Abstract
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (GWASs), the GWAS Catalog, MEGASTROKE, and Open GWAS, to identify novel genetic loci linked to IS. Our meta-analysis revealed 124 new IS-associated loci, with enrichment in genes involved in cerebrovascular function, inflammation, and metabolism. Candidate genes like CPNE1, HSD17B12, and SFXN4 are linked to lipid metabolism, immune response, and iron metabolism, indicating diverse pathogenic mechanisms in IS. Further analyses, including expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL), confirmed the relevance of these genes in the brain. Mendelian randomization and colocalization analyses highlighted seven genes with potential causal relationships to IS. Single-cell RNA sequencing identified differential gene expression in endothelial cells, implicating these genes in vascular dysfunction. Functional validation in knockout mouse models showed HSD17B12's role in fatty acid metabolism, linking it to cerebrovascular diseases. We also developed StrokeGene, an intelligent assistant based on large language models (LLMs) to aid IS genetic research. StrokeGene offers insights into IS pathophysiology. Collectively, these findings substantially advance the understanding of IS genetics and provide a foundation for precision medicine strategies in stroke prevention and treatment.