Refractive errors are the most common eye disorders worldwide and the largest source of visual impairment. 1,2 In particular, high myopia is associated with a significant risk of visual complications, such as myopic macular degeneration, glaucoma, and retinal detachment (Figure 1).3-5 The absolute risk of severe visual impairment increases significantly with each diopter of myopic refractive error, ranging from 3% to 5% in individuals with errors of -6.00 D to more than 40% in those with -15.00 D or more (Klaver, personal communication).
Reports have shown that the prevalence of myopia is on the rise.6-8 In the United States, the prevalence of myopia increased by 145% during the past 3 decades, and the rate of high myopia increased by 820%.7 In South Korea, the increase in the prevalence of myopia and high myopia was 334% and 891%, respectively.8 Although the same trends are found in African and European populations,9-11 the prevalence of myopia is currently highest in Asians. In Singapore, 80% to 90% of young adults are myopic (Figure 2).12
These figures are dramatic and demand effective counteractions. The first question is, “Why do eyes become myopic?” This article summarizes current insights into the development and pathogenesis of this trait.
COURSE OF REFRACTIVE ERROR
Children are born hyperopic and become emmetropic by age 6 to 9 years due to emmetropization.13 Although the cornea stabilizes at around age 6,14 the power of the lens usually changes until age 12, and the eye’s axis may continue to elongate up to age 20 to 25.14,15 There is a strong correlation between the severity of adult myopia and age of onset: Onset of high myopia usually occurs in the first decade of life, while mild myopia can develop in the teenage years or even in early adulthood.
RISK FACTORS FOR MYOPIA
Genetic associations. The evidence for the heritability of refractive error and myopia stems from studies of familial clustering,16 high heritability values in twins,17,18 and high recurrence rates in offspring.19,20 The search for the genes responsible for heritability was initiated by linkage (MYP 1-18) and candidate gene studies (CTNND2) performed in high-risk groups.21-31 Although these investigations provided some success, there was a lack of validation across studies.
A more powerful approach proved to be the use of genome-wide association study (GWAS) analyses, which robustly investigated numerous single nucleotide polymorphisms (SNPs) across the genome in large populations. Genomic hits for commonly occurring refractive errors were first found by Dutch and British researchers. 32-34 The loci they found were located on chromosome 15, and the closest genes were GJD2 and RASGRF1, respectively. Identifying the functions of these genes opened new hypotheses on myopia development, as each plays a role in retinal neurotransmission. The GJD2 gene forms a gap junction between neuronal cells in the retina, enabling intracellular exchange of small molecules and ions,35-38 while RASGRF1 is a nuclear exchange factor involved in synaptic transmission of photoreceptor responses.39,40 Signaling defects in the retina became a likely cause for myopia.
Following these reports, the international Consortium for Refractive Error and Myopia (CREAM) was formed to identify more genes. This group found genome-wide significance for another 24 loci in 45,758 individuals.41 Almost simultaneously, the commercial direct-to-consumer genetic testing company 23andMe identified 22 genomic loci in 45,771 individuals using diagnosed with myopia and age of first glasses as outcome variables.42 The results from 23andMe were strikingly similar to those of the CREAM consortium; 14 genome-wide significant hits overlapped. Additionally, the effect sizes of most of the associations were linearly related,43 indicating that these genetic associations were robust and generalizable to other populations. The striking similarity of genetic associations between Caucasians and Asians strengthened this conception.41
How much risk for development of myopia do these refractive error genes convey? For individuals carrying the highest number of risk alleles, one study showed a tenfold increase over those with an average number of alleles.41 Despite the clinical significance of this risk, the currently known 68 refractive error genes24,44,45 explain only 5% of phenotypic variance.41
This leaves us with a high degree of missing heritability; in other words, many genetic risk variants are still undiscovered. Researchers are currently exploiting new avenues for gene identification, such as exome sequencing, to find the rarer genetic risk factors on coding DNA.46-48 Interrelationships between genes and the environment also determine a large proportion of the variance in complex traits;49 therefore, a focus on the identification of gene-environment interactions is needed as well.
