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Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets

Genes & Immunity volume 20, pages 577–588 (2019)Cite this article

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Abstract

Genome-wide association studies have identified ~170 loci associated with Crohn’s disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.

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Acknowledgements

This work was supported by the HPC facilities operated by, and the staffs of, the Yale Center for Research Computing and the Yale Center for Genome Analysis, as well as NIH grant 1S10OD018521–01, which helped fund the cluster.

Funding

This study was supported by NIH research grants (R01 DK092235, U01 DK062429, U01 DK062422, R01 DK106593, and P30 DK078392), as well as the Crohn’s and Colitis Foundation, the Helmsley Charitable Trust, and the Sanford Grossman Charitable Trust.

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Authors and Affiliations

  1. Department of Genetics, Yale University, New Haven, Connecticut, 06510, USA

    Kyle Gettler

  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA

    Mamta Giri, Ephraim Kenigsberg, Jerome Martin, Ling-Shiang Chuang, Nai-Yun Hsu, Gabriel Hoffman & Judy H. Cho

  3. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Oio, USA

    Lee A. Denson

  4. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, Connecticut, USA

    Jeffrey S. Hyams

  5. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    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, Children’s Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ottawa, Ontario, Canada

    David R. Mack

  9. Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA

    Richard Kellermayer

  10. Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, 06510, USA

    Clara Abraham

  11. Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA

    Subra Kugathasan

  12. Children’s Healthcare of Atlanta, Atlanta, Georgia, USA

    Subra Kugathasan

  13. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA

    Judy H. Cho

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  1. Kyle Gettler
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Correspondence to Judy H. Cho.

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Gettler, K., Giri, M., Kenigsberg, E. et al. Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets. Genes Immun 20, 577–588 (2019). https://doi.org/10.1038/s41435-019-0059-y

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