Myopia Insights Through the Lens of Omics

This article elucidates the utility of these approaches in dissecting the molecular underpinnings of myopia and its secondary sequalae. The authors argue that ‘omics’ techniques provide the ideal platform for not only understanding the physiological processes underlying myopia, but also a future basis for the development of personalised, precision interventions.

Knowledge that the worldwide prevalence of myopia is dramatically increasing would be of no surprise to those in practice.^1-3 Current data estimates the incidence of myopia at between 20–40%, with rates as high as 80% in South East Asia.^4-6 Clearly, there is a heritability component underlying predisposition towards developing myopia,^7-9 but converging epidemiological and experimental evidence highlights the substantial contribution of environmental factors in driving the condition.^7,10

From an epidemiological perspective, we see increases in myopia incidence coinciding with the introduction of universal access to education and higher rates of continued study, as well as factors such as reduced outdoor light exposure and increased close work and technology use.^11-15 These observations support the conceptualisation of myopia as a physiological adaptation of a biological system to modern visual demands. Unfortunately, a corollary of greater rates of myopia, and thus high myopia, is the greater population risk of secondary, sightthreatening conditions and blindness.^1,16,17 Thus, understanding the mechanisms underlying the abnormal elongation and volume characteristic of the condition is imperative for developing effective, evidencebased, and accessible interventions and therapeutic management strategies, and to relieve the significant socio-economic burden of the condition.^18,19

Basic research provides the ideal avenue for achieving this goal. Animal models designed to replicate the induction of refractive error via ocular occlusion or defocussing lenses show a large degree of cross species conservation of both morphological growth and physiological responses, that closely mirror the characteristic features of myopia.^20-22 The chick, our model of choice, is a popular animal model^23,24 as chicks rapidly and reliably respond to experimental manipulation and exhibit growth changes remarkably like humans on most physical and physiological levels. Other commonly used species are tree shrews, guinea pigs, monkeys, and zebra fish.²⁵

INDUCING REFRACTIVE ERROR

Experimental models generate growth analogous to myopia by exploiting refractive compensation mechanisms and measuring changes during the induction of form deprivation (FD) or blur, or recovery from such.^22,23,25-27 Growth following FD induction is not unlike growth associated with visual disease or ocular occlusion that eliminates or degrades the image on the retina in humans.^28-32 Comparatively, inducing signed blur with defocussing lenses (LD) drives a more precise refractive compensation process, generating growth adaptation towards the power of the lens. Both techniques cause the eye to rapidly initiate adjustments in axial dimensions to compensate for the loss of focus, measurable within hours.³³ Alterations in axial length and vitreous chamber depth are accompanied by alterations in the thickness of the vascular choroid,^34-38 decreased fluid flow and changes in vascular dimensions, in conjunction with changes in vascular and lymphatic structure,^37,39-41 remodelling of the scleral extracellular matrix, and changes in cell density.^42-46 Finally, the gross morphological structure and ultrastructure of the retina is also altered in myopia.^39,47-49 This includes damage to cone outer segments, alterations to inner segments, density changes,⁴⁷ and altered glial function,^50-52 with many of these changes indicative of metabolic dysfunction and inflammation.⁵³

The ability to induce refractive error has enabled investigation of the mechanisms driving growth and potential avenues for disrupting such growth, thus ‘preventing’ myopia. Many groups have focussed on pharmacological agents, neurotransmitters, peptides and other molecules,^28,49,54-60 as well as temporal, spatio-temporal^61-63 and wavelength^64-67 properties of light using combinations of animal rearing, immunohistochemical, molecular, and electrophysiological techniques to probe the issue.

While a number of these investigations have reported meaningful findings contributing to our understanding of myopia development, we have not yet been able to find a resolution on the signal driving refractive change, and thus must look more systematically through the powerful lens of ‘omics’ to address the question.

OMICS TECHNIQUES

Biological systems are multi-layered. DNA housed inside our cells is transcribed into RNA, which is then translated into proteins. Proteins serve as the workhorses of the cell, performing a wide array of functions including catalysing metabolic reactions as enzymes, providing structural support, and regulating cellular processes. They interact with metabolites – small molecules involved in metabolism – by facilitating their conversion into energy, signalling molecules, or building blocks for cellular structures. Metabolites, in turn, influence cellular processes and can feedback to affect gene expression and protein activity, creating a dynamic and interconnected network essential for life. Epigenetic modifications such as DNA methylation add another layer of complexity, influencing how genes are expressed in response to environmental factors without altering the DNA sequence itself. Omics techniques allow researchers to examine, at a broad scale, changes within each of these layers – the epigenome, genes, transcripts, proteins, and metabolites – and to dissect the complex interactions of these molecules in health and disease⁶⁸ (Figure 1).

