Genetic Correlations between Corneal Biophysical Parameters and Anthropomorphic Traits

Abstract

Purpose : Although keratoconus has a significant heritable component, the genetic basis of the disease remains poorly understood. Epidemiological evidence suggests a relationship between keratoconus, corneal biophysical parameters, and anthropomorphic measures. To identify potential molecular factors underlying keratoconus, we analyzed genetic correlations between corneal biophysical parameters and anthropomorphic traits.

Methods : We assembled genome-wide association study summary statistics from European-derived participants in the UK Biobank including biophysical parameters (central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], and 3mm index of keratometry result [3mmK]), and anthropomorphic traits (body mass index [BMI], weight, and height). We calculated global and focal genetic correlations (r_g) between traits using linkage disequilibrium (LD) score regression, applying Bonferroni’s correction for multiple hypothesis testing. Finally, we identified genes located within significantly correlated regions and identified patterns of tissue expression and pathway enrichment using gene set enrichment analysis.

Results : We observed significant genetic correlations between height and corneal biophysical parameters, but not keratometry. Global LD score regression revealed significant negative correlations between height and both CH (r_g = -0.12; p = 2.0 × 10^-7) and CRF (r_g = -0.11; p = 6.9 × 10^-7). Focal analysis revealed 68 genomic regions exhibiting significant local genetic covariance between CRF and height, containing 763 protein-coding genes, including 15 with known keratoconus associations in DisGeNet (Table). Gene set enrichment analysis on the list of genes in regions with significant focal r_g revealed enrichment among metabolic pathways with known keratoconus associations, including oxytocin signaling and transient receptor potential (TRP) channel regulation (p < 0.001; Figure).

Conclusions : These results suggest that interrogating the shared genetic heritability between CH, CRF and height may inform the genetic architecture for ectatic corneal disease and possibly provide new disease insights for keratoconus.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Table. Keratoconus-associated genes in regions exhibiting significant local genetic correlation. The Bonferroni-adjusted significance threshold is 0.00238.

 

Figure. Pathway enrichment among genes in regions with significant local genetic correlation between CRF and height.