Integrative multi-omics analysis identifies genetically supported druggable targets for inflammatory bowel disease

Area of Science:

• Genetics and Genomics
• Immunology
• Pharmacology

Background:

• Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated gastrointestinal disorder with rising global prevalence.
• Existing treatments for IBD are limited, necessitating the identification of novel therapeutic targets.

Purpose of the Study:

• To systematically identify druggable genes with potential causal roles in IBD using integrated multi-omics data.
• To leverage genetic, transcriptomic, and epigenomic datasets for novel target discovery in IBD.

Main Methods:

• Summary-data-based Mendelian randomization (SMR) and Bayesian colocalization were employed to assess gene causality in IBD.
• Multi-omics analyses integrated GWAS, methylation, and gene expression data, with replication in the FinnGen cohort.
• Phenome-wide association studies (PheWAS), in silico drug repurposing, and molecular docking simulations were performed.

Main Results:

• Thrombospondin-3 (THBS3), RORC, and TNFRSF25 were identified as potential druggable targets for IBD.
• These genes demonstrated consistent associations with IBD across multiple biological layers and validation datasets.
• Molecular docking predicted several candidate drugs, including AM580 and Dasatinib, with high binding affinities to the identified targets.

Conclusions:

• A multi-layered omics approach provided genetically supported evidence for THBS3, RORC, and TNFRSF25 as druggable targets in IBD.
• The study identified promising candidate drugs for IBD therapeutic intervention.
• Further clinical validation is required to develop effective IBD treatments based on these novel targets.