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

Abstract

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 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 linking genetic risk to specific genes and cell types in IBD, and a framework for effector gene discovery in complex disease.