A genome wide association study of electroretinogram oscillatory potentials

Abstract

Purpose : Oscillatory potentials (OPs) are high frequency components present on the ascending limb of the b-wave in the flash electroretinogram ERG, thought to derive from amacrine cells. They are potentially of clinical importance, for example being selectively lost in subclinical diabetic retinopathy. In this study, we undertook an exploratory genome-wide association study (GWAS) of OPs.

Methods : Adult twins were recruited from the TwinsUK registry for full-field ERGs (Espion system, Diagnosys, Lowell, MA) recorded in response to international standard stimuli, using conductive fibre electrodes, following mydriasis. OPs were extracted by high pass filtering of standard scotopic flash responses (3 cd m^-2 s). The averaged amplitudes and peak time from the first three OP peaks from both eyes were quantified and normalised for association testing using linear mixed models with adjustment for age, sex and familial relatedness. Cell type enrichment analysis by LD score regression was subsequently performed to explore which retinal cells are highly associated with OPs by gene expression.

Results : The first three OPs peak time and amplitudes were collected from 178 genotyped twins (mean age 64.0±9.9 years). No associations reached genome-wide significance while 91 loci near 37 genes reached suggestive significance (p<1x10^-5). The strongest association was a locus within LRRTM4 (p=7.58x10^-7), which encodes a protein enriched at GABAergic synapses on rod bipolar cell axon terminals. Other interesting associations included GSK3B (p=8.7x10^-7), expressed in amacrine cells, horizontal cells, bipolar cells, and retinal ganglion cells, and RBFOX1, a gene highly specifically expressed in amacrine cells and also identified as a myopia risk gene. In retinal cell enrichment analysis, for the first OP amplitude, highest enrichment was in GABAergic and glycinergic amacrine subtypes. For all 3 OP peak times, retinal ganglion cells (RGCs) consistently showed highest enrichment.

Conclusions : Whilst no genetic loci attained genome-wide significance, some interesting genes emerged amongst the top hits, with loci reaching suggestive significance. The retinal cell enrichment findings could yield insight into retinal electrophysiology. For example, the first OPs amplitude appears correlated with amacrine cell subtypes; the OP peak times may be influenced by RGC activity.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.