Genome-wide association studies (GWAS) involve obtaining DNA samples, typically from peripheral blood, and scanning them for hundreds of thousands of genetic markers such as single nucleotide polymorphisms, to identify those associated with specific traits or diseases.⁶⁹ Human GWAS have linked hundreds of genes to axial length⁷⁰ and refractive error.⁹

While these analyses can provide detailed information on the genetic variations that predispose some individuals to myopia, most of the identified loci have small effect sizes, and only a small portion of the variation in spherical equivalent can be explained by genetic variation.⁹

By comparison, transcriptomics, proteomics, and metabolomics studies directly profile the expression or abundance of molecules within the tissues or biofluids expected to be affected by a disease. Because of this, they can offer insight into how genetic and environmental factors combine to determine the functional state of a tissue. Human ocular tissue and biofluid specimens aren’t easily obtained and, when available, are often affected by disease states in addition to myopia.^71,72

Consequently, studies have primarily used animal models to examine how myopia affects the ocular transcriptome, proteome, and metabolome. Such studies have identified thousands of differentially expressed genes and proteins,⁷³ and hundreds of differentially expressed metabolites,^71,74 in the retina, choroid, and sclera, in models of occlusion and lens-induced myopia. Collectively, refractive error ‘omics’ studies demonstrate that no single molecule or process controls eye growth; indeed, human and animal studies have implicated genes involved in the development and functioning of every anatomical component of the eye, and all cell types of the neurosensory retina.^9,75,76 Although the molecular processes underlying myopia are complex, when the implicated molecules are grouped together systematically, commonalities emerge that facilitate a mechanistic understanding of the processes involved.

LINKING OMICS BETWEEN HUMANS AND ANIMAL MODELS

We systematically compared the genes implicated in human GWAS of refractive error with those differentially expressed in the retina, retinal pigment epithelium (RPE), choroid, and sclera in animal models of lens- and occluder-induced myopia. We found that gene and protein expression changes are conserved across animal models of environmentally driven myopia. The genes implicated in these animal models overlap significantly with the genes near human GWAS refractive error loci.⁷³ These results are consistent with a model in which genetic and environmental factors control ocular growth via similar biological pathways, and/ or a model in which genetic variants alter susceptibility to environmental factors rather than being causative in and of themselves, as previously suggested.⁷⁷

When we looked more closely at the pattern of overlapping findings across studies, we found that, as pointed out in many individual studies,^77-79 different genes are involved in the onset versus the persistence and progression of refractive change in animal models. Interestingly, the genes linked to myopia in humans were most like those involved in the early stages of myopia development in animals.

Retinal Neurotransmission

Many of the genes implicated in myopia GWAS, and differentially expressed in the retina during early myopia induction in animals, are involved in retinal neurotransmission, consistent with the established understanding that environmentally-induced myopia involves a light-dependent signalling cascade initiated in the retina that ultimately induces scleral remodelling. Here, identification of genes involving phototransduction, ion transport, and glutamate signalling have suggested a key role for the photoreceptor-bipolar cell interface.^{9,33,75,80-85}

Electroretinogram studies have also identified changes to photoreceptor function and the balance of ON/OFF bipolar cell signalling in human myopes^86-88 and animal lens- and occlusion-myopia models.^33,89 GABA, an essential neurotransmitter in shaping signal transmission from bipolar cells to other neurons in the retina, has also been implicated in lens- and occluderinduced myopia in animals.^85,90 The primary GABAergic channels implicated in experimental myopia in animals are ionotropic, which implicates ion homeostasis, particularly chloride^91,92 and associated fluid movement.^75,84,93,94

