Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia

Abstract

Significance Myopia prevalence has increased dramatically over recent decades. Genome-wide association studies have identified numerous loci, but mechanisms by which genotypic identity confers myopia susceptibility are unknown. The common variant most strongly associated with myopia is near a gene encoding retinal gap junctions. We analyzed retinal electrophysiological responses from 186 twins genotyped at this locus, finding association between cone-driven, but not rod-driven, electroretinogram signals and allelic genotype. Examination of responses to further, nonstandard testing protocols, together with recordings from patients with selective loss of bipolar cell signals, points to an effect on cone-driven hyperpolarizing (“OFF”) signals. The pattern of retinal expression of this gene appears consistent with these findings, which support a potential role for altered cone-driven signaling in myopia development.

Flash Electroretinography as a Measure of Retinal Function in Myopia and Hyperopia: A Systematic Review

“…Multiple theories exist regarding the biological mechanisms and cell types within the retina that are directly involved in regulating ocular growth, with many postulating that the function of the outer retina and ON/OFF bipolar cell pathways may be particularly important [ 16 , 17 ]. The retina has a laminar structure, with the outer retina composed of rod and cone photoreceptors that transduce light into a neural signal that is transmitted to bipolar and ganglion cells in the inner retina.…”

“…In animal models, neurotoxic agents that disrupt amacrine and ganglion cell functioning alone have little effect on the growth of the vitreous chamber [ 23 , 24 , 25 , 26 ], while those that affect bipolar or photoreceptor function do alter the rate of postnatal vitreous enlargement and visually induced ocular growth [ 21 , 23 , 24 , 27 , 28 ], suggesting that functional changes at the photoreceptor/RPE/bipolar cell interface may be central to myopia etiology. Recent studies of genetic variants associated with a greater risk of myopia in humans have also implicated photoreceptor and bipolar cell function [ 17 , 29 ], further suggesting that outer retinal function is central to the pathophysiology of the disorder.…”

“…Electroretinography can be used to non-invasively assess phototransduction and retinal processing of light at the cellular level in humans and animals [ 17 ]. The Electroretinogram (ERG) is an established electrophysiological diagnostic technique that is widely used in clinical and laboratory settings [ 30 , 31 ].…”

“…Although it is well accepted that the excessive ocular growth observed in animal models of myopia is locally controlled within the retina, the evidence and theories regarding the particular cell types involved in the control of ocular growth and the progression to secondary pathology in humans and animal models are still under debate [ 16 , 17 ]. Furthermore, to develop effective treatments and to facilitate the identification of those at higher risk of progressive myopic eye growth and later development of sight-threatening pathology, a better understanding of cellular contributions to myopia is necessary.…”

Education interacts with genetic variants near GJD2, RBFOX1, LAMA2, KCNQ5 and LRRC4C to confer susceptibility to myopia

“…GJD2 is one of the most intensively studied myopia-susceptibility genes [ 34 – 36 ]. GJD2 encodes the neuronal gap junction protein connexin-36 (Cx36), which is thought to play a role in ON-bipolar cell signaling and cone-driven OFF pathways in the retina [ 35 , 37 , 38 ]. Loss-of-function mutations in connexin-36 in a Zebrafish model inhibit eye growth and diminish the electroretiniogram B-wave amplitude [ 35 ].…”