An integrated taxonomy for monogenic inflammatory bowel disease

Research output: Contribution to journalArticlepeer-review


Background and aims: Monogenic forms of inflammatory bowel disease (IBD)
illustrate the essential roles of individual genes in pathways and networks
safeguarding immune tolerance and gut homeostasis. A comprehensive
taxonomy of monogenic IBD utilizing a quantitative framework of clinical and
systems biology data is required.
Methods: To generate a model, 137 monogenic disorders associated with IBD
were assessed, stratified by penetrance and disease phenotypes were
integrated with multi-omics datasets for 82 highly-penetrant genes. We
integrate: (1) overlapping syndromic features; (2) response to hematopoietic
stem cell transplantation; (3) bulk RNA-seq across tissues and single-cell RNAseq of >50 cell subsets from the intestine of healthy individuals, paediatric and
adult IBD patients, and (4) proteomes across 43 immune subsets. We validate
the robustness of the classification against 28 newly-identified gene defects and
treatment responses. As a proof of concept, we explore the intersection between
immunometabolism and antimicrobial activity for a group of defects
Results: Our integrated taxonomy defines the diverse cellular landscape of
monogenic IBD gene expression across 103 disorders with high and moderate
penetrance. We confirm known cellular networks and highlight expression
profiles across understudied cell types (such as CD8+ T cells, neutrophils and
endothelial cells), define genotype-phenotype associations (perianal disease
and defective antimicrobial activity), implicate pathways that are shared across
syndromic groups and highlight cellular immunometabolism with mTOR
activation as a key converging pathway. The overlap of genes and enriched cellspecific expression between monogenic and polygenic IBD suggests our
approach is relevant beyond rare disease genetics.
Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data and
provides testable hypotheses for disease functions and treatment responses.
Original languageEnglish
Publication statusAccepted/In press - 8 Nov 2021


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