Energy Metabolism

The functional activity and metabolic needs of the retina are closely related. It is one of the body’s most energy-demanding tissues, with most of this energy being used to power photoreceptor Na+/K+ ATPase ion channels.^95,96 Energy metabolism also provides the biosynthetic precursors required for structural remodelling and growth of tissues.⁹⁷ The retina requires both glycolysis and oxidative phosphorylation for vision,⁹⁵ and omics studies of myopia have repeatedly identified extensive changes in the abundance of molecules in the retina participating in both of these metabolic processes.^{33,80,84,90,98-103} Dysregulation of energy metabolism in the sclera has also been demonstrated, where hypoxia-induced changes within the glycolytic pathway during myopia induction have recently been shown to increase lactate levels, ultimately promoting scleral extracellular matrix remodelling and thinning via lactate-derived histone lactylation (a newly identified form of epigenetic modification),¹⁰⁴ and contributing to an advancing knowledge about the epigenetic changes associated with myopia development.^105,106 Although human studies cannot directly profile the metabolic state of retina and sclera, human GWAS have linked glucose metabolism with axial length and myopia age of onset,^{8, 83,107} and studies of serum samples from patients with high myopia have identified metabolic profiles indicative of abnormal glycometabolism.¹⁰⁸

Immune Responses and Inflammation

Immune and inflammatory processes have long been known to promote structural remodelling of tissues,^109,110 and these processes have been increasingly implicated in the myopic eye.¹¹¹ Here, omics studies suggest a particular role for the complement system, a key component of innate immunity that also assists in maintaining metabolic homeostasis in cells.^84,112-114 Indeed, when we meta-analysed datasets profiling gene expression in the retina, RPE, and choroid during refractive error induction in the widely used chick animal model, many of the growth-specific genes (i.e., genes showing bidirectional expression across myopia and hyperopia conditions) encoded proteins that form a highly connected network involved in inflammation-mediated extracellular matrix remodelling.¹⁰¹ This finding was recently mirrored in a proteomic study of the cornea in human myopes.¹¹⁵ Mechanistically, in addition to directly driving structural change, prolonged subclinical inflammation in myopia may cause endothelial dysfunction, reducing oxygen supply, and exacerbating hypoxia-linked scleral remodelling.¹¹¹

CONCLUSION

The functional, metabolic and inflammatory processes that we’ve described are part of a large-scale shift in ocular homeostasis that occurs during myopia development. Outside of the ‘omics’ literature, targeted studies have identified changes in the abundance of many single molecules such as dopamine, VIP, ERG1, ZENK, BMP (and more).^{5,25,49,116-119} And within the omics space, processes not described in depth here, such as circadian rhythm disturbance,⁹ have also been documented across studies. This shift in homeostasis provides a cascade of signals propagating from the retina through to the sclera that induce changes in the expression of genes involved in regulating cellular and extracellular structure,⁷³ ultimately resulting in axial elongation of the eye. This abnormal eye growth, in turn, has long been understood to produce mechanical and ischemic/vascular stress that underlies the development of secondary pathologies.^{10,16,120-123} Many of the biological pathways associated with myopia’s secondaries – such as oxidative stress and complement-mediated inflammation – are implicated in animal models of myopia before the emergence of any pathological structural change,^80,101 suggesting that environmentally-induced expression shifts act together with structural changes to promote the development of age-related secondary complications in myopic eyes.

Just as the molecular mechanisms underlying myopia and its sequelae are complex, it is likely that the mechanisms behind the effectiveness of myopia-control interventions are complex as well. Evidence to date has shown that effective interventions can target the myopic homeostasis shift at different levels. For example, behavioural interventions, like spending greater time outdoors, presumably target the maladaptive neurotransmission patterns underlying the retina-sclera signalling myopia. Thus, while current treatments have a broad spectrum approach showing a degree of efficacy, an ‘omics’ perspective may provide greater nuance in elaborating the cellular underpinnings from a systems biology approach, providing potential for precise and individualised care.

Dr Nina Riddell BPsySci (Hon), PhD is a lecturer in neuroscience at the Department of Psychology and Counselling at La Trobe University. Her PhD, completed at La Trobe University, focussed on the systems biology of myopia and associated secondary conditions. She has held research contracts with Hoya Vision.

Dr Loretta Vocale BMedSci (Hon), PhD is a lecturer in neuroscience and psychology at RMIT University. Her PhD investigated the biological mechanisms underlying myopia. She is completing an ARCfunded post-doctorate research fellowship focussed on understanding how brain inflammation can be detected by observing changes in the retina.

Dr Melanie Murphy BBehavSci (Hon), PhD is a lecturer in the Department of Psychology and Counselling at La Trobe University. Her expertise is in vision neuroscience ranging from the cellular basis of visual processing in animal and human models, to cognitive development and neurodegeneration of visual processing.

