Bidirectional Causal Relationships between Corneal Biomechanics and Glaucoma or Intraocular Pressure.

Objective: To investigate the bidirectional causal relationships between corneal biomechanics (corneal hysteresis [CH] and corneal resistance factor [CRF]) and glaucoma subtypes or intraocular pressure (IOP), and to evaluate the mediating role of IOP in these associations.

Design: Bidirectional univariable 2-sample Mendelian randomization (MR), multivariable MR, and mediation MR study using genome-wide association study (GWAS) summary statistics.

Subjects: Genetic data from large-scale GWAS cohorts of European ancestry, including individuals with measurements of CH/CRF, glaucoma subtypes (primary open-angle glaucoma [POAG], primary angle-closure glaucoma [PACG], normal-tension glaucoma [NTG], exfoliation glaucoma [XFG], juvenile open-angle glaucoma [JOAG], glaucoma suspect, neovascular glaucoma, secondary glaucoma, and other unspecified glaucoma), and glaucoma endophenotypes (IOP, retinal nerve fiber layer thickness, vertical cup-to-disc ratio).

Methods: Bidirectional univariable 2-sample MR analyses were performed to assess the causal effects between CH/CRF and glaucoma subtypes. Multivariable MR and mediation analysis were used to evaluate the role of IOP. Inverse-variance weighted, weighted median, MR-Egger regression, and MR-Pleiotropy RESidual Sum and Outlier were used to evaluate the causal effects, pleiotropy, and heterogeneity.

Main Outcome Measures: The primary outcomes included causal estimates (odds ratios or β-coefficients) for the associations between CH/CRF and glaucoma subtypes (POAG, PACG, NTG, XFG, JOAG, neovascular glaucoma, etc.) and the mediation effects of IOP. Secondary outcomes included relationships between glaucoma medication or surgery and CH/CRF.

Results: Corneal hysteresis and CRF were causally associated with increased risks of total glaucoma and most subtypes, except for the protective effect of CH against neovascular glaucoma. Both CH and CRF elevated IOP. Adjusting for IOP attenuated CH/CRF-glaucoma associations. Glaucoma inversely affected CH but positively influenced CRF. Glaucoma surgery reduced CH and CRF.

Conclusions: This study suggests that CH and CRF are risk factors for glaucoma and its subtypes, with IOP playing a mediating role in this relationship. These findings highlight the role of corneal biomechanics in glaucoma pathophysiology and clinical management.

Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.