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

Area of Science:

• Genetics
• Ophthalmology
• Endocrinology

Background:

• Keratoconus (KC) is a complex eye condition with poorly understood genetic and hormonal influences.
• Sex hormones are hypothesized to play a role in KC pathogenesis, but direct causal evidence is lacking.

Purpose of the Study:

• To investigate potential causal relationships between genetically determined sex hormone levels and keratoconus risk using Mendelian randomization.
• To explore the association between sex hormones and corneal biomechanical properties.

Main Methods:

• Utilized large-scale genome-wide association study (GWAS) summary data for Mendelian randomization (MR) analysis.
• Employed inverse-variance weighted (IVW) and weighted median methods, with MR-Egger regression for pleiotropy assessment.
• Conducted sensitivity analyses including MR-PRESSO and leave-one-out tests, with FDR correction for multiple comparisons.

Main Results:

• Higher genetically predicted total testosterone levels in males were nominally associated with reduced KC risk and significantly associated with increased corneal resistance factor.
• Sex hormone-binding globulin (SHBG) showed a nominal protective association with KC in females, which did not reach statistical significance after FDR correction.
• Sensitivity analyses indicated no significant heterogeneity or directional pleiotropy in the primary models.

Conclusions:

• Preliminary genetic evidence suggests testosterone-related pathways may influence keratoconus development, particularly in males.
• The findings are hypothesis-generating and require further validation due to several nominal associations.
• This research highlights potential genetic links between sex hormones and corneal health, warranting further investigation.