To systematically characterize genetic links and mediation mechanisms between glioma susceptibility and brain microstructure, metabolic profiles, and region-specific gene expression.
Approach:
Study Design: Utilized GWAS data from 12,488 glioma cases and 18,169 controls, performing two-sample MR (TSMR) and summary data-based MR (SMR) analyses.
Data Evaluation: Evaluated 587 brain imaging-derived phenotypes, levels of 962 brain tissue metabolites, 440 cerebrospinal fluid metabolites, and 1,400 plasma metabolites.
Gene Expression Analysis: Conducted eQTL based gene expression analysis across 13 brain regions.
Mediation Analysis: Employed a two-step MR design for mediation analysis, focusing on the key gene HEATR3.
Key Findings:
Six IDPs significantly associated with all glioma subtypes were identified.
Elevated intracellular volume fraction (ICVF) in the corpus callosum and cingulum increased glioma risk.
Increased mean diffusivity (MD) in the posterior limb of the right internal capsule was protective.
HEATR3 expression across all brain regions significantly increases glioma risk.
Higher levels of orotate in plasma, CSF, and brain tissue significantly increase GBM risk.
Interpretation:
HEATR3's effect on glioma risk is partially mediated by specific white matter IDPs, and metabolic dysregulation, particularly involving orotate, plays a significant role in glioma development.
Limitations:
The study may not account for all potential confounding factors.
Findings are based on observational data, which may limit causal inferences.
Conclusion:
The study provides evidence for the roles of white matter microstructural abnormalities, metabolic dysregulation, and regional gene expression in glioma development.
