Causal Effects of Corneal Traits on the risk of Keratoconus Using Genetic Instruments

Purpose To determine the causal effects of corneal traits on keratoconus (KC) using Mendelian randomization (MR) analysis. Design This is a two-sample Mendelian randomization (MR) study. Methods We performed two-sample MR analyses using European-ancestry genetic data. Genetic instruments for central corneal thickness (CCT), corneal hysteresis (CH), and corneal resistance factor (CRF) were analyzed against KC risk. Inverse variance weighted (IVW) regression served as the primary method to estimate causal effects. Results IVW analysis demonstrated that thicker CCT (per 1 mm) was causally associated with reduced KC risk (OR: 0.978, 95% CI: 0.961 to 0.995, P=0.01). Genetically predicted increases in right/left CH and right/left CRF (per 1 mmHg) were strongly inversely associated with KC (OR range: 0.165 to 0.198; all P<1.9×10⁻¹⁵). Sensitivity analyses confirmed robustness and directionality of these effects. Conclusion A causal effect between corneal traits and KC were indicated. Corneal biomechanical integrity, reflected by increased central corneal thickness, hysteresis, and resistance factor, causally protects against KC while established disease accelerates corneal degradation.