Examining the Casual Role of Central Corneal Thickness in Glaucoma: A Mendelian Randomization Approach. C. Y. Cheng1,2,3, T. H. Tham1,2, J. M. Liao2, T. Y. Wong1,2,3, T. Aung1,2 1) Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; 2) Department of Ophthalmology, National University of Singapore and National University Health System, Singapore; 3) Duke-National University of Singapore Graduate Medical School, Singapore.

   Thin central corneal thickness (CCT) has been previously reported to be associated with glaucoma. Nevertheless, its causal role in glaucoma remains controversial. In this study, we aimed to determine the causal relationship between CCT and glaucoma by using the Mendelian randomization (MR) approach with CCT-associated SNPs as instrumental variables. Participants across 3 ethnicity cohorts of the Singapore Epidemiology Eye Disease (SEED) Study were included in this analysis. We first identified SNPs which were most strongly associated with CCT in our cohorts, by examining 100kb within 15 previously established CCT genes. Based on the selected SNPs, we then constructed a multi-locus genetic risk score (GRS) by summing the number of alleles of each SNP, weighted by its effect size with CCT. We examined the association between CCT with primary open angle glaucoma (POAG) and all glaucoma using conventional logistic regression analyses, while adjusted for age, gender, intraocular pressure and axial length. We also performed MR analyses which used CCT GRS as instrument variables to test the associations between CCT and glaucoma. Each cohort was analyzed separately and the estimates were combined across cohorts with fixed effect meta-analysis. A total of 6,945 participants (2,529 Malay, 2,531 Indian, and 1,885 Chinese) across the 3 study cohorts were included in the analyses. There were a total of 222 glaucoma cases, of which 142 were POAG. Conventional logistic regression analyses showed that each 10 m decrease in CCT was significantly associated with increased risk of glaucoma (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.03 to 1.13, P = 0.001) and POAG (OR 1.09, 95% CI 1.03 to 1.15, P = 0.003). However, MR analyses revealed no evidence of causal relationships between CCT with glaucoma (OR 1.05, 95% CI 0.98 to 1.13, P = 0.197) and POAG (OR 1.00, 95% CI 0.92 to 1.00, P = 0.937). As opposed to findings from conventional analyses, MR approach showed that thinner CCT is not causally associated with glaucoma and POAG. These findings do not collectively provide consistent evidence to substantiate the causal role of CCT in glaucoma development.

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