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PURPOSE: To investigate the causal effect of elevated blood pressure on primary open-angle glaucoma (POAG) and POAG endophenotypes.METHODS: Two-sample Mendelian randomization (MR) was performed to investigate the causal effect of elevated systolic blood pressure (SBP) (N = 757,601) and diastolic blood pressure (DBP) (N = 757,601) on intraocular pressure (IOP) (N = 139,555), macular retinal nerve fiber layer (mRNFL) thickness (N = 33,129), ganglion cell complex (GCC) thickness (N = 33,129), vertical cup-to-disc ratio (VCDR) (N = 111,724), and POAG liability (Ncases = 16,677, Ncontrols = 199,580). The primary analysis was conducted using the inverse-variance weighted approach. Sensitivity analyses were performed to investigate robustness to horizontal pleiotropy, winner's curse, and collider bias. Multivariable MR was performed to investigate whether any effect of blood pressure on retinal ganglion cell degeneration was mediated through increased IOP.RESULTS: Increased genetically predicted SBP and DBP associated with an increase in IOP (0.17 mm Hg [95% CI = 0.11 to 0.24] per 10 mm Hg higher SBP, P = 5.18 × 10-7, and 0.17 mm Hg [95% CI = 0.05 to 0.28 mm Hg] per 10 mm Hg higher DBP, P = 0.004). Increased genetically predicted SBP associated with a thinner GCC (0.04 Âµm [95% CI = -0.07 to -0.01 Âµm], P = 0.018) and a thinner mRNFL (0.04 Âµm [95% CI = -0.07 to -0.01 Âµm], P = 0.004), an effect that arises independently of IOP according to our mediation analysis. Neither SBP nor DBP associated with VCDR or POAG liability.CONCLUSIONS: These findings support a causal effect of elevated blood pressure on retinal ganglion cell degeneration that does not require intermediary changes in IOP. Targeted blood pressure control may help preserve vision by lowering IOP and, independently, by preventing retinal ganglion cell degeneration, including in individuals with a normal IOP.