Genetic and epigenetic architectures of stroke: Insights from GWAS to precision medicine.

Abstract

Stroke remains a leading cause of death and disability, driven by complex interactions among genetic, epigenetic, and environmental factors. Advances in genomic technologies have elucidated the role of common polygenic variants and rare monogenic mutations in determining susceptibility to stroke subtypes. Genome-wide association studies have identified key loci, including Histone Deacetylase 9 (HDAC9), Paired-like Homeodomain Transcription Factor 2 (PITX2), Zinc Finger Homeobox 3 (ZFHX3), and Collagen Type IV Alpha 1 Chain (COL4A1), associated with vascular inflammation, atrial fibrillation, and small vessel dysfunction. Monogenic disorders such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; NOTCH3), Fabry disease (GLA), and Sickle Cell Disease (SCD; HBB) illustrate the impact of single-gene mutations on early-onset or familial stroke. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) regulate pathways related to apoptosis, inflammation, angiogenesis, and blood-brain barrier dysfunction. Pharmacogenomic profiling, involving genes such as CYP2C19, VKORC1, and SLCO1B1, can guide individualized therapy with antiplatelets, anticoagulants, and statins. Collectively, these advances are steering stroke care toward precision medicine, integrating multi-omics data and gene-targeted strategies for improved prevention, diagnosis, and treatment.