Central corneal thickness and the risk of primary open-angle glaucoma: a Mendelian randomization mediation analysis

The association of central corneal thickness (CCT) with primary open-angle glaucoma (POAG) remains uncertain. Although, several observational studies assessing this relationship, have reported an inverse association between CCT and POAG, this could be the result of collider bias. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) the effect of CCT on POAG risk, and whether this effect is mediated by intraocular pressure (IOP) changes. We used 24 single-nucleotide polymorphisms (SNPs) associated with CCT (P-value < 5×10^-8) from a genome-wide association study (GWAS) (N = 17,803) provided by the International Glaucoma Genetics Consortium and 53 SNPs associated with IOP (P-value < 5×10^-8) from a GWAS of UK Biobank (UKBB) (N = 97,653). We related these instruments with POAG using a GWAS meta-analysis of 8,283 POAG cases and 753,827 controls from UKBB and FinnGen. MR analysis suggested a positive association between CCT and POAG (odds ratio of POAG per 50μm increase in CCT: 1.38; 95% confidence interval: 1.18 to 1.61; p-value < 0.01). MR mediation analysis showed that 28.4% of the total effect of CCT on POAG risk was mediated through changes in IOP. The primary results were consistent with estimates of pleiotropy-robust MR methods. In conclusion, contrary to most observational studies, our results support a positive effect of CCT on the risk of POAG.