GWAS of corneal biomechanics identifies over 200 novel associated loci providing additional insight into the genetic aetiology of ocular disease

Abstract

Purpose : Corneal hysteresis (CH) and corneal resistance factor (CRF) are measures of dynamic corneal biomechanics. Results from previous studies indicate that these measures may be clinically informative for ocular diseases. The purpose of this study was to identify genetic variants associated with corneal biomechanics, and assess their relation to other ocular traits.

Methods : The discovery cohort consisted of 106,000 unrelated European participants in the UK Biobank. Measures of CH and CRF were used as outcome variables in separate linear regressions, adjusted for age, sex and population structure. Two independent cohorts, TwinsUK and EPIC-Norfolk were used for replication. Uncorrelated, significantly associated (p<5x10^-8) variants were used as genetic instruments for Mendelian Randomisation to determine causal relationships between corneal biomechanics and other ocular phenotypes.

Results : Variants clustered at 157 and 181 distinct loci were associated with genome-wide significance for CH and CRF respectively. Most of these loci are novel, but several overlapped with known genetic risk factors for other ocular diseases. Strong associations were observed for the FNDC3B (P_CH=6.7x10^-91; P_CRF=6.9x10^-134) and COL6A1 (P_CH=7.5x10^-98; P_CRF=1.1x10^-101) loci, both associated with central corneal thickness. Strong association was also present within the TCF4 gene for variants that are among the greatest risk factors for Fuchs Endothelial Corneal Dystrophy (FECD) (P_CH=2.0x10^-77; P_CRF=3.9x10^-92). CRF was significantly associated with variants within GAS7 (p=1.4x10^-30) which is also associated with intraocular pressure (IOP) and Primary Open Angle Glaucoma (POAG). A relationship between CRF and POAG was further supported with the identification of significant genetic correlation (r=0.3, P=1.4x10^-10) using LD score regression. Mendelian randomisation implicated a unidirectional, causative effect of IOP over both CH and CRF.

Conclusions : Corneal biomechanical properties are highly polygenic and this GWAS has identified a considerable proportion of their genetic architecture. The overlapping and correlated genetic factors between corneal biomechanics and ocular disease indicate that these results may provide additional insight into the genetic aetiology of POAG and FECD.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.