Environmental risk factors. Beyond doubt, myopia is caused by nature as well as nurture. Many studies have shown that lifestyle factors play a crucial role in the onset and progression of this trait.50,51 In particular, education is a risk factor that is highly associated with myopia; individuals with a university or higher vocational education have a five to eight times higher risk of myopia than those who have attended only primary school.52,53 Similar effects are observed for urban versus rural areas. Urban regions have a much higher prevalence of myopia.54
Explanations for these risks were sought, and two observations stood out: (1) Myopic children spent less time outdoors than nonmyopic children, and (2) they performed more near work at an earlier age.55-57 The protection conveyed by being outdoors is thought to be determined by light intensity;58 while illuminance indoors is about 500 lux, light levels outdoors are generally greater than 20,000 lux. Higher light intensity has been associated with higher dopamine release in the retina,59 and animal studies have shown that higher dopamine levels slow the elongation of the eyeball.60
The association with near work is less apparent. Type of near work has been a difficult factor to study, and factors such as use of handheld digital tablets and reading show inconsistency and low reproducibility in studies.61,62 A current hypothesis is that near work triggers myopia due to the long duration of defocus in the peripheral retina,63 particularly in eyes with a prolate shape (Figure 3).64
Gene-environment interactions. In a disease caused by both genetic and environmental factors, there is likely to be considerable interaction between these factors.53 This is the case with myopia. Education and genetic risk have been shown to interact: Individuals with a high genetic load in combination with university-level education had a much higher risk of myopia than those with only one of these two factors.65 This interaction was specifically found for the genes SHISA6-DNAH9, GJD2, and ZMAT4-SFRP1.66 It is expected that many more gene-environment interactions determine the variance of refractive error and myopia.
REFRACTIVE ERROR STUDIES IN ANIMALS
Studies of refractive error in various species including chicks, rodents, marmots, guinea pigs, and monkeys have formed the foundation for our understanding of the effect of visual input on eye growth. Several strategies have been used to induce myopia in animals, including form deprivation by blurring the eye, visual deprivation by lid suture,67-70 and placement of a negative (concave) lens in front of the eye.71-74 Placing a positive lens in front of the eye counteracts myopia development, as it slows eye growth.75 The lens effects appeared to be independent of visual transmission to the brain because they worked similarly in animals with a disrupted optic nerve. Recent animal studies have demonstrated that the peripheral retina is more responsive to blur than the macula,64,76 and monkey and chicken experiments have supported the notion that peripheral retinal defocus is a stimulus for myopiagenesis.64,77
Chickens with negative lens wear and exposure to high illuminance showed retarded myopia progression compared with chickens with exposure to low illuminance.78 The wavelength of light appeared to play a role as well. Chiclid fish living under red, long-wavelength light circumstances developed higher axial lengths compared with fish kept in blue, short-wavelength light.79 Rhesus monkeys showed a significant myopic shift after growing up (for up to 51 weeks) in red light.31 In contrast, blue light had an inhibiting effect on myopia development in guinea pigs.80
Various pharmacologic studies have been performed in animals, in particular intervention studies aimed at neurotransmitters and hormonal molecules. Many showed a potent inhibitory effect on eye growth with atropine. This effect is mediated by muscarine receptors, and the receptors M1 and M4 are most important here.81-83 Exactly how atropine inhibits eye growth is still subject to debate, but a direct effect of these receptors on the sclera seems likely. Dopamine, like atropine, appeared to have an inhibiting effect on eye growth in rabbits and guinea pigs, and dopamine antagonists abolished the protective effect of high illuminance in chicks.59
