ArticleDiscover oncology2025
Mendelian randomization and single-cell analysis reveal novel genetic risk factors and cellular heterogeneity in glioblastoma.
Article in Discover oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundGlioblastoma is the most aggressive primary brain tumor with limited therapeutic options and poor prognosis. Understanding the genetic determinants and cellular complexity of glioblastoma is crucial for developing novel therapeutic strategies.
methodsWe conducted a comprehensive Mendelian randomization (MR) analysis to investigate causal relationships between genetic exposures and glioblastoma risk, employing multiple MR methods including MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode approaches. Single-cell RNA sequencing was performed to characterize cellular heterogeneity within the glioblastoma microenvironment. Extensive sensitivity analyses including funnel plots and leave-one-out analyses were conducted to ensure robust causal inference. RT-PCR validation was conducted using BV2 glioma cell line compared to normal brain tissue controls. Integration analysis linked genetic risk factors to cellular expression patterns and biological pathways.
resultsThe Mendelian randomization analysis identified several genes with robust causal relationships to glioblastoma risk. Protective associations were observed for TIMP3 (OR = 0.675, 95% CI: 0.473-0.965, p = 0.031), TREM1 (OR = 0.631, 95% CI: 0.411-0.968, p = 0.035), FLRT3 (OR = 0.661, 95% CI: 0.512-0.853, p = 0.001), and IL12B (OR = 0.644, 95% CI: 0.448-0.925, p = 0.017). Conversely, risk-increasing associations were identified for TALDO1 (OR = 12.433, 95% CI: 1.808-85.507, p = 0.010) and PDCD6 (OR = 4.532, 95% CI: 1.429-14.368, p = 0.010). RT-PCR validation confirmed significant downregulation of protective genes in BV2 glioma cells: TIMP3 (2.48-fold decrease, p = 0.031), TREM1 (2.74-fold decrease, p = 0.035), FLRT3 (2.91-fold decrease, p = 0.001), and IL12B (2.33-fold decrease, p = 0.017). Single-cell analysis revealed distinct cellular populations with cell-type-specific expression patterns of identified risk genes.
conclusionsThis study provides robust evidence for novel genetic risk factors in glioblastoma development and reveals the complex cellular landscape of the tumor microenvironment. The identified protective and risk genes offer potential targets for therapeutic intervention and biomarker development.
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