Transcriptome-wide association studies associated with Crohn's disease: challenges and perspectives

Area of Science:

• Genetics
• Gastroenterology
• Computational Biology

Background:

• Crohn's disease (CD) is a chronic, progressive inflammatory condition affecting the gastrointestinal tract and other organs.
• Genome-wide association studies (GWAS) have identified numerous genetic loci associated with CD risk.
• Transcriptome-wide association studies (TWAS) integrate gene expression data with genetic association data to identify specific genes contributing to disease susceptibility.

Purpose of the Study:

• To review and summarize seven reported TWAS of Crohn's disease.
• To discuss the methodologies and key steps in TWAS that influence the prioritization of susceptibility genes.
• To explore tissue-specific susceptibility genes and their potential pathological mechanisms in CD.

Main Methods:

• Systematic review of published TWAS studies on Crohn's disease.
• Analysis of study designs, methodologies, and gene prioritization strategies used in TWAS.
• Gene Ontology (GO) pathway enrichment analysis for identified susceptibility genes.

Main Results:

• Identified potential roles for ileal lipid metabolism and colonic extracellular vesicles in CD pathogenesis.
• Highlighted significant variability and low reproducibility in current TWAS findings for CD.
• Summarized key methods influencing susceptibility gene identification and prioritization.

Conclusions:

• TWAS is a valuable approach for identifying CD susceptibility genes, but methodological inconsistencies limit reproducibility.
• Ileal lipid metabolism and colonic extracellular vesicles represent promising avenues for further research into CD pathology.
• Future TWAS efforts should focus on large-scale, unified cohorts and standardized analysis pipelines for improved reliability.