Integrative Multi-Omics Mendelian Randomization Analysis Identifies NIT2 as a Potential Metabolic Risk Gene in Hepatocellular Carcinoma.

BACKGROUND: Metabolic pathways are crucial in hepatocellular carcinoma (HCC) pathogenesis, but causal metabolic genes remain unclear. This study used Summary data-based Mendelian Randomization (SMR) and colocalization to identify metabolism-related genetic loci influencing HCC risk. METHODS: Differentially expressed genes in hepatic malignancy phenotype versus normal tissues from TCGA and GTEx were analyzed. Metabolism-related candidates were examined via SMR and colocalization using multi-omics data: methylation (mQTL), expression (eQTL), and protein (pQTL) quantitative trait loci. RESULTS: Multi-omics integration identified NIT2 as a key metabolic regulator for HCC. The cg13016775 locus of NIT2 was associated with elevated HCC risk at gene (OR = 1.618, 95% CI: 1.199-2.182) and protein (OR = 4.432, 95% CI: 1.783-11.018) levels. Colocalization supported a shared causal variant (PPH4 > 0.6), linking NIT2 to hepatocarcinogenesis via metabolic regulation. CONCLUSIONS: This study provides multi-omics evidence for NIT2 as a potential causal gene in HCC, enhancing understanding of metabolic contributions to HCC pathogenesis and highlighting integrative genomics for uncovering causal relationships.