Causal associations between sex hormones and keratoconus: a two-sample Mendelian randomization study.

INTRODUCTION

This Mendelian randomization (MR) study evaluated potential causal associations between sex hormones and keratoconus (KC) using large-scale GWAS summary data.

METHODS

The primary analysis utilized the inverse-variance weighted (IVW) method, supplemented by weighted median, MR-Egger regression, and Radial MR for outlier detection. Sensitivity analyses, including MR-PRESSO and leave-one-out tests, were performed alongside FDR correction to ensure robustness and control for multiple testing.

RESULTS

After outlier correction, higher total testosterone levels (TTL) in males showed a nominal association with reduced KC risk (OR = 0.78, 95% CI: 0.66-0.93, p = 0.005; FDR-adjusted p = 0.068) and a statistically significant positive association with increased corneal resistance factor (OR = 1.09, 95% CI: 1.03-1.15, p = 0.0015; FDR-adjusted p = 0.0405). Conversely, female sex hormone-binding globulin (SHBG) showed only a nominally protective association with KC (OR = 0.76, 95% CI: 0.58-1.00, p = 0.048) that lost significance after FDR adjustment (p = 0.429). Sensitivity analyses revealed no substantial heterogeneity or directional pleiotropy in the key models.

DISCUSSION: In conclusion, these findings provide preliminary genetic evidence that testosterone-related pathways may influence KC development, particularly in males. However, as several findings remained nominal, they should be interpreted as hypothesis-generating rather than definitive and require further validation in future research.