Single-Cell Mapping Study Pinpoints the Genetic and Cellular Drivers of Inflammatory Bowel Disease

Scientists at the Wellcome Sanger Institute, Open Targets, and Cambridge University Hospitals NHS Foundation Trust have created the most detailed single-cell map to date showing how genetic variation drives inflammatory bowel disease. The findings, published in Nature, identify specific genes and cell types responsible for IBD risk and demonstrate how single-cell approaches can unlock the biology of complex human diseases.

IBD, which includes Crohn's disease and ulcerative colitis,  affects over 4.9 million people worldwide and is characterized by chronic inflammation of the gastrointestinal tract. While inherited DNA changes are known to play a major role in IBD susceptibility, translating that knowledge into biological understanding has been difficult. More than 90% of DNA changes linked to IBD lie outside protein-coding regions of the genome, meaning they influence disease by altering how strongly genes are switched on or off. Identifying which genes and cell types are affected has been a persistent challenge, largely because most cellular studies analyze whole tissue samples that blend many cell types together, masking effects that only occur in specific cells. 

To address this, the team collected blood and gut samples from just over 400 individuals, including 125 people with Crohn's disease. Using single-cell RNA sequencing, they generated "IBDverse"—the largest single-cell dataset from gut tissue and blood in Crohn's disease and healthy patients—containing gene expression data from roughly 2.2 million individual cells. They then linked inherited genetic differences to changes in gene expression and compared these to known IBD risk regions.

Many genetic effects linked to IBD only appeared in specific cell types and were missed when studying whole tissue. The team identified likely effector genes at more than half of known IBD-associated genetic regions. A notable cluster of genetic effects occurred in dendritic cells, resulting in reduced Notch signaling,  a pathway involved in regulating immune responses in the gut. Additional effects were found in epithelial cells, where dysregulation of Wnt-regulated genes reduced tissue renewal, potentially weakening the gut lining and contributing to IBD susceptibility.

"To our surprise, many of the newly nominated effector genes regulate pathways that were previously underappreciated in the context of IBD risk," said co-first author Bradley Harris. "This work really helps us understand the overall picture of what molecular changes cause IBD, and in which cell types and tissues."

The study also carries broader implications. Among the identified genes, researchers found a potential explanation for why metformin,  one of the most widely prescribed drugs for type 2 diabetes,  commonly causes gastrointestinal side effects, suggesting that single-cell genetic mapping could help anticipate the tissue-specific effects of existing drugs.

"Genome-wide association studies have told us where in the genome IBD risk resides, but this study tells us which genes these risk variants disrupt and in which cell types this occurs," said co-senior author Carl Anderson. "Single-cell sequencing at scale provides a high-resolution view of disease biology, and by combining that with genetic variation, we can now make the insights needed to drive better drug target identification."