References

1. Haberman, I.D., Epidemiology of high myopia, in refractive surgery for high myopia: options and special considerations. 2023, Springer. p. 1–7.
2. Bullimore, M.A., et al., IMI—onset and progression of myopia in young adults. Investigative ophthalmology and visual science, 2023. 64(6): p. 2–2.
3. Landreneau, J.R., N.P. Hesemann, and M.A. Cardonell, Review on the myopia pandemic: epidemiology, risk factors, and prevention. Missouri Medicine, 2021. 118(2): p. 156.
4. Lee, S.S.–Y., et al., Incidence and progression of myopia in early adulthood. JAMA Ophthalmology, 2022. 140(2): p. 162–169.
5. Baird, P.N., et al., Myopia. Nature Reviews Disease Primers, 2020. 6(1): p. 99.
6. Morgan, I.G., et al., The epidemics of myopia: aetiology and prevention. Progress in Retinal and Eye research, 2018. 62: p. 134–149.
7. Yii, F., et al., Factors associated with pathologic myopia onset and progression: A systematic review and meta‐analysis. Ophthalmic and Physiological Optics, 2024.
8. Jiang, C., et al., A multiethnic genome-wide analysis of 19,420 individuals identifies novel loci associated with axial length and shared genetic influences with refractive error and myopia. Frontiers in Genetics, 2023. 14: p. 1113058.
9. Hysi, P.G., et al., Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia. Nature Genetics, 2020. 52(4): p. 401–407.
10. Martínez-Albert, N., Bueno-Gimeno, I., and Gené-Sampedro, A., Risk factors for myopia: A review. Journal of Clinical Medicine, 2023. 12(18): p. 6062.
11. Biswas, S., et al., The influence of the environment and lifestyle on myopia. Journal of Physiological Anthropology, 2024. 43(1): p. 7.
12. Ba, M., Li, Z., The impact of lifestyle factors on myopia development: insights and recommendations. AJO International, 2024: p. 100010.
13. Yu, M., et al., Global risk factor analysis of myopia onset in children: A systematic review and meta-analysis. Plos One, 2023. 18(9): p. e0291470.
14. Plotnikov, D., et al., Effect of education on myopia: evidence from the United Kingdom ROSLA 1972 reform. Investigative Ophthalmology & Visual Science, 2020. 61(11): p. 7–7.
15. Grzybowski, A., et al., A review on the epidemiology of myopia in school children worldwide. BMC Ophthalmology, 2020. 20: p. 1–11.
16. Manley, A., et al., Cellular and molecular mechanisms of pathogenesis underlying inherited retinal dystrophies. Biomolecules, 2023. 13(2): p. 271.
17. Fricke, T.R., et al., Global prevalence of visual impairment associated with myopic macular degeneration and temporal trends from 2000 through 2050: systematic review, meta-analysis and modelling. British Journal of Ophthalmology, 2018. 102(7): p. 855–862.
18. Foo, L.L., et al., Cost of myopia correction: a systematic review. Frontiers in Medicine, 2021. 8: p. 718724.
19. Bullimore, M.A., Brennan, N.A., Myopia: An ounce of prevention is worth a pound of cure. Ophthalmic and Physiological Optics, 2023. 43(1): p. 116-121.
20. Siegwart Jr., J.T., Norton, T.T., Goggles for controlling the visual environment of small animals. Lab Anim Sci, 1994. 44(3): p. 292–4.
21. Wildsoet, C.F., Active emmetropization – evidence for its existence and ramifications for clinical practice. Ophthalmic Physiol Opt, 1997. 17(4): p. 279–90.
22. Zadnik, K., Mutti, D.O., How applicable are animal myopia models to human juvenile onset myopia? Vision Res, 1995. 35(9): p. 1283–8.
23. Wallman, J., Turkel, J., Trachtman, J., Extreme myopia produced by modest change in early visual experience. Science, 1978. 201: p. 1249–1251.
24. Rymer, J., Wildsoet, C.F., The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Vis Neurosci, 2005. 22(3): p. 251–61.
25. Troilo, D., et al., IMI–Report on experimental models of emmetropization and myopia. Investigative ophthalmology & visual science, 2019. 60(3): p. M31–M88.
26. Troilo, D., Wallman, J., The regulation of eye growth and refractive state: an experimental study of emmetropization. Vision Res, 1991. 31(7–8): p. 1237–50.
