An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Chrissy Bolton; Christopher S Smillie; Sumeet Pandey; Rasa Elmentaite; Gabrielle Wei; Carmen Argmann; Dominik Aschenbrenner; Kylie R James; Dermot P B McGovern; Marina Macchi; Judy Cho; Dror S Shouval; Jochen Kammermeier; Sibylle Koletzko; Krithika Bagalopal; Melania Capitani; Athena Cavounidis; Elisabete Pires; Carl Weidinger; James McCullagh; Peter D Arkwright; Wolfram Haller; Britta Siegmund; Lauren Peters; Luke Jostins; Simon P L Travis; Carl A Anderson; Scott Snapper; Christoph Klein; Eric Schadt; Matthias Zilbauer; Ramnik Xavier; Sarah Teichmann; Aleixo M Muise; Aviv Regev; Holm H Uhlig

doi:10.1053/j.gastro.2021.11.014

An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Gastroenterology. 2022 Mar;162(3):859-876. doi: 10.1053/j.gastro.2021.11.014. Epub 2021 Nov 13.

Authors

Chrissy Bolton¹, Christopher S Smillie², Sumeet Pandey³, Rasa Elmentaite⁴, Gabrielle Wei⁵, Carmen Argmann⁵, Dominik Aschenbrenner³, Kylie R James⁶, Dermot P B McGovern⁷, Marina Macchi³, Judy Cho⁵, Dror S Shouval⁸, Jochen Kammermeier⁹, Sibylle Koletzko¹⁰, Krithika Bagalopal³, Melania Capitani³, Athena Cavounidis³, Elisabete Pires¹¹, Carl Weidinger¹², James McCullagh¹¹, Peter D Arkwright¹³, Wolfram Haller¹⁴, Britta Siegmund¹², Lauren Peters⁵, Luke Jostins¹⁵, Simon P L Travis¹⁶, Carl A Anderson⁴, Scott Snapper¹⁷, Christoph Klein¹⁸, Eric Schadt⁵, Matthias Zilbauer¹⁹, Ramnik Xavier²⁰, Sarah Teichmann²¹, Aleixo M Muise²², Aviv Regev²³, Holm H Uhlig²⁴

Affiliations

¹ Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Institute of Child Health, University College London, London, UK.
² Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
⁴ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, Australia.
⁷ F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁸ Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah-Tiqva, Israel, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁹ Gastroenterology Department, Evelina London Children's Hospital, London, UK.
¹⁰ Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany; Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.
¹¹ Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, UK.
¹² Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health Department of Gastroenterology, Rheumatology and Infectious Disease, Campus Benjamin Franklin, Berlin, Germany.
¹³ Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK.
¹⁴ Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham, UK.
¹⁵ The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹⁶ Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Biomedical Research Center, University of Oxford, Oxford, UK.
¹⁷ Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁸ Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.
¹⁹ Department of Paediatric Gastroenterology, Hepatology and Nutrition, Addenbrooke's Hospital, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
²⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
²¹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EBI), Wellcome Genome Campus, Hinxton UK.
²² Gastroenterology Division, The Hospital for Sick Children, Toronto, Ontario, Canada; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
²³ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
²⁴ Translational Gastroenterology Unit, University of Oxford, Oxford, UK; The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, United Kingdom. Electronic address: holm.uhlig@ndm.ox.ac.uk.

Abstract

Background & 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.

Methods: 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 individuals 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).

Results: 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⁺ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD.

Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.

Keywords: Genomics; Immunodeficiency; Next-Generation Sequencing; RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Age of Onset
Antiporters / genetics
Cells, Cultured
Classification
Gene Expression Profiling
Genetic Association Studies
Genotype
Glucose-6-Phosphatase / genetics
Glucose-6-Phosphate / metabolism
Humans
Inflammatory Bowel Diseases / classification*
Inflammatory Bowel Diseases / genetics*
Inflammatory Bowel Diseases / metabolism
Macrophages
Metabolomics
Monosaccharide Transport Proteins / genetics
Penetrance
Phenotype
Signal Transduction / genetics

Substances

Antiporters
Monosaccharide Transport Proteins
SLC37A4 protein, human
Glucose-6-Phosphate
Glucose-6-Phosphatase
G6PC3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding