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

Key Points:

• The study involved recruitment of 421 individuals (125 with Crohn’s Disease (CD) and 296 controls) from Addenbrooke’s Hospital, UK, with gastrointestinal biopsies and blood samples collected for single-cell RNA sequencing (scRNA-seq) and genotyping.
• A comprehensive single-cell dissociation and sequencing protocol was applied, yielding over 2 million high-quality cells across multiple cell lineages (epithelial, mesenchymal, immune, etc.), with detailed clustering and annotation based on canonical marker genes.
• Expression quantitative trait locus (eQTL) mapping was performed using TensorQTL on pseudobulked scRNA-seq data, identifying cis-eQTLs and interaction eQTLs (ieQTLs) with correction for multiple testing and population structure, enabling discovery of genetic regulation in specific cell types and conditions.
• Colocalization analyses between eQTLs and inflammatory bowel disease (IBD) genome-wide association study (GWAS) loci were conducted, revealing cell type-specific disease effector genes and pathways, including enrichment in Notch and Wnt signaling pathways.
• Additional analyses included enrichment of eQTLs in genomic regulatory annotations, assessment of therapeutic targets linked to colocalized genes, and rigorous quality control and validation steps to ensure robustness of findings.