27. Irving, E.L., M.G. Callender, and J.G. Sivak, Inducing myopia, hyperopia, and astigmatism in chicks. Optom Vis Sci, 1991. 68(5): p. 364–8.
28. Calossi, A., Increase of ocular axial length in infantile traumatic cataract. Optom Vis Sci, 1994. 71(6): p. 386–91.
29. Gee, S.S., Tabbara, K.F., Increase in ocular axial length in patients with corneal opacification. Ophthalmology, 1988. 95(9): p. 1276–8.
30. Hoyt, C.S., et al., Monocular axial myopia associated with neonatal eyelid closure in human infants. Am J Ophthalmol, 1981. 91(2): p. 197–200.
31. Nathan, J., et al., Disease-associated visual image degradation and spherical refractive errors in children. American Journal of Optometry and Physiological Optics, 1985. 62(10): p. 680–8.
32. Robb, R.M., Refractive errors associated with hemangiomas of the eyelids and orbit in infancy. Am J Ophthalmol, 1977. 83(1): p. 52–8.
33. Riddell, N., Murphy, M.J., Crewther, S.G., Electroretinography and gene expression measures implicate phototransduction and metabolic shifts in chick myopia and hyperopia models. Life (Basel), 2021. 11(6).
34. Wallman, J., Retinal influences on sclera underlie visual deprivation myopia. Ciba Found Symp, 1990. 155: p. 126–34.
35. Wallman, J., et al., Moving the retina: a third mechanism of focusing the eye. Investigative Ophthalmology and Visual Science, 1992. Supp. 33: p. 1053.
36. Wildsoet, C., Wallman, J., Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vision Res, 1995. 35(9): p. 1175–94.
37. Junghans, B., et al., Lymphatics in chick choroid? ANZ J Ophthalmol, 1996. 24(2): p. 47–9.
38. Marmor, M.F., Wolfensberger, T.J., eds. The Retinal Pigment Epithelium. 1998, Oxford University Press: New York.
39. Beresford, J.A., et al., Comparison of refractive state and circumferential morphology of retina, choroid, and sclera in chick models of experimentally induced ametropia. Optom Vis Sci, 2001. 78(1): p. 40–9.
40. Shih, Y.F., et al., Influence of ophthalmic nerve fibers on choroidal blood flow and myopic eye growth in chicks. Exp Eye Res, 1999. 69(1): p. 9–20.
41. Fitzgerald, M.E., Wildsoet, C.F., Reiner, A., Temporal relationship of choroidal blood flow and thickness changes during recovery from form deprivation myopia in chicks. Exp Eye Res, 2002. 74(5): p. 561–70.
42. Gottlieb, M.D., Joshi, H.B., Nickla, D.L., Scleral changes in chicks with form–deprivation myopia. Curr Eye Res, 1990. 9(12): p. 1157–65.
43. Kusakari, T., Sato, T., Tokoro, T., Regional scleral changes in form-deprivation myopia in chicks. Exp Eye Res, 1997. 64(3): p. 465–76.
44. Rada, J.A., Achen, V.R., Rada, K.G., Proteoglycan turnover in the sclera of normal and experimentally myopic chick eyes. Invest Ophthalmol Vis Sci, 1998. 39(11): p. 1990–2002.
45. Nickla, D.L., Wildsoet, C., Wallman, J., Compensation for spectacle lenses involves changes in proteoglycan synthesis in both the sclera and choroid [published erratum appears in Curr Eye Res 1997 Jun;16(6):624–5]. Curr Eye Res, 1997. 16(4): p. 320–6.
46. Yinon, U., et al., Lid suture myopia in developing chicks: optical and structural considerations. Curr Eye Res, 1982. 2(12): p. 877–82.
47. Liang, H., et al., A role for photoreceptor outer segments in the induction of deprivation myopia. Vision Research, 1995. 35(9): p. 1217–1225.
48. Noller, N.J., Eye enlargement in the chick following visual deprivation. 1984, Melbourne.
49. Crewther, D.P., The role of photoreceptors in the control of refractive state. Prog Retin Eye Res, 2000. 19(4): p. 421–57.
50. Goodyear, M.J., et al., A role for aquaporin-4 during induction of form deprivation myopia in chick. Molecular vision, 2008. 14: p. 298.
51. Zhang, X., et al., Functions of retinal astrocytes and Müller cells in mammalian myopia. BMC Ophthalmology, 2022. 22(1): p. 451.
52. Lin, C., et al., Myopia alters the structural organization of the retinal vasculature, GFAP-positive glia, and ganglion cell layer thickness. International Journal of Molecular Sciences, 2022. 23(11): p. 6202.