Two hormones that help to balance glucose levels, glucagon and insulin,84 were reported to play opposite roles in myopiagenesis. Glucagon inhibited eye growth, whereas insulin had a stimulatory effect. Glucagon acts via transcription factor ZENK,85 and, interestingly, experiments showed that ZENK RNA fragments formed after lens-induced myopia rapidly down-regulated when atropine was injected into the eyes of chickens.86 Other molecules that were investigated include retinoic acid, vasoactive intestine polypeptide, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophospate (cGMP). Retinoic acid is a metabolite of vitamin A.87 In form-deprived myopic chickens with accelerated axial elongation, retinoic acid appeared to be elevated in the retina. In the fellow eye (without form deprivation and inhibited axial elongation), the levels were lower.88 cGMP, a signaling molecule in the phototransduction cascade, was shown to increase eye growth and myopia development; the antagonist inhibited the myopic effect.89 cAMP, another signaling molecule, was also up-regulated in the retinas of form-deprived eyes.90 Last, a vasoactive intestinal peptide receptor antagonist was shown to inhibit form-deprived myopia in chicks by counteracting the up-regulation of this neurotransmitter.91
Animal studies focusing on gene function are gaining popularity, and several functional studies of myopia genes have been carried out. The genes DLX1 and ZIC2 were shown to influence retinal development in the mouse: DLX1 misexpression increased the number of amacrine and bipolar cells and decreased the number of cones;92 ZIC2, a zinc finger gene, was shown to be capable of axonal guiding to the optic chiasm midline.93 RORB, a transcription factor and member of the nuclear receptor family, was shown to be important for cone maturation and amacrine and horizontal cell development in mice.94,95 The developmental genes PRSS56 and SIX6 have been associated with microphthalmus and glaucoma.96,97
Zebrafish studies showed that CHD7 is also involved in determination of retinal structure.98 In humans, this gene is mutated in the majority of patients with coloboma, heart defect, atresia choanae (CHARGE) syndrome. Interestingly, in CHD7-mutated mice, expression of another gene, BMP4, appeared down-regulated in neuronal cells.99 BMP4 had been shown to be up-regulated in the retinal pigment epithelium after negative lens wear.100
RDH5 is a gene involved in vitamin A metabolism by its ability to oxidize or reduce cis-retinoid isomers. Knockout mice of this gene mostly showed disturbance of rod function; electroretinography shows a slow recovery after bleaching,101,102 and the dark-adapted retinoid profile shows increased levels of 11-cis retinol and cis retinyl esters. CYP26A1 is another gene related to retinoid acid and metabolism in the retina.103 The gene RGR is involved in rhodopsin regeneration, and, in knockout mice, this process was slowed down by a factor three.104
As mentioned above, RASGRF1 is a gene related to defective neurotransmission without structural retinal defects in mutant mice.39 The GJD2 gene is coding for a gap junction, which appears closely related to the gap junction accessory protein TJP2.105 CACNA1D is a calcium channel coding gene that is expressed in cones. Its function resembles that of the CACNA1F gene, which causes congenital stationary night blindness with high myopia.106 KCNQ5 is coding for an M-type potassium current in the retinal pigment epithelium and neural retina.107 CD55 (decay-activating factor) is increased in retinal Mueller cells in mice with mutations of complement factor H, a risk factor associated with age-related macular degeneration.108
DISEASE MECHANISMS
From the genes, several pathways can be annotated (Table 1). These pathways fit into the current hypothesis on myopia pathogenesis: A visually evoked signaling cascade (neurotransmission, signaling, retinoic acid genes), which originates from the retina (neuronal development, ganglion cell genes), traverses the retinal pigment epithelium and choroid (signaling, intracellular movement genes), and terminates in the sclera, where active remodelling of extracellular matrix (extracellular matrix genes, retinoic acid, apoptosis genes) results in elongation of the eye. The eye and neuronal developmental genes may have their actions at various sites in this signaling cascade.
CONCLUSION
The question of why eyes become myopic cannot be answered lightly. Many factors determine the route from emmetropization to myopiagenesis. Genetic factors provide the susceptibility, but environmental factors are key players in triggering this conversion. Future focus on the network of molecules involved and their response to environmental stimuli should open new strategies for intervention and prevention, with the ultimate aim to diminish severe visual impairment caused by myopia.
Caroline C.W. Klaver, MD, PhD, is a Professor of Ophthalmology and Epidemiology at Erasmus Medical Center, Rotterdam, Netherlands. Dr. Klaver states that she has no financial interests in the products or companies mentioned. She may be reached at e-mail: c.c.w.klaver@erasmusmc.nl.
Jan-Roelof Polling is an orthoptist and PhD candidate at Erasmus Medical Center, Rotterdam, Netherlands, and a Senior Lecturer at the University of Applied Sciences Utrecht in Utrecht, Netherlands. Mr. Polling states that he has no financial interests in the products or companies mentioned. He may be reached at e-mail: j.polling@erasmusmc.nl.
