Integration of multi-omics Mendelian randomization, neuroimaging mediation, and functional validation identifies PYGL as a neuroprotective causal gene for stroke prognosis.

Genetic variants associated with stroke prognosis remain poorly characterized at the functional level. Here, we integrated summary-data-based Mendelian randomization with brain expression quantitative trait locus data, Bayesian colocalization, and cell-type-specific analyses to identify causal genes for functional outcome measured by the modified Rankin Scale at three months post-ischemic stroke. We identified four genes with robust evidence: PYGL, GSTA1, and PTGIS as protective factors, and NFATC1 as a risk factor. Cell-type-specific analyses revealed that PYGL exerts its protective effect primarily through excitatory neurons, while the detrimental effect of NFATC1 is specific to oligodendrocytes. Mediation analyses demonstrated that white matter tract integrity and cortical thickness partially mediate the associations between these genes and stroke outcomes. Functional validation in hippocampal neuronal cells confirmed that PYGL overexpression significantly attenuated apoptosis induced by oxygen-glucose deprivation/reperfusion, whereas PYGL silencing exacerbated injury. These findings delineate a causal gene regulatory network underlying stroke prognosis, highlight the importance of neuronal energy metabolism and oligodendrocyte function in recovery, and nominate PYGL as a potential therapeutic target for promoting functional recovery after ischemic stroke.