53. Crewther, S.G., et al., Ionic control of ocular growth and refractive change. Proc Natl Acad Sci USA, 2006. 103(42): p. 15663–8.
54. Wang, W-Y., et al., Pharmacotherapeutic candidates for myopia: a review. Biomedicine & Pharmacotherapy, 2021. 133: p. 111092.
55. Crewther, D.P., Crewther, S.G., Pharmacological modification of eye growth in normally reared and visually deprived chicks. Curr Eye Res, 1990. 9(8): p. 733–40.
56. Westbrook, A.M., et al., Formoguanamine-induced inhibition of deprivation myopia in chick is accompanied by choroidal thinning while retinal function is retained. Vision Res, 1995. 35(14): p. 2075–88.
57. Pickett Seltner, R.L., Stell, W.K., The effect of vasoactive intestinal peptide on development of form deprivation myopia in the chick: a pharmacological and immunocytochemical study. Vision Research, 1995. 35(9): p. 1265–1270.
58. Seko, Y., Shimizu, M., Tokoro, T., Retinoic acid increases in the retina of the chick with form deprivation myopia. Ophthalmic Res, 1998. 30(6): p. 361–7.
59. Stone, R.A., Lin, T., Laties, A.M., Retinal dopamine and form deprivation myopia. Proceedings of the National Academy of Sciences, 1989. 86: p. 704–706.
60. Wang, G.Y., Liets, L.C., Chalupa, L.M., Nitric oxide differentially modulates ON and OFF responses of retinal ganglion cells. J Neurophysiol, 2003. 90(2): p. 1304–13.
61. Crewther, S.G., et al., Low frequency temporal modulation of light promotes a myopic shift in refractive compensation to all spectacle lenses. Exp Eye Res, 2006. 83(2): p. 322–8.
62. Murphy, M.J., et al., Light modulation, not choroidal vasomotor action, is a regulator of refractive compensation to signed optical blur. British journal of pharmacology, 2011. 164(6): p. 1614–1626.
63. Murphy, M.J., et al., Temporal whole field sawtooth flicker without a spatial component elicits a myopic shift following optical defocus irrespective of waveform direction in chicks. PeerJ, 2019. 7: p. e6277.
64. Riddell, N., et al., Long-wavelength–filtered light transiently inhibits negative lens-induced axial eye growth in the chick myopia model. Translational Vision Science & Technology, 2021. 10(9): p. 38–38.
65. Nickla, D.L., et al., Effects of morning or evening narrow-band blue light on the compensation to lens-induced hyperopic defocus in chicks. Optometry and Vision Science, 2023. 100(1): p. 33–42.
66. Rucker, F.J., Eskew Jr, R.T., Taylor, C., Signals for defocus arise from longitudinal chromatic aberration in chick. Experimental Eye Research, 2020. 198: p. 108126.
67. Gisbert, S., Wahl, S., Schaeffel, F., Impact of cone abundancy ratios and light spectra on emmetropization in chickens. Experimental Eye Research, 2022. 219: p. 109086.
68. Dai, X., Shen, L., Advances and trends in omics technology development. Front Med (Lausanne), 2022. 9: p. 911861.
69. Uffelmann, E., et al., Genome-wide association studies. Nature Reviews Methods Primers, 2021. 1(1): p. 59.
70. Jackson, D., Moosajee, M., The genetic determinants of axial length: from microphthalmia to high myopia in childhood. Annu Rev Genomics Hum Genet, 2023. 24: p. 177–202.
71. Tang, Y.P., et al., Vitreous metabolomic signatures of pathological myopia with complications. Eye (Lond), 2023. 37(14): p. 2987–2993.
72. Xue, M., et al., Proteomic analysis of aqueous humor in patients with pathologic myopia. Journal of Proteomics, 2021. 234: p. 104088.
73. Riddell, N., Crewther, S.G., Integrated Comparison of GWAS, transcriptome, and proteomics studies highlights similarities in the biological basis of animal and human myopia. Invest Ophthalmol Vis Sci, 2017. 58(1): p. 660–669.
74. Liang, C., et al., Metabolomic profiling of ocular tissues in rabbit myopia: Uncovering differential metabolites and pathways. Exp Eye Res, 2024. 240: p. 109796.
75. Tedja, M.S., et al., Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nature Genetics, 2018. 50(6): p. 834–848.
