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

Most genetic variants associated with complex diseases lie in non-coding regions, complicating efforts to identify effector genes and relevant cell types. Here, we map cis-eQTLs across 2.2 million single cells from blood and intestinal biopsies of 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 over two-fold more likely to colocalise with IBD GWAS loci than eQTLs detected at tissue-level resolution. We nominate effector genes at over half of known IBD loci, including , and in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt regulated genes, including , in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map linking genetic risk to specific genes and cell types in IBD, and a framework for effector gene discovery in complex disease.