Integrative multi-omics analysis identifies TGFA as a novel glioma susceptibility gene and therapeutic target

Gliomas are among the most aggressive brain tumors, with high mortality and limited treatments. Despite genetic advances, their molecular mechanisms remain unclear, hindering diagnostic biomarkers and targeted therapies. This study investigates novel glioma susceptibility genes using integrative multi-omics.

Cross-tissue transcriptome-wide association analyses integrated glioma GWAS data with eQTLs from 49 GTEx v8 tissues, utilizing UTMOST (cross-tissue), FUSION (single-tissue), and MAGMA (gene-level). Prioritized genes underwent Mendelian randomization, Bayesian colocalization, and phenome-wide association. TGFA expression was assessed in glioma samples via public genomic repositories and immunohistochemistry. Drug repurposing employed Comparative Toxicogenomics Database (CTD) and CB-Dock2 for molecular docking.

Five candidate genes were identified (SLC16A8, TGFA, PLA2G6, MAFF, TMEM184B), with Transforming Growth Factor Alpha (TGFA) as the strongest candidate. TGFA showed significant glioma associations across brain tissues and causal relationships via Mendelian randomization (OR: 1.27-1.39), supported by Bayesian colocalization. Elevated TGFA expression occurred in WHO grade 2/3 gliomas and 1p/19q co-deleted tumors, validated by immunohistochemistry. Drug repurposing identified 40 FDA-approved TGFA-targeting drugs; irinotecan exhibited the highest binding affinity (-62.0 kcal/mol) in docking studies.

TGFA is a novel glioma susceptibility gene with subtype-specific expression. Its therapeutic targeting offers opportunities for precision therapy, potentially advancing glioma clinical management.