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

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Xiaofan Jiang, Zihe Xu, Talha Soorma, Ambreen Tariq, Taha Bhatti, Alexander J Baneke, Nikolas Pontikos, Shaun M Leo, Andrew R Webster, Katie M Williams, Christopher J Hammond, Pirro G Hysi, Omar A Mahroo

Bibliographical note

Funding Information: ACKNOWLEDGMENTS. This work was supported by the Wellcome Trust (206619/Z/17/Z), Moorfields Eye Charity, Fight for Sight UK, and the National Institute for Health and Care Research Biomedical Research Centre at Moorfields Eye Hospital and the University College London Institute of Ophthalmology. TwinsUK receives support from the Wellcome Trust and the Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. The funding organizations had no role in the design or conduct of this research. The views expressed are those of the authors and not the funding organizations. This research was funded in whole or in part by the Wellcome Trust. Publisher Copyright: Copyright © 2022 the Author(s).

King's Authors


Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and myopia usually results from an excessively long eye. The common variant most strongly associated with myopia is near the GJD2 gene, encoding connexin-36, which forms retinal gap junctions. Light-evoked responses of retinal neurons can be recorded noninvasively as the electroretinogram (ERG). We analyzed these responses from 186 adult twin volunteers who had been genotyped at this locus. Participants underwent detailed ERG recordings incorporating international standard stimuli as well as experimental protocols aiming to separate dark-adapted rod- and cone-driven responses. A mixed linear model was used to explore association between allelic dosage at the locus and international standard ERG parameters after adjustment for age, sex, and family structure. Significant associations were found for parameters of light-adapted, but not dark-adapted, responses. Further investigation of isolated rod- and cone-driven ERGs confirmed associations with cone-driven, but not rod-driven, a-wave amplitudes. Comparison with responses to similar experimental stimuli from a patient with a prior central retinal artery occlusion, and from two patients with selective loss of ON-bipolar cell signals, was consistent with the associated parameters being derived from signals from cone-driven OFF-bipolar cells. Analysis of single-cell transcriptome data revealed strongest GJD2 expression in cone photoreceptors; bipolar cell expression appeared strongest in OFF-bipolar cells and weakest in rod-driven ON-bipolar cells. Our findings support a potential role for altered signaling in cone-driven OFF pathways in myopia development.

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