Genetic risk factors associated with ischemic stroke and etiological subtypes

Abstract

Abstract Background: Ischemic stroke is a multifactorial pathology caused by an interruption of the blood flow to the brain, causing the brain not to receive oxygen and nutrients. Although research has advanced in identifying genetic factors linked to IS, there is a notable gap in studies centered on the Spanish population, which remains underrepresented. Methods and Results: We conducted a genome-wide association study (GWAS) on a Spanish repli-cation cohort of 3,882 individuals (457 IS cases and 3,425 controls), derived from a larger primary cohort of 9,081 individuals (3,493 IS cases and 5,588 controls). A meta-analysis combining both cohorts was performed, followed by functional annotation, gene-based, and gene-set analyses. We identified a replicated locus associated with ischemic stroke, rs7092141-C (beta (SE) = 0.04 (0.019), p = 0.027). Our metanalysis identified three loci with genome-wide significance: rs184652834-G, rs76757388-A, and rs7092141-C. Additionally, eight loci showed nominal significance in the replica-tion cohort, which was also significant in the main cohort, involving genes such as ANKH, LATS2, and GPR158. Gene-set analyses highlighted suggestive pathways, including the G protein-coupled receptor signaling pathway (p-value =4.37×10-3), activation of NOXA and mitochondrial translocation pathway (p-value =3.18×10-3), and diseases: endometriosis (p-value =1.74×10-4) and coronary artery (p-value =2.33×10-2). Conclusion: Our findings underscore the importance of conducting genetic studies in specific popu-lations like the Spanish cohort. The identified loci and suggestive pathways provide a foundation for further research into the genetic mechanisms underlying ischemic stroke, which may ultimately lead to improved prevention and treatment strategies.