Cell-type specific analyses in blood and gut identify cis-eQTL matching 140 IBD risk loci and entrectinib as 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 cis-eQTL analysis in 27 sorted blood cell populations and 43 intestinal cell types identified by single cell RNA-Seq in the ileum, colon and rectum, with information on gene expression in patients, to search for putative drug targets for inflammatory bowel disease. We detect >95 K cis-eQTL that affect >13 K e-genes and cluster in >24 K regulatory modules. We uncover matching regulatory modules for 140 risk loci, implicating >300 e-genes not previously connected with inflammatory bowel disease, and find 152 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 possible repurposing candidate. Inflammatory bowel disease risk variants can identify genes and pathways involved in disease mechanisms. Here, the authors integrate blood and intestinal eQTL maps with patient gene expression data to prioritise candidate drug targets and identify entrectinib as a potential repurposing candidate.