation (LEAP; to Y.F.) from the Japan Agency for Medical Research and Development (AMED), U01HG008451 (to J.Z.), NIH R01HL128066 (to N.S.), and RO1 AI092093 and R21 AI109020 (to B.M.I.).

Author information


  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Lauren A Peters
    • , Won-min Song
    • , Sean R Llewellyn
    • , Antonio Di Narzo
    • , Brian A Kidd
    • , Yongzhong Zhao
    • , Khader Shameer
    • , Riccardo Miotto
    • , Bojan Losic
    • , Eunjee Lee
    • , Minghui Wang
    • , Jeremiah J Faith
    • , Andrew Kasarskis
    • , Carmen Argmann
    • , Ke Hao
    • , Panos Roussos
    • , Jun Zhu
    • , Bin Zhang
    •  & Eric E Schadt
  2. Icahn Institute of Genomics and Multi-scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Lauren A Peters
    • , Won-min Song
    • , Sean R Llewellyn
    • , Antonio Di Narzo
    • , Brian A Kidd
    • , Yongzhong Zhao
    • , Khader Shameer
    • , Riccardo Miotto
    • , Bojan Losic
    • , Hardik Shah
    • , Eunjee Lee
    • , Minghui Wang
    • , Jeremiah J Faith
    • , Andrew Kasarskis
    • , Carmen Argmann
    • , Ke Hao
    • , Panos Roussos
    • , Jun Zhu
    • , Bin Zhang
    •  & Eric E Schadt
  3. Sema4, a Mount Sinai venture, Stamford, Connecticut, USA.

    • Lauren A Peters
    • , Jun Zhu
    •  & Eric E Schadt
  4. Janssen Research and Development, LLC., Spring House, Pennsylvania, USA.

    • Jacqueline Perrigoue
    • , Eric M Neiman
    • , Shannon E Telesco
    • , Aleksandar Stojmirovic
    • , Jocelyn Sendecki
    • , Carrie Brodmerkel
    • , Mark Curran
    • , Anuk Das
    • , Joshua R Friedman
    •  & Radu Dobrin
  5. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

    • Arthur Mortha
  6. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Arthur Mortha
  7. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.

    • Alina Iuga
  8. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Sean R Llewellyn
  9. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Sean R Llewellyn
    • , Jeremiah J Faith
    •  & Lloyd F Mayer
  10. Institute for Next-Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Riccardo Miotto
  11. Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

    • Yoshinori Fukui
  12. University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Mary Beth Humphrey
  13. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.

    • Brian M Iritani
  14. Department of Medicine (Cardiovascular Division), Albert Einstein College of Medicine, Bronx, New York, USA.

    • Nicholas Sibinga
  15. Thurston Arthritis Research Center and Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Teresa K Tarrant
  16. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Teresa K Tarrant
  17. Bristol-Myers Squibb, Research & Development, Pennington, New Jersey, USA.

    • Radu Dobrin
  18. Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Lloyd F Mayer


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L.A.P. and E.E.S. conceived of, designed, managed, and performed all analysis in the study. J.P. and E.M.N. performed macrophage knockdown experiments. W.-m.S. performed network enrichments. A.M. performed flow cytometry. A.I. performed histological scoring of mouse tissue, and S.R.L. and L.A.P. performed adoptive T cell transfer colitis experiments. L.A.P. designed and managed DSS experiments, A.D.N. and K.H. performed polygenic risk score and variant calling, A.D.N., K.H., and P.R. performed CRE SNP enrichments, B.A.K. generated differential expression signatures, Y.Z. generated clinical correlations, A.S. performed cell enrichments, J.S., S.E.T., W.-m.S., and Y.Z. performed statistical analysis on macrophage experiments, K.S., R.M., P.R., and L.A.P. constructed the eQTL database, B.L. and H.S. performed RNA-seq analysis, E.L. performed transcription factor analysis, M.W. and C.A. provided visualization tools, C.B., M.C., A.D., J.R.F., J.P., and L.F.M. provided patient population guidance, Y.F., M.B.H., B.M.I., N.S., and T.K.T. provided reagents and guidance, A.K., C.A., and J.J.F. provided project support, J.Z. constructed Bayesian networks, B.Z. constructed coexpression networks, and L.A.P. and E.E.S. wrote the manuscript. C.A., B.Z., J.P., J.R.F., and R.D. provided critical review of the manuscript.

Competing interests

J.P., E.M.N., A.S., J.S., S.E.T., C.B., M.C., A.D., J.R.F., and R.D. were employees of Janssen during the time this work was completed.

Corresponding author

Correspondence to Eric E Schadt.

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