ABSTRACT NUMBER: ESOC2026A198 IDENTIFYING SEX-SPECIFIC AND X-CHROMOSOME GENETIC RISK FACTORS FOR ISCHEMIC STROKE THROUGH STRATIFIED GWAS ANALYSES

Abstract Background and aims Ischemic stroke (IS) is a complex disorder influenced by genetic, sex, and environmental factors. Sex-stratified genome-wide association studies (GWAS) and X-chromosome analyses have not been performed in stroke. We aimed to identify sex-specific genetic risk factors for IS, focusing on X-chromosome and TOAST effects. Methods We analyzed 8,064,232 autosomal and X-chromosome variants after TOPMed-based imputation. Associations were tested using SNPTEST under an additive model, adjusting for age and 10 principal components. Five TOAST phenotypes: cardioembolic (CE), large-artery atherosclerosis (LAA), small-vessel occlusion (SVO), undetermined etiology (UE), and overall IS; were evaluated in men, women, and combined. Genome-wide significance was applied, and significant loci were annotated using the Open Targets Platform. Results The cohort included 6,731 men (2,276 IS) and 6,618 women (1,899 IS). Sex-stratified analyses revealed distinct genetic patterns: in men, significant loci were identified at Xq21.31 (PCDH11X) for CE, 21q21.2, 3q21.1 (MYLK), 4q27 for SVO, and 2q22.2 for UE; in women, loci included 10q23.31 (RNLS) for LAA and 6p22.3 (RIPOR2) for overall IS. GTEx annotation indicated tissue-specific expression: PCDH11X in aorta/brain, RNLS in muscle, uterus, and aorta, and RIPOR2 in whole blood (higher in females). Functional interpretation suggested sex-specific pathways such as vascular integrity and neuronal repair in men and immune regulation, blood pressure, and extracellular matrix remodeling in women. Conclusions Our findings reveal sex- and subtype-specific genetic contributors to IS. The associated loci highlight pathways in vascular structure, immune regulation, and blood pressure control, underscoring the value of sex-stratified and X-chromosome-inclusive analyses in understanding IS mechanisms and guiding precision prevention strategies. Conflict of interest Nothing to disclose.