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

Abstract

Background: 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 randomisation (MR) the effect of CCT on POAG risk and whether this effect is mediated by intraocular pressure (IOP) changes.

Methods: 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 the UK Biobank (UKBB) (N=97 653). We related these instruments to POAG using a GWAS meta-analysis of 8283 POAG cases and 753 827 controls from UKBB and FinnGen.

Results: MR analysis suggested a positive association between CCT and POAG (OR of POAG per 50 µm increase in CCT: 1.38; 95% CI: 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.

Conclusion: Contrary to most observational studies, our results showed that a higher CCT is associated with an increased risk of POAG.

Keywords: Cornea; Genetics; Glaucoma.

Figure 1. Directed acyclic graph showing the existence of collider bias when assessing the association of central corneal thickness (CCT) with primary open-angle glaucoma (POAG). Measured IOP is a collider since both CCT and true IOP are causally associated with it (black arrows). In cases of adjustment for measured IOP in the analysis or stratification of the analysis based on measured IOP or selection of the study participants based on measured IOP, a spurious relationship (dashed red line) will occur between CCT and POAG via true IOP, even if no true causal association between CCT and POAG exists (there is no arrow connecting CCT with POAG).

Figure 2. Mendelian randomisation estimates for the effect of central corneal thickness on primary open-angle glaucoma. Estimates are reported as changes in odds of primary open-angle glaucoma per 50 µm increase in central corneal thickness. MR-PRESSO, Mendelian randomisation pleiotropy residual sum and outlier; SNP, single-nucleotide polymorphism.

Figure 3. Directed acyclic graphs of the mediation analysis with Mendelian randomisation. The indirect effect of central corneal thickness (CCT) on primary open-angle glaucoma (POAG) can be calculated by multiplying α times β, where α is the effect of CCT on intraocular pressure (IOP), and β is the effect of IOP on POAG. The proportion mediated can be estimated by dividing the indirect effect by the total effect of CCT on POAG. Estimates of the CCT effect on IOP and POAG are shown per 50 µm increase in CCT. logOR, logarithm of OR.