Single-cell multi-omic integration analysis prioritizes druggable genes and reveals cell-type-specific causal effects in glioblastomagenesis

Gliomas, particularly aggressive glioblastoma (GBM), pose significant therapeutic challenges due to limited understanding of their single-cell drivers. Here, we integrate large glioma genetic data with brain multi-omics (bulk and single-cell) to identify causal genes and their cell-type-specific roles. We prioritize 11 high-confidence and 47 potential causal genes; 41 are novel associations. Analyses suggest most of these 58 genes are druggable, supported by CRISPR/RNAi screens showing essentiality/dependency for 53.7% novel candidates in glioma cell lines. Single-cell data identifies astrocytes and oligodendrocyte precursor cells (OPCs) as likely GBM cells-of-origin and reveals increased tumor microenvironment (TME) communication involving neurons. We uncover 14 cell-type-specific causal gene effects, including EGFR in astrocytes, CDKN2A in OPCs, and JAK1 in excitatory neurons. Notably, 85.7% effects occur in non-risk populations (glial and neural), highlighting complex interplays. This study provides critical cell-resolved insights into glioma susceptibility mechanisms and identifies potential therapeutic targets within complex intratumoral interactions, advancing targeted precision therapies.