Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
- Tobi Alegbe
- Bradley T. Harris
- Laura Fachal
- Lucia Ramirez-Navarro
- Marcus Tutert
- Monika Krzak
- Mennatallah Ghouraba
- Michelle Strickland
- Matiss Ozols
- Celeste E. Cohen
- Saniya Khullar
- Eleonora Khabirova
- Nikolaos I. Panousis
- David Ochoa
- Noor Wana
- May Xueqi Hu
- Jason Skelton
- Jasmin Ostermayer
- Kimberly Ai Xian Cheam
- D. Leland Taylor
- Yong Gu
- Claire Dawson
- Tina Thompson
- Kenneth Arestang
- Nilanga Nishad
- Biljana Brezina
- Charry Queen Caballes
- Wendy Garri
- Steven Leonard
- Vivek Iyer
- Miles Parkes
- Chris Wallace
- Rebecca E. McIntyre
- Cristina Cotobal Martin
- Gareth-Rhys Jones
- Tim Raine
- Carl A. Anderson
2026-06-03
Most genetic variants associated with complex diseases lie in non-coding regions 1 , 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.