Genetics in Ischemic Stroke: Current Perspectives and Future Directions

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TL;DR

This review synthesizes current knowledge on the genetic underpinnings of ischemic stroke, highlighting that monogenic causes account for 1–5% of cases while polygenic influences contribute to approximately 38% of heritability. Key findings include the identification of numerous risk loci through genome-wide association studies (GWASs), the role of pharmacogenetics in tailoring antiplatelet therapy (e.g., CYP2C19 genotyping for clopidogrel), and emerging insights into stroke recovery genetics. The clinical significance lies in the potential for personalized risk prediction, treatment optimization, and novel therapeutic targets, though translation into routine practice remains limited.

Full summary

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**Background:** Ischemic stroke is a heterogeneous, multifactorial disease and a leading cause of disability and death worldwide. Genetic factors play a significant role, with heritability estimated at approximately 37.9% overall, varying by subtype: 40.3% for large-vessel disease, 32.6% for cardioembolic, and 16.1% for small-vessel disease. Monogenic causes account for 1–5% of all ischemic strokes, while polygenic influences are more common. This narrative review aims to summarize current perspectives on the genetics of ischemic stroke, including mechanisms, study approaches, genes related to occurrence, treatment response, and recovery, as well as future directions.

**Methods:** The authors conducted a narrative review of the literature, synthesizing findings from key genetic studies including linkage analyses, genome-wide association studies (GWASs), and pharmacogenetic trials. They describe major monogenic disorders (e.g., CADASIL due to NOTCH3 mutations, CARASIL due to HTRA1, Fabry disease due to GLA) and summarize large-scale GWASs such as MEGASTROKE (over 520,000 subjects, 89 loci), STROMICS (10,241 Chinese cases, 77 loci), and COMPASS (over 22,000 African ancestry subjects). The review also covers polygenic risk scores (PRS), pharmacogenetics of thrombolytics (rtPA), antiplatelets (aspirin, clopidogrel, ticagrelor), and anticoagulants (warfarin, DOACs), as well as genetic studies of stroke recovery.

**Key Results:** The review reports that monogenic strokes are caused by single pathogenic variants in genes such as NOTCH3, HTRA1, COL4A1, COL3A1, FBN1, RNF213, HBB, JAK2, and others. Polygenic stroke is influenced by multiple variants with small-to-moderate effect sizes; the MEGASTROKE meta-analysis identified 89 independent loci, including SH3PXD2A and FURIN. The STROMICS study found 77 risk loci in Chinese populations, with over 42% novel. For pharmacogenetics, CYP2C19 loss-of-function (LOF) variants (CYP2C19*2, *3) are associated with poorer response to clopidogrel; the CHANCE trial showed that among 2933 patients, 58.8% were CYP2C19 LOF carriers, and clopidogrel plus aspirin reduced stroke risk only in non-carriers. The CHANCE-2 trial demonstrated that ticagrelor–aspirin reduced 90-day stroke recurrence compared to clopidogrel–aspirin in LOF carriers (6.0% vs. 7.6%, HR 0.77, 95% CI 0.64–0.94, p=0.008). For warfarin, VKORC1 and CYP2C9 variants influence bleeding risk. In stroke recovery, the GISCOME meta-analysis (6165 cases) identified variant rs1842681 associated with better functional outcome, and the PATJ gene was linked to worse 3-month outcome. The review also notes that SARS-CoV-2 infection shares genetic risk loci with large artery stroke (ISLR2 network) and cardioembolic stroke (PITX2, HS6ST1, RFFL).

**Clinical Implications:** Genetic insights are beginning to inform clinical practice, particularly in monogenic stroke diagnosis (e.g., CADASIL), pharmacogenetic-guided antiplatelet therapy (CYP2C19 testing for clopidogrel), and risk prediction using polygenic risk scores. However, the review emphasizes that most genetic findings are from European-ancestry populations, limiting generalizability. Future directions include large-scale sequencing in diverse populations, multi-omics integration, gene therapy, and precision medicine approaches. The authors conclude that while genetics holds promise for personalized prevention and treatment, more research is needed to translate these findings into routine clinical care.