Genetic inference of the etiological crosstalk between primary glaucomas and retinal vascular occlusions

Purposes The etiological connection between types of primary glaucoma and the risk of retinal vascular occlusions remains elusive. We conducted a two-sample bidirectional Mendelian Randomization (MR) study with mediation analysis to elucidate causal genetic relationships and investigate potential mediating pathways. Methods Genetic instruments of primary glaucomas and retinal vascular occlusions were derived from the UK Biobank and the Finngen, respectively. A two-sample MR and reverse MR were conducted to elucidate directional and causal relationships. Ocular and systemic risk factors, including glaucomatous endophenotypes, retinal vasculature indexes, diabetes, hypertension, blood pressure, cardiovascular diseases, and stroke, were also obtained from independent GWAS studies to investigate the mediating effects. Inverse variance weighting (IVW) was the primary analytical tool used to identify causality, and the results were verified through comprehensive and sensitivity tests for pleiotropy, heterogeneity, and stability. Results Genetically predicted primary open-angle glaucoma (POAG) may elevate retinal vein occlusion (RVO, central or branch) risk (OR=1.103, 95% CI: 1.008-1.208, p=0.032). In the reverse direction, RVO (central or branch) was associated with an odds ratio of 1.258 for primary angle-closure glaucoma (PACG); however, this association did not reach statistical significance (95% CI: 0.996-1.589, p=0.054). Mediation analysis suggested that 7.4% and 4.9% of the total effect of POAG on RVO (central or branch) risk were mediated in part through systolic and diastolic blood pressure, respectively. These primary results remained robust through a variety of sensitivity tests. Conclusions Our findings suggest that POAG may increase the risk of RVO, and this causal effect may be mediated in part through systolic and diastolic blood pressure.