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Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking., Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data., Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P =4.34×10 -8 ). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings., Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice., Competing Interests: Dr Arenillas reports compensation from Medtronic, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer for consultant services; grants from AstraZeneca, Instituto de Salud Carlos III, European Commission and Gerencia de Salud Castilla y León; compensation from Philips for data and safety monitoring services; travel support from Daiichi Sankyo Company. Dr Ribo reports stock holdings in Methinks, Nora, and Ancaonda Biomed; compensation from Cerenovus, Vesalio, Stryker Corporation, Philips, Rapid Pulse, AptaTargets, and Medtronic MiniMed Inc for consultant services; compensation from Sensome for data and safety monitoring services. Dr Heitsch reports employment by Washington University School of Medicine in St. Louis; reports funding from National Institutes of Health and American Heart Association. Dr Dhar reports grants from National Institute of Neurological Disorders and Stroke. The other authors report no conflicts.