Evaluation of stroke-associated risk alleles in a multi-ethnic Singaporean ischemic stroke cohort

Ischemic stroke, caused by restricted blood flow to the brain, is a major cause of mortality and disability worldwide. While genetic factors are proven to contribute to stroke susceptibility, most genome-wide association studies (GWAS) have been conducted in predominantly European populations. The relevance of these findings to other populations, including Southeast Asian, remains unclear. In this study, we evaluated 29 single-nucleotide polymorphisms (SNPs) previously reported as stroke-associated in a cohort of 1304 Singaporeans (911 ischemic stroke cases, 393 healthy controls). Genotyping was performed using the Agena MassARRAY platform. Logistic regression adjusted for age and sex, with Benjamini-Hochberg correction for multiple testing, was conducted under additive, dominant, and recessive genetic models. A weighted genetic risk score (wGRS), constructed using published GIGASTROKE effect sizes, was also evaluated. None of the 29 SNPs showed a statistically significant association with ischemic stroke after correction for multiple testing. Four models involving three SNPs (rs2397816, rs2738158, rs56393506) showed nominally significant associations (raw p < 0.05), but these did not survive multiple testing correction (adjusted p = 0.72). The wGRS also showed no association with ischemic stroke risk (OR per SD = 1.02, 95% CI 0.90-1.15, p = 0.79). Observed effect sizes were modest with wide confidence intervals. The failure to replicate the rs2405068 association-originally reported in an African-ancestry subgroup-likely reflects ancestry-specific effects rather than limited portability. These findings provide preliminary evidence that the 29 tested genetic variants, representing only a subset of the 89 variants reported by GIGASTROKE, may not directly translate to Singaporeans. However, given the limited coverage of GIGASTROKE loci and the limited statistical power to detect small effect sizes, these findings should be interpreted with caution. Larger studies evaluating the full set of reported variants with comprehensive phenotyping and genome-wide coverage are needed to definitively assess the relevance of stroke-associated variants in Southeast Asian populations.