Transcriptomics-Guided Drug Repurposing Identifies Candidate Compounds for Improving Long-Term Stroke Outcome

BackgroundFunctional recovery after ischemic stroke is a complex and polygenic process influenced by genetically regulated molecular pathways. Although genome-wide association studies (GWAS) have identified variants associated with stroke outcome, translating these findings into actionable therapeutic targets remains challenging. Transcriptome-wide association studies (TWAS) provide a framework to link genetic variation to gene expression and functional phenotypes, enabling mechanism-driven drug repurposing strategies. ObjectiveTo identify candidate compounds capable of improving long-term functional outcome after ischemic stroke by integrating GWAS summary statistics with brain transcriptomic data and large-scale perturbational drug signatures. MethodsWe performed TWAS integrating summary statistics from a stringent GWAS of long-term stroke outcome (modified Rankin Scale at three months, mRS3; N = 1,791; 8,895,027 variants) from the GODS study with brain eQTL data from ten regions in the GTEx project. Pathway enrichment analysis was conducted using WebGestalt. Drug repurposing was performed using the Trans-phar pipeline by comparing TWAS-derived transcriptional signatures with compound-induced gene expression profiles from the Connectivity Map (CMap) L1000 dataset across five neural cell lines. Compounds showing inverse transcriptional correlations were prioritized and further evaluated based on existing clinical and preclinical evidence in stroke. ResultsTWAS identified 22 genes consistently ranked within the top 10% across all ten regions. Pathway enrichment analysis highlighted transcriptional regulation processes, with the RNA polymerase pathway reaching statistical significance after FDR correction in the broader gene set. Drug repurposing analysis identified nine compounds whose transcriptional signatures inversely correlated with genetically predicted expression profiles associated with poor functional outcome. Among these, anandamide and progesterone had prior clinical evidence in stroke, while Z-guggulsterone demonstrated preclinical neuroprotective potential. ConclusionsIntegration of GWAS and brain eQTL data identifies robust transcriptional signatures associated with long-term stroke outcome and supports transcriptomics-driven drug repurposing strategies. This human genetics-guided framework prioritizes candidate compounds with potential translational relevance for improving functional recovery after ischemic stroke.