The Association of Glaucoma with Ischemic Stroke and Functional Outcome after Ischemic Stroke from the Perspective of Causality

Introduction: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. Methods: We obtained single-nucleotide polymorphisms (SNPs) related to glaucoma from the genome-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS = 0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS = 3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.02-1.14, p = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR = 1.64; 95% CI = 1.27-2.13, p = 0.0001) and functional outcome after IS (OR = 1.45, 95% CI = 1.12-1.87, p = 0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. Conclusion: Our study provides evidence suggesting potential genetic causal effects of glaucoma on an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings.