Integrated cell type-specific analysis of blood and gut identifies matching eQTL for 140 IBD risk loci and entrectinib as possible repurposing candidate

Abstract

Genes whose expression is affected in a consistent manner by GWAS-identified risk variants and the disease process, constitute preferred drug targets. We herein combine integrated cis-eQTL analysis in 27 blood cell populations and 43 intestinal cell types of the ileum, colon and rectum, and information on gene expression in patients, to search for putative drug targets for inflammatory bowel disease (IBD). We detect >95K cis-eQTL that affect >13K e-genes and cluster in >24K regulatory modules (RM). We uncover matching RM for 140 risk loci, implicating >300 e-genes not previously connected to IBD, and find 152 IBD-matching e-genes whose expression is perturbed in the blood or gut of patients. We identify entrectinib, a small molecule inhibiting the NRLP3 inflammasome by binding NEK7, as a promising repurposing candidate for IBD.