Single-cell analysis of chromatin accessibility in the human intestine identifies regulatory programs and clarifies genetic associations in Crohn’s disease

Crohn’s disease is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial and environmental factors. Cell-type-specific contributions to Crohn’s disease etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type-resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from 23 patients with active and inactive Crohn’s disease and 16 healthy controls. We identified cell-type-specific, anatomical location-specific and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of patients with Crohn’s disease. These cell-type-resolved data confirmed that Crohn’s disease heritability is primarily enriched in adaptive immune cells, in particular T cells, and in innate immune cells, including neutrophils. Using fine-mapped, noncoding Crohn’s disease variants, we identified 30 variants located within cCREs. Our atlas provides a comprehensive resource to study gene-regulatory effects in Crohn’s disease and health and highlights the cellular complexity underlying Crohn’s disease risk. This study uses single-cell ATAC–seq to map chromatin accessibility in the intestinal mucosa from patients with Crohn’s disease and healthy controls to characterize regulatory programs associated with inflammation and genetic effects.