Causal Association between Glaucoma and Risk of Retinal Vascular Occlusion: A Mendelian Randomization Study

Abstract

Background Retinal vein occlusion (RVO) is a common retinal vascular disease that leads to visual impairment. In the elderly, risk factors may include glaucoma. Some studies suggest a correlation between glaucoma and RVO, but it remains unknown if the association is causal. The aim of this study was to perform Mendelian randomization(MR) analyses to evaluate the causal contribution of genetically predicted glaucoma to RVO. Methods A two-sample MR analysis using the inverse‐variance weighted (IVW), weighted median and MR‐Egger regression methods was performed. We used the publicly available summary statistics data sets of genome‐wide association studies (GWAS) meta‐analyses for glaucoma in individuals of European descent (n = 351696;133492 cases and 90939 controls) as the exposure and a GWAS for RVO Finn Gen biobank study (n = 204613;1595 cases and 203018 controls) as the outcome. We conducted univariable MR analyses to identify the causal effects of RVO. Although inverse variance weighted (IVW) was the primary method used for MR analyses, MR–Egger and weighted-median methods were used as supplements to IVW. We determined the heterogeneity of IVs using Cochrane’s Q test and I2, and used the MR–Egger intercept and MR-PRESSO Global test to detect horizontal pleiotropy. Results Genetically predicted glaucoma was found to be causally associated with RVO risk (beta = 0.267,SE = 0.051, odds ratio (OR) = 1.306, 95% confidence interval (CI): 1.181–1.445, P = 3.26×10− 3). This association was supported by sensitivity analyses using the weighted median (beta = 0.211,SE = 0.074,OR = 1.235, 95% CI: 1.064–1.429,P = 0.112), weighted mode (beta = 0.491,SE = 0.132,OR = 1.633, 95% CI: 1.261–2.116, P = 0.05), and MR-Egger (beta = 0.3900,SE = 0.138,OR = 1.476, 95% CI: 1.128–1.933, P = 6.237×10− 2) methods. The MR analyses using the validation dataset obtained consistent results. Conclusion The results of MR analysis support that glaucoma may be causally associated with an increased risk of RVO. Furthermore, this is the first study to discuss the causal relationship between glaucoma and RVO at the genetic level. Future studies are required to elucidate the underlying mechanisms.

Intraocular pressure, primary open-angle glaucoma and the risk of retinal vein occlusion: a Mendelian randomization mediation analysis

“…Mendelian randomization (MR) serves as a robust methodology utilizing genetic variants derived from genome-wide association studies (GWAS) as instrumental variables to elucidate the causal relationship between modifiable exposures and disease outcomes [11]. A recent MR study has identified a positive association between POAG and RVO [12]. However, it was not assessed whether this observed effect is intrinsic to POAG itself or if it is a consequence of the elevated intraocular pressure that is mediated through POAG.…”