Imaging-mediated genetic effects link brain microstructure, metabolic profiles, and regional transcription to glioma susceptibility
Background This study aimed to systematically characterize genetically links and Mediation mechanism between glioma susceptibility and brain microstructure, cross-compartment metabolic profiles, and region-specific gene expression, followed by functional validation. Methods Using GWAS data from 12,488 glioma cases and 18,169 controls, we performed two-sample MR (TSMR) and summary data-based MR (SMR) analyses. We evaluated 587 brain imaging-derived phenotypes (IDPs) from diffusion and structural MRI; levels of 962 brain tissue metabolites, 440 cerebrospinal fluid (CSF) metabolites, and 1,400 plasma metabolites; and eQTL based gene expression across 13 brain regions. A two-step MR design was employed for mediation analysis, and the key gene identified, HEATR3, underwent clinical correlation and in vitro functional validation. Results TSMR identified 6 IDPs significantly associated with all glioma subtypes. Specifically, elevated intracellular volume fraction (ICVF) in the corpus callosum and cingulum increased risk, while increased mean diffusivity (MD) in the posterior limb of the right internal capsule was protective. Integrated SMR and TSMR revealed that elevated HEATR3 expression across all 13 brain regions significantly increases glioma risk. Functional experiments confirmed HEATR3 is upregulated in glioma, correlates with poor patient prognosis, and promotes malignant progression in vitro. Mediation analysis showed that HEATR3’s effect on glioma risk is partially mediated by specific white matter IDPs. Metabolic analysis revealed that higher levels of orotate—a product of de novo pyrimidine synthesis—in plasma, CSF, and brain tissue significantly increase GBM risk. Mediation analysis suggested that the effect of plasma orotate on glioma risk is partially mediated by the ICVF in the right cingulum hippocampus. Enrichment analyses indicated that significant regional genes are heavily involved in DNA metabolism and cell cycle pathways. Conclusion This study provides robust multi-layered evidence for the causal roles of white matter microstructural abnormalities, metabolic dysregulation, and regional gene expression in glioma development. These findings offer novel genetic insights and potential therapeutic targets for precision medicine in glioma.