Phenotypic consequences of GJD2, the first GWAS hit for common myopia

Abstract

Purpose : The GJD2 gene, encoding the gap junction protein connexin 36, has been implicated in refractive error and myopia through many genome-wide association studies. The effect of the GJD2 risk genotype on ocular phenotype has not been studied extensively. Here, we investigated ocular biometry parameters as a function of GJD2 genotype in large population-based adult and children studies, and a high myopia case control study.

Methods : A total of 11,636 adults (mean age 63.6 (SD 10.7) years, 42.5% male) from the population-based Rotterdam Study and the cross-sectional MYST Study, and 4132 children (mean age 6.2 (SD 0.51) years; 50.7% male) from Generation R were included in our study. Non-cycloplegic refraction and ocular biometry data, i.e. axial length (AL), corneal thickness (CT), anterior chamber depth (ACD), lens thickness (LT) and vitreous depth (VD), were measured with Topcon RM-A2000 Auto-Refractor in adults, with Canon R50 instrument in children. The axial length/corneal radius (ALCR) ratio was used as a proxy for refractive error in children. The genotype of the most commonly associated GJD2 SNP (rs524952; TT, TA, AA) was determined using Illumina SNP platform.
We compared differences in refractive error and ocular biometry between the 3 genotypes using ANOVA or independent t-test for normally distributed data, with Kruskal Wallis test or Mann Whitney test for skewed data. To correct for possible differences in eye size between genotypes, analyses were adjusted for AL.

Results : Minor allele frequency of the genetic variant in the adult and children study population was 48.2% and 48.5% respectively. We identified a more myopic refractive error, larger AL and longer VD in adults carrying two risk alleles (AA vs TT -0.36D vs 0.32D; 24.3mm vs 23.8 mm; 16.7mm vs 16.2mm; p<0.001, respectively). Correction for AL did not change results, except for a thinner lens and cornea (AA vs TT 0.18 vs 0.19; 0.0226 vs 0.0231 p<0.001 for LT and CT respectively). ALCR was larger in children carrying two risk alleles at age 5 and 9 years (AA vs TT 2.88 vs 2.87, and 3.00 vs 2.96 P<0.001, respectively).

Conclusions : The GJD2 risk genotype leads to myopia by mainly an enlarged VD, possibly compensated by thinning of the cornea and lens. The effect of this risk genotype appears to start at a young age. This study helps to unravel the possible mechanisms leading to myopia in humans.

This is a 2020 ARVO Annual Meeting abstract.