A set of downregulated pleiotropic genes are possible multi-omics biomarkers underlying the irritable bowel syndrome-non-alcoholic fatty liver disease comorbidity.

OBJECTIVE: To investigate the genetic relationship between irritable bowel syndrome (IBS) and non-alcoholic fatty liver disease (NAFLD). METHODS: Mendelian randomization (MR) was used to assess causality between IBS and NAFLD in a genome-wide association study (GWAS) data. Genetic correlation was evaluated by linkage disequilibrium score regression (LDSC). Shared loci were identified using PLACO, coloc, and MAGMA for pleiotropic gene mapping. Functional enrichment (Gene Ontology [GO]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) was performed. Single-cell RNA-sequencing of NAFLD liver samples was used to assess gene dysregulation and calculate activation scores. Mouse models were used to validate gene expression. The identified pleiotropic gene set and their dysregulation signatures provide a foundational resource for future development of predictive multi-omics biomarkers. RESULTS: MR revealed a significant causal effect of IBS on NAFLD risk (Inverse-variance weighted: OR = 1.118, 95% CI = 1.03-1.21, P = 0.006; Steiger P < 0.05). Significant genetic correlation was observed (LDSC P < 0.05). Analyses identified 194 pleiotropic SNPs, mapping to 12 genes (e.g., GCKR, ARHGAP25, SNX17). These genes were enriched in nucleotide, carbohydrate, and lipid metabolism pathways. Tissue-specific analysis indicated a decreased activation pattern of pleiotropic genes in the liver tissues. Single-cell analysis showed dysregulation in NAFLD hepatocytes/immune cells. In addition, activation scores negatively correlated with disease severity (P < 0.001). Mouse models confirmed overall downregulation of these genes, significant for GCKR, GPN1, and SLC4A1AP at both mRNA and protein levels. CONCLUSIONS: IBS exhibits a unidirectional causal effect on NAFLD, and there is a significant genetic association between them. The collective downregulation of shared pleiotropic genes (ADCY2, ARHGAP25, C2orf16, CCDC121, GCKR, GPN1, LINC01460, SLC4A1AP, SNX17, ZNF512, ZNF513, and EIF2B4) may mediate increased susceptibility to NAFLD in the IBS population.