Studies in the electroretinogram i‐wave: Evidence for off pathway origin and association with a myopia risk locus

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Aims/Purpose: A myopia‐risk locus near the GJD2 gene has been associated with cone‐driven electroretinograms (ERGs), specifically cone‐driven OFF pathway signals. In light‐adapted ERGs to a standard flash, conventionally measured components are the a‐wave and b‐wave. A later component, the “i‐wave”, is thought to originate in retinal OFF pathways, as evidenced by pharmacological experiments in primates. We investigated this component in human ERGs, testing the hypothesis that an association would be found with the myopia risk locus.Methods: ERGs were examined from patients with rare monogenic post‐phototransduction deficits affecting only ON pathways, or both ON and OFF pathways, to explore which gave rise to the i‐wave. ERGs were then analysed from genotyped healthy adults from the TwinsUK cohort. The i‐wave amplitude was measured in the standard flash ERG by two investigators independently. We investigated association with allelic identity, adjusting for age, sex and inter‐individual relatedness. Separately, we adjusted for refractive error where this was available.Results: Patient recordings showed i‐waves persisted in absence of ON pathway signals, but were abolished when both ON and OFF pathways were impaired. Recordings and genotypes were available in 184 TwinsUK individuals (95% female). Mean (SD) age was 64.1 (9.7) years. Allelic dosage at the risk locus was significantly associated with i‐wave amplitude Refractive error was available for 175 participants. The association in these individuals remained significant both before and after adjusting for refractive error (p = 0.035 and p = 0.043 respectively).Conclusions: ERGs in patients are consistent with the human i‐wave arising from cone‐driven OFF pathways. i‐wave amplitudes associated significantly with allelic dosage at the myopia risk locus. This supports importance of cone‐driven signalling in myopia development and adds evidence that this locus affects cone‐driven OFF pathway signals.