Cell-type-resolved genetic variation shapes inflammatory bowel disease risk

Article Cell-type-resolved genetic variation shapes inflammatory bowel disease risk https://doi.org/10.1038/s41586-026-10627-z Received: 24 June 2025 Accepted: 6 May 2026 Published online: xx xx xxxx Open access Check for updates Tobi Alegbe1,2,3,9, Bradley T. Harris1,9, Laura Fachal1, Lucia Ramirez-Navarro1, Marcus Tutert1, Monika Krzak1, Mennatallah Ghouraba1, Michelle Strickland1, Matiss Ozols1, Celeste E. Cohen1, Saniya Khullar1, Eleonora Khabirova1, Nikolaos I. Panousis4, David Ochoa2,3, Noor Wana1, May Xueqi Hu1, Jason Skelton1, Jasmin Ostermayer1, Kimberly Ai Xian Cheam1, D. Leland Taylor1, Yong Gu1, Claire Dawson5, Tina Thompson5, Kenneth Arestang5, Nilanga Nishad5, Biljana Brezina5, Charry Queen Caballes5, Wendy Garri5, Steven Leonard1, Vivek Iyer1, Miles Parkes5, Chris Wallace6,7, Rebecca E. McIntyre1, Cristina Cotobal Martin1, Gareth-Rhys Jones8, Tim Raine2,5,10 ✉ & Carl A. Anderson1,2,10 ✉ Most genetic variants associated with complex diseases lie in non-coding regions1, 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. Common complex diseases cause substantial morbidity and mortality worldwide, yet the biological mechanisms that underlie susceptibility remain incompletely understood. Genetic variation contributes considerably to disease susceptibility, and GWASs have identified hundreds of thousands of associations between genetic variants and complex diseases and traits2. However, more than 90% of GWAS signals map to non-coding regions of the genome1, complicating efforts to identify dysregulated genes, pathways and cell types. Non-coding variants are thought to influence disease risk by altering expression of nearby genes. This has prompted large-scale efforts to map cis-eQTLs and integrate them with GWAS findings. Although these studies have advanced our understanding of disease biology3–7, most GWAS loci remain unannotated. This lack of functional resolution poses a major challenge for therapeutic development, as drug targets supported by human genetic evidence are substantially more likely to progress successfully through clinical trials8–11. One possible explanation for this annotation gap is that eQTL and GWAS signals often have different genomic contexts: eQTLs are more frequently found in promoters, whereas GWAS signals are enriched in enhancers12. However, this divergence may reflect methodological biases in current eQTL discovery efforts, which often rely on low-resolution bulk RNA sequencing of heterogeneous tissues or coarsely sorted cell populations13–16. These approaches may favour detection of regulatory effects that are shared across multiple cell types, which are more likely to reside in promoters than enhancers17. Single-cell RNA sequencing (scRNA-seq) can capture gene expression variation at much higher cellular resolutions, enabling the identification of cell-type-specific eQTLs that may be inaccessible to bulk tissue studies7,18–23. However, it remains unclear to what extent eQTLs identified at different cellular resolutions improve effector gene nomination at GWAS loci. We hypothesized that GWAS signals would be preferentially enriched among cell-type-specific single-cell eQTLs (sc-eQTLs) as contextual restriction of their regulatory effects may mean they face weaker selective pressures. To test this, we established the IBDverse project, generating large-scale scRNA-seq datasets from blood and intestinal biopsies of the terminal ileum and rectum—the sites that are most commonly affected in Crohn’s disease (CD) and ulcerative colitis (UC), respectively. These diseases represent the two main forms of IBD, a debilitating group of gastrointestinal disorders affecting more than 4.9 million people worldwide. Using nearly 2.2 million single-cell transcriptomes from more than 400 individuals, including 125 with IBD, we comprehensively mapped eQTL effects across a broad range of cellular resolutions, from individual cell types to tissue-level groupings. Our analyses enabled the Wellcome Sanger Institute, Hinxton, UK. 2Open Targets, Hinxton, UK. 3EMBL-EBI, 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. 9These authors contributed equally: Tobi Alegbe, Bradley T. Harris. 10These authors jointly supervised this work: Tim Raine, Carl A Anderson. ✉e-mail: ; 1 Nature | www.nature.com | 1 Article nomination of candidate effector genes and cell types for more than half of the 321 known IBD loci, including 74 loci where an effector gene is nominated for the first time. Furthermore, we systematically quantified the contribution of eQTLs detected at different cellular resolutions to GWAS association signals, demonstrating that cell-type-level eQTLs are substantially enriched among IBD GWAS loci and preferentially reside in distinct genomic contexts compared to eQTLs detected across broader cell groupings. These findings highlight the power of single-cell resolution for interpreting complex disease genetics and provide a general framework for effector gene discovery across diverse diseases. A cellular atlas of intestine and blood To enable large-scale sc-eQTL mapping at sites relevant to IBD, we created IBDverse, comprising scRNA-seq data generated from 275 healthy rectal biopsies, 119 CD terminal ileal biopsies, 243 healthy terminal ileal biopsies and 95 blood samples from individuals with CD (Fig. 1a). After stringent quality control, we obtained more than 1.8 million high-quality cells, which we clustered into 86 transcriptionally distinct groups across 9 major cell populations (Supplementary Fig. 1 and Extended Data Fig. 1). Samples from all anatomical sites were analysed join (...truncated)