The Electroretinogram I-Wave, a Component Originating in the Retinal OFF-Pathway, Associates With a Myopia Genetic Risk Polymorphism.

Purpose: One of the strongest genetic associations with myopia is near the GJD2 gene. Recently, this locus was associated with cone-driven electroretinograms (ERGs), with findings highlighting OFF pathway signals specifically. The ERG i-wave is thought to originate in retinal OFF pathways. We explored this component and tested the hypothesis that it would be associated with the myopia risk locus. Methods: International standard LA3 ERGs, recorded with conductive fiber electrodes, were analyzed, first from patients with rare monogenic deficits impairing the ON pathway, or both ON and OFF pathways, to explore effects on the i-wave. Responses were then analyzed from adult participants from the TwinsUK cohort: i-wave amplitudes were measured by two investigators independently, blinded to genotype at the GJD2 locus. We investigated the association between i-wave amplitude and allelic identity at this locus, adjusting for age, sex, and familial relatedness. Results: Patient recordings showed the i-wave persisted in the absence of ON pathway signals, but was abolished when both ON and OFF pathways were impaired. For TwinsUK participants, recordings and genotypes were available in 184 individuals (95% female participants; mean standard deviation [SD] age, 64.1 [9.7] years). Mean (SD) i-wave amplitude was 14.5 (SD = 6.5) microvolts. Allelic dosage at the risk locus was significantly associated with i-wave amplitude (P = 0.027). Conclusions: Patient ERGs were consistent with the i-wave arising from cone-driven OFF pathways. Amplitudes associated significantly with allelic dosage at the myopia risk locus, supporting the importance of cone-driven signaling in myopia development and further highlighting relevance of the OFF pathway in relation to this locus.