Integrative multi-omics analysis-based Mendelian randomization identifies association of DNA repair–related genes with oral cancer

BackgroundThis study aimed to identify DNA repair-related genes causally affecting OCC risk by integrating multi-omics data using summary data-based Mendelian randomization (SMR).MethodsSMR analyses were performed using GWAS, mQTL, eQTL, and pQTL data. Causal associations were assessed via SMR and HEIDI tests, and colocalization analysis identified shared genetic variants. Findings were validated in the FinnGen_OCC cohort.ResultsThis study identified 160 methylation sites (96 genes), 30 eQTLs, and 2 pQTLs linked to OCC. Colocalization confirmed 96 mQTLs, 20 eQTLs, and 2 pQTLs (GPN1, HNRNPAB). Five mQTLs (ANK1, HLA C, TERT, TUBB, VHL) replicated in FinnGen. Integration of mQTL and eQTL data highlighted VHL, TP73, and JMJD1C, implicating DNA methylation-mediated regulation. Multi-omics and tissue analyses identified VHL as the most consistent risk gene, supported by colocalization, TCGA HNSC transcriptomic validation (P < 0.01), and DepMap functional data. GEN1 and POU5F1 expression in salivary gland tissue also associated with OCC risk.ConclusionThis multilayer SMR study reveals causal links between DNA repair-related genes and OCC, highlighting VHL as a key driver and suggesting targets for early detection and precision therapy.