Pathway paradigms revealed from the genetics of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune–microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

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Fig. 1: Strategies in human genetics and functional genomics to dissect mechanisms of disease.
Fig. 2: IBD genes and pathways controlling mucosal immunity.
Fig. 3: Pathway paradigms highlighted by IBD genetics.
Fig. 4: Coding variants associated with a phenotypic spectrum across different diseases.

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Acknowledgements

This work is supported by grants from the Helmsley Charitable Trust and NIH (to R.J.X.). We thank H. Kang for valuable scientific input, editorial assistance and illustrative design.

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D.B.G. and R.J.X. conceived and wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Daniel B. Graham or Ramnik J. Xavier.

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Graham, D.B., Xavier, R.J. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539 (2020). https://doi.org/10.1038/s41586-020-2025-2

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