What is the clinical evidence from this study?

Study design: Observational. Population: Ischemic stroke (n=13349). Intervention: Sex-stratified and X-chromosome genetic risk factors. Primary outcome: Genetic associations with five TOAST phenotypes of ischemic stroke.

May 8, 2026Open Access

Abstract Number: Esoc2026a198 Identifying Sex-Specific and X-Chromosome Genetic Risk Factors for Ischemic Stroke Through Stratified Gwas Analyses

Key Result

Sex-stratified GWAS identified distinct genetic risk loci for ischemic stroke, including Xq21.31 in men for cardioembolic stroke and 10q23.31 in women for large-artery atherosclerosis.

Key Points

The aim is to identify sex-specific and X-chromosome genetic risk factors for ischemic stroke using stratified analyses.
Analyzed 8,064,232 variants with TOPMed-based imputation.
Used SNPTEST under an additive model, adjusting for age and principal components.
Evaluated five TOAST phenotypes across sex-stratified cohorts.
In men, significant loci were found at Xq21.31 for cardioembolic stroke and others for small-vessel occlusion and undetermined etiology.
In women, critical loci were identified for large-artery atherosclerosis and overall ischemic stroke.
Distinct sex-specific pathways were indicated for vascular integrity in men and immune regulation in women.

Study Design

Type

Observational (n=13,349)

Structured PICO

What are the sex-specific and X-chromosome genetic risk factors for ischemic stroke and its subtypes?

Population

13,349 individuals (6,731 men including 2,276 with ischemic stroke, and 6,618 women including 1,899 with ischemic stroke)

Intervention

Sex-stratified genome-wide association studies (GWAS) and X-chromosome analyses

Outcome

Genetic loci associated with ischemic stroke and TOAST subtypes (cardioembolic, large-artery atherosclerosis, small-vessel occlusion, undetermined etiology)surrogate

Sex-stratified GWAS reveals distinct genetic loci and pathways contributing to ischemic stroke subtypes in men and women, highlighting the importance of sex-specific genetic analyses.

Abstract

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.