Ischemic stroke remains a leading cause of disability, yet the molecular determinants of neuronal vulnerability and recovery are incompletely understood. Glutamate-mediated excitotoxicity, characterized by excessive extracellular glutamate and dysregulated receptor or transporter activity, is a central mechanism of ischemic injury. However, the genetic architecture underlying inter-individual variation in glutamate handling and its contribution to stroke outcomes has not been systematically explored in humans.
This project aims to identify genetic variants associated with glutamate-related pathways that influence stroke risk, lesion characteristics, and post-stroke outcomes. We will perform genome-wide association and pathway-based analyses using UK Biobank data, integrating genotype information with brain imaging phenotypes (e.g., white-matter hyperintensity volume, diffusion-MRI indices) and clinical outcomes (ischemic stroke subtypes, modified Rankin Scale). Metabolomic profiles will be used to estimate peripheral glutamate levels and infer metabolic activity.
The objectives are (1)to identify genetic loci and molecular networks involved in glutamate transport, receptor signaling, and neuronal excitotoxicity using genome-wide association and pathway-based analyses; (2) to integrate genetic signals with metabolic and neuroimaging phenotypes, including plasma glutamate-related metabolites, white matter hyperintensities (WMH), and diffusion MRI measures, to explore multi-omic correlations with ischemic stroke risk and outcome; (3) to validate the findings in external summary-level datasets such as FinnGen and GWAS Catalog, ensuring no exchange or integration of individual-level data.
This integrative multi-omic approach will clarify how inherited variation in glutamate-excitotoxicity networks modulates neuronal injury and repair after ischemic stroke, providing potential biomarkers and therapeutic targets for precision neuroprotection.
