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Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice

Genes & Immunity volume 21, pages 311–325 (2020)Cite this article

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Abstract

Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity, we utilized a panel of chromosome (Chr) substitution strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background, as well as their parental B6 and PWD strains. Two models of IBD were used, TNBS- and DSS-induced colitis. Compared with B6 mice, PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we identified several PWD-derived loci that exhibited profound effects on IBD susceptibility. The most pronounced of these were loci on Chr1 and Chr2, which yielded high susceptibility in both IBD models, each acting at distinct phases of the disease. Leveraging transcriptomic data from B6 and PWD immune cells, together with a machine learning approach incorporating human IBD genetic associations, we identified lead candidate genes, including Itga4, Pip4k2a, Lcn10, Lgmn, and Gpr65.

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Fig. 1: PWD mice are resistant to DSS-induced colitis.
Fig. 2: PWD mice are highly susceptible to TNBS-induced colitis.
Fig. 3: PWD loci regulate susceptibility to DSS-induced colitis.
Fig. 4: PWD loci regulate susceptibility to TNBS-induced colitis.
Fig. 5: B6.Chr12PWD mice are highly susceptible to DSS-induced colitis.
Fig. 6: Identification and prioritization of novel gene candidates associated with IBD susceptibility.

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Code availability

All R code used for the SVM analysis can be accessed at https://github.com/MahoneyLabGroup/IBD.

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Acknowledgements

This work was supported by the following grants: NIH/NINDS R01 NS097596, NIH/NIAID R21 AI145306, and VCIID COBRE Pilot Project award to D.N.K. (supported by NIH/NIGMS grant P30 GM118228; PI: Ralph Budd); NIH NLM R21 LM012615 to A.L.T. and J.M.M.; and N.I.H. DK113800 to G.M.M.

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Authors and Affiliations

  1. Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA

    Karolyn G. Lahue, Mahalia M. McGill & Dimitry N. Krementsov

  2. Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA

    Montana K. Lara, Alisha A. Linton, Brigitte Lavoie, Gary M. Mawe & J. Matthew Mahoney

  3. Department of Medicine, University of Vermont, Burlington, VT, 05405, USA

    Qian Fang & Cory Teuscher

  4. Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, 05405, USA

    Jessica W. Crothers & Cory Teuscher

  5. The Jackson Laboratory, 600 Main St., Bar Harbor, ME, 04609, USA

    Anna L. Tyler

  6. Department of Computer Science University of Vermont, Burlington, VT, 05405, USA

    J. Matthew Mahoney

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Lahue, K.G., Lara, M.K., Linton, A.A. et al. Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice. Genes Immun 21, 311–325 (2020). https://doi.org/10.1038/s41435-020-00110-8

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