Accessible chromatin maps of inflammatory bowel disease intestine nominate cell-type mediators of genetic disease risk

• Published in: bioRxiv : the preprint server for biology
• Main Authors: Wayman, Joseph A, Yang, Zi, Angerman, Elizabeth, Bonkowski, Erin, Jurickova, Ingrid, Chen, Xiaoting, Bejjani, Anthony T, Parks, Lois, Parameswaran, Sreeja, Miethke, Alexander G, VanDussen, Kelli L, Dhaliwal, Jasbir, Weirauch, Matthew T, Kottyan, Leah C, Denson, Lee A, Miraldi, Emily R
• Format: Journal Article
• Language: English
• Published: United States 13.02.2024

Inflammatory Bowel Disease ( ) is a chronic and often debilitating autoinflammatory condition, with an increasing incidence in children. Standard-of-care therapies lead to sustained transmural healing and clinical remission in fewer than one-third of patients. For children, TNFα inhibition remains the only FDA-approved biologic therapy, providing an even greater urgency to understanding mechanisms of response. Genome-wide association studies ( ) have identified 418 independent genetic risk loci contributing to IBD, yet the majority are noncoding and their mechanisms of action are difficult to decipher. If causal, they likely alter transcription factor ( ) binding and downstream gene expression in particular cell types and contexts. To bridge this knowledge gap, we built a novel resource: multiome-seq (tandem single-nuclei ( )RNA-seq and chromatin accessibility ( )-seq) of intestinal tissue from pediatric IBD patients, where anti-TNF response was defined by endoscopic healing. From the snATAC-seq data, we generated a first-time atlas of chromatin accessibility (putative regulatory elements) for diverse intestinal cell types in the context of IBD. For cell types/contexts mediating genetic risk, we reasoned that accessible chromatin will co-localize with genetic disease risk loci. We systematically tested for significant co-localization of our chromatin accessibility maps and risk variants for 758 GWAS traits. Globally, genetic risk variants for IBD, autoimmune and inflammatory diseases are enriched in accessible chromatin of immune populations, while other traits (e.g., colorectal cancer, metabolic) are enriched in epithelial and stromal populations. This resource opens new avenues to uncover the complex molecular and cellular mechanisms mediating genetic disease risk.