Abstract
BACKGROUND: Primary open-angle glaucoma (POAG) is the leading cause of irreversible vision loss. However, its genetic risk factors, such as the vascular hypothesis of POAG, remain unclear. Here, we aimed to explore the genetic associations between mean ocular perfusion pressure (MOPP) and POAG. We performed genome-wide analysis with gene-based analysis from the UK Biobank (N = 459,195), which includes genetic data and ocular phenotypes. Bidirectional two-sample Mendelian randomisation (MR), multivariable MR, and mediation analysis were conducted using summary statistics from a previous meta-analysis of genome-wide association studies (N = 216,257). RESULTS: CEP85L, GRIA4, GRIN2A, LRFN5, MAGI1, POU6F2, RBFOX1, RBMS1, RBMS3, RBPMS, TRHDE, TUBB3, ZFHX3, and ZMAT4 were significantly correlated with various ocular phenotypes. Furthermore, POAG shared strong genetic associations with corneal resistance factor (CRF), intraocular pressure (IOP), refractive error (RE), and MOPP but none with corneal hysteresis (CH). Univariable MR showed a negative causal effect of CH, CRF, and MOPP and a positive causal effect of IOP on POAG occurrence. In multivariable MR, MOPP exhibited a direct causal effect on POAG, which was supported by the mediation analysis results. CONCLUSIONS: We successfully determined 14 genetic loci related to CH, CRF, IOP, RE, and MOPP. In univariable and multivaribale MR analyses, a causal effect of MOPP on POAG were observed. In addition, the mediation analysis supported that MOPP exerted direct and indirect causal effects on POAG. This finding indicates that MOPP may serve as a potential causal factor in POAG, providing valuable insights into the pathophysiology of POAG as vascular theory.