76. Giummarra, L., Crewther, S., Genes, proteins and biological pathways in human and animal myopia. Ophthalmology and Ophthalmic Surgery, 2019. 2(1).
77. Stone, R.A. Khurana, T.S., Gene profiling in experimental models of eye growth: clues to myopia pathogenesis. Vision Res, 2010. 50(23): p. 2322–33.
78. Guo, L., et al., Gene expression signatures in tree shrew sclera in response to three myopiagenic conditions. Invest Ophthalmol Vis Sci, 2013. 54(10): p. 6806–19.
79. He, L., et al., Gene expression signatures in tree shrew choroid during lens–induced myopia and recovery. Exp Eye Res, 2014. 123: p. 56–71.
80. Riddell, N., et al., The retina/RPE proteome in chick myopia and hyperopia models: Commonalities with inherited and age-related ocular pathologies. Mol Vis, 2017. 23: p. 872–888.
81. Stone, R.A., et al., Image defocus and altered retinal gene expression in chick: clues to the pathogenesis of ametropia. Invest Ophthalmol Vis Sci, 2011. 52(8): p. 5765–77.
82. Kiefer, A.K., et al., Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia. PLoS Genetics, 2013. 9(2): p. e1003299.
83. Wojciechowski, R., Cheng, C.Y., Involvement of multiple molecular pathways in the genetics of ocular refraction and myopia. Retina, 2018. 38(1): p. 91-101.
84. Giummarra, L., et al., Pathway analysis identifies altered mitochondrial metabolism, neurotransmission, structural pathways and complement cascade in retina/RPE/ choroid in chick model of form-deprivation myopia. PeerJ, 2018. 6: p. e5048.
85. Vocale, L.G., et al., RNA-seq and GSEA identifies suppression of ligand-gated chloride efflux channels as the major gene pathway contributing to form deprivation myopia. Scientific Reports, 2021. 11(1): p. 5280.
86. Gupta, S.K., Chakraborty, R., Verkicharla, P.K., Electroretinogram responses in myopia: a review. Documenta Ophthalmologica, 2022. 145(2): p. 77–95.
87. Zahra, S., et al., Flash electroretinography as a measure of retinal function in myopia and hyperopia: a systematic review. Vision, 2023. 7(1): p. 15.
88. Poudel, S., et al., Contrast sensitivity of ON and OFF human retinal pathways in myopia. Journal of Neuroscience, 2024. 44(3).
89. Fujikado, T., Hosohata, J., Omoto, T., ERG of form deprivation myopia and drug induced ametropia in chicks. Current Eye Research, 1996. 15(1): p. 79–86.
90. Barathi, V.A., et al., Involvement of GABA transporters in atropine-treated myopic retina as revealed by iTRAQ quantitative proteomics. Journal of Proteome Research, 2014. 13(11): p. 4647–4658.
91. Lynch, J.W., Molecular structure and function of the glycine receptor chloride channel. Physiological Reviews, 2004. 84(4): p. 1051–1095.
92. Takeuchi, H., Watanabe, K., Tamura, H., Penetrable and impenetrable anions into the GABA-activated chloride channel on the postsynaptic neuromembrane of an identifiable giant neurone of an African giant snail (Achatina fulica Ferussac). Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1978. 61(2): p. 309–315.
93. Bialek, S., Miller, S.S., K+ and Cl‐transport mechanisms in bovine pigment epithelium that could modulate subretinal space volume and composition. The Journal of Physiology, 1994. 475(3): p. 401–417.
94. Marmor, M.F., Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol, 1999. 97(3–4): p. 239–49.
95. Ames, A., et al., Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. Journal of Neuroscience, 1992. 12(3): p. 840–853.
96. Hurley, J.B., Lindsay, K.J., Du, J., Glucose, lactate, and shuttling of metabolites in vertebrate retinas. Journal of Neuroscience Research, 2015. 93(7): p. 1079–1092.
97. Lunt, S.Y., Vander Heiden, M.G., Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol, 2011. 27: p. 441–64.
98. Feng, J., et al., Widespread involvement of acetylation in the retinal metabolism of form-deprivation myopia in guinea pigs. ACS Omega, 2023. 8(26): p. 23825–23839.
99. Yu, F-J., et al., Alteration of retinal metabolism and oxidative stress may implicate myopic eye growth: Evidence from discovery and targeted proteomics in an animal model. Journal of Proteomics, 2020. 221: p. 103684.
