Genetic Correlations Among Corneal Biophysical Parameters and Anthropometric Traits

Abstract

Purpose: The genetic architecture of corneal dysfunction remains poorly understood. Epidemiological and clinical evidence suggests a relationship between corneal structural features and anthropometric measures. We used global and local genetic similarity analysis to identify genomic features that may underlie structural corneal dysfunction.

Methods: We assembled genome-wide association study summary statistics for corneal features (central corneal thickness, corneal hysteresis [CH], corneal resistance factor [CRF], and the 3 mm index of keratometry) and anthropometric traits (body mass index, weight, and height) in Europeans. We calculated global genetic correlations (rg) between traits using linkage disequilibrium (LD) score regression and local genetic covariance using ρ-HESS, which partitions the genome and performs regression with LD regions. Finally, we identified genes located within regions of significant genetic covariance and analyzed patterns of tissue expression and pathway enrichment.

Results: Global LD score regression revealed significant negative correlations between height and both CH (rg = -0.12; P = 2.0 × 10-7) and CRF (rg = -0.11; P = 6.9 × 10-7). Local analysis revealed 68 genomic regions exhibiting significant local genetic covariance between CRF and height, containing 2874 unique genes. Pathway analysis of genes in regions with significant local rg revealed enrichment among signaling pathways with known keratoconus associations, including cadherin and Wnt signaling, as well as enrichment of genes modulated by copper and zinc ions.

Conclusions: Corneal biophysical parameters and height share a common genomic architecture, which may facilitate identification of disease-associated genes and therapies for corneal ectasias.

Translational relevance: Local genetic covariance analysis enables the identification of associated genes and therapeutic targets for corneal ectatic disease.

Figure 1.

Expression in human ocular tissue of genes in regions of significant genetic covariance. (A) Distribution of single-cell expression levels in ocular cell types for genes in regions of significant covariance reveals high expression in cornea-related cell types, including Schwalbe cells and corneal epithelial cells. BeamCella, type A beam cells; BeamCellb, type B beam cells; CollectorChnIAqVein, collector channel cells; CribiformJCT, juxtacanalicular tissue cells; NKT, natural killer cells; ScEndo, Schlemm canal cells; SchwannCell-my, myelinating Schwann cells; SchwannCell-nmy, nonmyelinating Schwann cells. (B, C) Overall expression levels of genes in regions of high covariance were significantly greater in bulk corneal tissue from keratoconus patients than in corneal tissue from controls.

Figure 2.

Enrichment of functional gene sets in regions of significant genetic covariance. (A) Gene set enrichment analysis of PANTHER pathways among genes in regions of high covariance reveals enrichment of pathways related to cell-cell adhesion and connective tissue development. (B) Analysis of drug target gene sets shows enrichment of genes modulated by zinc, copper, and calcium ions in correlated regions, as well as enrichment of targets for tamoxifen.