Poster Presentation 46th Lorne Genome Conference 2025

Leveraging population genetics and cellular transcriptomics to identify novel drug targets in Crohn's disease (#246)

Rika Tyebally 1 , Angli Xue 1 2 , Joseph Powell 1 3
  1. Translational Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  2. School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia
  3. UNSW Cellular Genomics Futures Institute, University of New South Wales, Kensington, Sydney, New South Wales, Australia

Common genetic variation contributes to Crohn’s disease, as revealed by genome wide association studies (GWAS). Extending this to causal genes and cell types reveals novel drug targets with genetic evidence. Single cell expression quantitative trait loci (sc-eQTL) can be used to identify candidate eGenes (i.e., a gene regulated by an eQTL) in specific cell types.

Here, we identified genes with genetic evidence of causality for Crohn's disease, and infer their regulatory pathways. We employed a Mendelian Randomisation approach developed for eQTL and GWAS data using Crohn’s disease GWAS results, and single cell eQTL data from the OneK1K cohort of 1,000 blood cells from 1,000 individuals.  Importantly, cell type specific eQTLs are not driven by cell type specific gene expression. We identified 143 candidate cell type-eGene pairs (p<6.4x10-06), composed of 40 unique eGenes. Of these, 12 (30%) were specific to one cell type. A gene-set enrichment analysis of these 40 eGenes using Metascape revealed antigen presentation, cytokine regulation and peptide metabolism pathways.  Highlights include UBE2L3 (an eGene in CD4+ T, CD8+ T, and NK cells), a ubiquitin conjugating enzyme which regulates Crohn’s disease drug target TNFα; and PTGER4 (eGene in NK cells specifically), which encodes the human prostaglandin E2 receptor 4 which is involved in T helper and T regulatory cell responses in inflammatory bowel disease. We then applied gene regulatory network inference on 100,000 OneK1K blood cells to reveal transcriptional networks (TFs and motif-enriched co-expressed genes). For example, we identified transcription factors SPIB and SPI1 regulate memory B cell eGenes ORMDL3, FADS1 and TUFM.  Next, we aim to contextualise these eGenes by overlapping them with differentially expressed genes and gene regulatory networks in Crohn’s disease blood samples. Our results reveal novel links between genetic associations and molecular pathways in Crohn’s disease, with implications for drug development.

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