100. Kim, H., et al., RNA-sequencing analysis reveals the role of mitochondrial energy metabolism alterations and immune cell activation in form-deprivation and lens-induced myopia in mice. Genes (Basel), 2023. 14(12).
101. Riddell, N., Crewther, S.G., Novel evidence for complement system activation in chick myopia and hyperopia models: A meta-analysis of transcriptome datasets. Sci Rep, 2017. 7(1): p. 9719.
102. Riddell, N., et al., Bidirectional expression of metabolic, structural, and immune pathways in early myopia and hyperopia. Front Neurosci, 2016. 10: p. 390.
103. Yang, J., et al., Changes in retinal metabolic profiles associated with form deprivation myopia development in guinea pigs. Sci Rep, 2017. 7(1): p. 2777.
104. Lin, X., et al., Augmentation of scleral glycolysis promotes myopia through histone lactylation. Cell Metabolism, 2024.
105. Pan, X-B., et al., Epitranscriptomic investigation of myopia-associated RNA editing in the retina. Frontiers in Neuroscience, 2023. 17: p. 1220114.
106. Vishweswaraiah, S., et al., Epigenetically dysregulated genes and pathways implicated in the pathogenesis of non-syndromic high myopia. Scientific reports, 2019. 9(1): p. 4145.
107. Han, X., et al., Novel loci for ocular axial length identified through extreme-phenotype genome-wide association study in Chinese populations. British Journal of Ophthalmology, 2024. 108(6): p. 865–872.
108. Hou, X.W., et al., Metabolomics facilitates the discovery of metabolic profiles and pathways for myopia: A systematic review. Eye (Lond), 2023. 37(4): p. 670–677.
109. Bonnans, C., Chou, J., Werb, Z., Remodelling the extracellular matrix in development and disease. Nature Reviews Molecular Cell Biology, 2014. 15(12): p. 786–801.
110. Masure, S., Opdenakker, G., Cytokine-mediated proteolysis in tissue remodelling. Experientia, 1989. 45(6): p. 542–549.
111. Xu, R., et al., Effects of inflammation on myopia: evidence and potential mechanisms. Front Immunol, 2023. 14: p. 1260592.
112. Gao, T-T., Long, Q., Yang, X., Complement factors C1q, C3 and C5b-9 in the posterior sclera of guinea pigs with negative lens-defocused myopia. International Journal of Ophthalmology, 2015. 8(4): p. 675.
113. Chou, Y-L., et al., Complement decay-accelerating factor inhibits inflammation-induced myopia development. Molecular Immunology, 2024. 171: p. 47–55.
114. Long, Q., et al., C-reactive protein and complement components in patients with pathological myopia. Optometry and Vision Science, 2013. 90(5): p. 501–506.
115. Huang, T., et al., Complement-mediated inflammation and mitochondrial energy metabolism in the proteomic profile of myopic human corneas. Journal of Proteomics, 2023. 285: p. 104949.
116. Schaeffel, F., Feldkaemper, M., Animal models in myopia research. Clinical and Experimental Optometry, 2015. 98(6): p. 507–517.
117. Brown, D.M., et al., Candidate pathways for retina to scleral signaling in refractive eye growth. Experimental Eye Research, 2022. 219: p. 109071.
118. Cardoso, J.C., et al., PACAP, VIP and their receptors in the metazoa: Insights about the origin and evolution of the ligand-receptor pair. Peptides, 2007. 28(9): p. 1902–19.
119. Witkovsky, P., Dopamine and retinal function. Doc Ophthalmol, 2004. 108(1): p. 17–40.
120. Curtin, B.J., Physiologic vs pathologic myopia: genetics vs environment. Ophthalmology, 1979. 86(5): p. 681–691.
121. Neelam, K., et al., Choroidal neovascularization in pathological myopia. Progress in retinal and eye research, 2012. 31(5): p. 495–525.
122. Wakabayashi, T., Ikuno, Y., Choroidal filling delay in choroidal neovascularisation due to pathological myopia. British Journal of Ophthalmology, 2010. 94(5): p. 611–615.
123. Dimitrova, G., et al., Retrobulbar circulation in myopic patients with or without myopic choroidal neovascularisation. British Journal of Ophthalmology, 2002. 86(7): p. 771–773.