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

Area of Science:

• Genomics
• Immunology
• Cell Biology

Background:

• Genetic variants in non-coding regions complicate complex disease gene identification.
• Understanding cell-type-specific gene regulation is crucial for disease mechanisms.

Purpose of the Study:

• To map cis-eQTLs (expression quantitative trait loci) across single cells to identify genes and cell types implicated in inflammatory bowel disease (IBD).
• To provide a mechanistic link between genetic risk loci and specific genes/cell types in IBD.

Main Methods:

• Single-cell RNA sequencing of 2.2 million cells from blood and intestinal biopsies of 421 individuals, including 125 with IBD.
• Analysis of cis-eQTLs at both cell-type and tissue levels to compare their characteristics and association with IBD GWAS loci.

Main Results:

• Cell-type-level eQTLs were more distal, enriched in enhancers, and showed stronger colocalization with IBD GWAS loci compared to tissue-level eQTLs.
• Identified effector genes in myeloid cells (e.g., MAML2, PSEN2, ZMIZ1) suggesting impaired Notch signaling in IBD.
• Identified Wnt-regulated genes (e.g., MYC) in epithelial stem/progenitor cells, suggesting impaired renewal contributes to IBD.

Conclusions:

• Provides a high-resolution map linking genetic risk to specific genes and cell types in IBD.
• Nominates novel effector genes and implicates specific signaling pathways (Notch, Wnt) in IBD pathogenesis.
• Establishes a framework for effector gene discovery in complex diseases using single-cell eQTL analysis.