Exploring genetic causal relationships between spinal cord injury and glioma: a Mendelian randomization study

Gliomas and spinal cord injuries represent significant health challenges with potential shared genetic underpinnings. Understanding the causal genetic relationships between these conditions could provide valuable insights for targeted therapeutic interventions. This study aimed to investigate potential causal genetic associations between spinal cord injury and glioma using Mendelian Randomization approaches.

We employed Mendelian Randomization (MR) to examine potential genetic associations between spinal cord injury and glioma. Four SNPs (rs1358980, rs217992, rs789990, and rs158541) were used as instrumental variables, identified from the FinnGen R11 release's "finngen_R11_C3_GBM_EXALLC" dataset. We applied three MR statistical approaches: MR Egger regression, Inverse Variance Weighted (IVW), and Weighted mode. Additionally, we analyzed gene expression patterns using RNA-sequencing data from TCGA and GEO databases, performed machine learning-based risk stratification, and validated our findings using single-cell RNA sequencing data from glioma patient tissues (GSE131928).

Forest plot analyses revealed that while individual SNPs did not show significant effects on spinal cord injury (confidence intervals crossing zero), different MR methods yielded varying results. The MR Egger method demonstrated a positive correlation trend between glioma-associated genetic factors and spinal cord injury risk, while other methods showed more gradual effects. The MR analysis with the finngen_R11_C3_GBM_EXALLC genetic instrument yielded odds ratios close to 1.000 across all statistical methods (MR Egger: OR = 1.001, 95% CI 0.997-1.004, p = 0.759; IVW: OR = 1.000, 95% CI 1.000-1.000, p = 0.634), suggesting no significant causal relationship. Heterogeneity test results indicated moderate heterogeneity. Additionally, risk stratification analysis revealed significant differences in immune cell infiltration, gene expression patterns, and survival outcomes between high-risk and low-risk groups.

Our comprehensive analysis using Mendelian randomization provides evidence of complex genetic relationships between glioma and spinal cord injury.