Publication
An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease
Publisher:
Elsevier BV
Date:
03-2022
DOI:
10.1053/J.GASTRO.2021.11.014
Abstract: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of in idual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy in iduals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8 Our taxonomy integrates genetic, clinical and multi-omic data providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.