Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
12 affiliations
- 1EMBL-EBI, Hinxton, UK
- 2Open Targets, Hinxton, UK
- 3Wellcome Sanger Institute, Hinxton, UK
- 4GlaxoSmithKline, Stevenage, UK
- 5Addenbrooke's Hospital, Cambridge, UK
- 6Department of Medicine, University of Cambridge, Cambridge, UK
- 7MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
- 8University of Edinburgh Centre for Inflammation Research, Queens Medical Research institute, Edinburgh, UK
- 9Addenbrooke's Hospital, Cambridge, UK. [email protected]
- 10Open Targets, Hinxton, UK. [email protected]
- 11Open Targets, Hinxton, UK. [email protected]
- 12Wellcome Sanger Institute, Hinxton, UK. [email protected]
Abstract
, complicating efforts to identify effector genes and relevant cell types. Here we map cis-expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2, PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC, in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
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BibTeX
@article{alegbe2026celltyperesolved,
title = {{Cell-type-resolved genetic variation shapes inflammatory bowel disease risk}},
author = {Tobi Alegbe and Bradley T. Harris and Laura Fachal and Lucia Ramirez-Navarro and Marcus Tutert and Monika Krzak and Mennatallah Ghouraba and Michelle Strickland and Matiss Ozols and Céleste E. Cohen and Saniya Khullar and Eleonora Khabirova and Nikolaos I. Panousis and David Ochoa and Noor Wana and Hu Xueqi May and Jason Skelton and Jasmin Ostermayer and Kimberly Ai Xian Cheam and Dennis Leland Taylor and Yong Gu and Claire Dawson and Tina Thompson and Kenneth Arestang and Nilanga Nishad and Biljana Brezina and Charry Queen Caballes and Wendy Garri and Leonard Steven and Vivek Iyer and Miles Parkes and Chris Wallace and Rebecca E. McIntyre and Cristina Cotobal and Gareth‐Rhys Jones and Tim Raine and Carl A. Anderson},
journal = {Nature},
year = {2026},
month = jun,
doi = {10.1038/s41586-026-10627-z},
url = {https://doi.org/10.1038/s41586-026-10627-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
AU - Tobi Alegbe
AU - Bradley T. Harris
AU - Laura Fachal
AU - Lucia Ramirez-Navarro
AU - Marcus Tutert
AU - Monika Krzak
AU - Mennatallah Ghouraba
AU - Michelle Strickland
AU - Matiss Ozols
AU - Céleste E. Cohen
AU - Saniya Khullar
AU - Eleonora Khabirova
AU - Nikolaos I. Panousis
AU - David Ochoa
AU - Noor Wana
AU - Hu Xueqi May
AU - Jason Skelton
AU - Jasmin Ostermayer
AU - Kimberly Ai Xian Cheam
AU - Dennis Leland Taylor
AU - Yong Gu
AU - Claire Dawson
AU - Tina Thompson
AU - Kenneth Arestang
AU - Nilanga Nishad
AU - Biljana Brezina
AU - Charry Queen Caballes
AU - Wendy Garri
AU - Leonard Steven
AU - Vivek Iyer
AU - Miles Parkes
AU - Chris Wallace
AU - Rebecca E. McIntyre
AU - Cristina Cotobal
AU - Gareth‐Rhys Jones
AU - Tim Raine
AU - Carl A. Anderson
PY - 2026
DA - 2026/06/03
JO - Nature
DO - 10.1038/s41586-026-10627-z
UR - https://doi.org/10.1038/s41586-026-10627-z
AB - , complicating efforts to identify effector genes and relevant cell types. Here we map cis-expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2, PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC, in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
SN - 0028-0836
SN - 1476-4687
ER -