Jan W.L. Tideman, MD, is a PhD candidate at Erasmus Medical Center, Rotterdam, Netherlands. Dr. Tideman states that he has no financial interests in the products or companies mentioned. He may be reached at e-mail: j.tideman@erasmusmc.nl.
Magda A. Meester-Smoor, PhD, is a biomedical scientist and post-doctoral fellow at Erasmus Medical Center, Rotterdam, Netherlands. Dr. Meester-Smoor states that she has no financial interests in the products or companies mentioned. She may be reached at e-mail: m.meester-smoor@erasmusmc.nl.
Virginie J.M. Verhoeven, MD, is a PhD candidate at Erasmus Medical Center, Rotterdam, Netherlands. Dr. Verhoeven states that she has no financial interests in the products or companies mentioned. She may be reached at e-mail: v.verhoeven@erasmusmc.nl.
1. Kempen JH, Mitchell P, Lee KE, et al. The prevalence of refractive errors among adults in the United States, Western Europe, and Australia. Arch Ophthalmol. 2004;122(4):495-505.
2. Wojciechowski R. Nature and nurture: the complex genetics of myopia and refractive error. Clin Genet. 2011;79:301-320.
3. Curtin BJ, Karlin DB. Axial length measurements and fundus changes of the myopic eye. Am J Ophthalmol. 1971;1:42-53.
4. Saw SM, Gazzard G, Shih-Yen EC, Chua WH. Myopia and associated pathological complications. Ophthalmic Physiol Opt. 2005;25:381-391.
5. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology. 2002;109:704-711.
6. Bar Dayan Y, Levin A, Morad Y, et al. The changing prevalence of myopia in young adults: a 13-year series of population-based prevalence surveys. Invest Ophthalmol Vis Sci. 2005;46(8):2760-2765.
7. Vitale S, Sperduto RD, Ferris FL 3rd. Increased prevalence of myopia in the United States between 1971-1972 and 1999-2004. Arch Ophthalmol. 2009;127:1632-1639.
8. Kim EC, Morgan IG, Kakizaki H, Kang S, Jee D. Prevalence and risk factors for refractive errors: Korean National Health and Nutrition Examination Survey 2008-2011. PLoS One. 2013;8(11):e80361.
9. Naidoo KS, Raghunandan A, Mashige KP, et al. Refractive error and visual impairment in African children in South Africa. Invest Ophthalmol Vis Sci. 2003;44(9):3764-3770.
10. Lewallen S, Lowdon R, Courtright P, Mehl GL. A population-based survey of the prevalence of refractive error in Malawi. Ophthalmic Epidemiol. 1995;2:45-49.
11. Wolfram C, Hohn R, Kottler U, et al. Prevalence of refractive errors in the European adult population: the Gutenberg Health Study (GHS). Br J Ophthalmol. 2014;98(7):857-861.
12. Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012;379:1739-1748.
13. Cook RC, Glasscock RE. Refractive and ocular findings in the newborn. Am J Ophthalmol. 1951;34:1407-1413.
14. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol. 1985;103:785-789.
15. Jones LA, Mitchell GL, Mutti DO, et al. Comparison of ocular component growth curves among refractive error groups in children. Invest Ophthalmol Vis Sci. 2005;46(7):2317-2327.
16. Guggenheim JA, Kirov G, Hodson SA. The heritability of high myopia: a reanalysis of Goldschmidt’s data. J Med Genet. 2000;37:227-231.
17. Sanfilippo PG, Hewitt AW, Hammond CJ, Mackey DA. The heritability of ocular traits. Surv Ophthalmol. 2010;55:561-583.
18. Young TL, Metlapally R, Shay AE. Complex trait genetics of refractive error. Arch Ophthalmol. 2007;125:38-48.
19. Farbrother JE, Kirov G, Owen MJ, Guggenheim JA. Family aggregation of high myopia: estimation of the sibling recurrence risk ratio. Invest Ophthalmol Vis Sci. 2004;45:2873-2878.
20. Mutti DO, Mitchell GL, Moeschberger ML, Jones LA, Zadnik K. Parental myopia, near work, school achievement, and children’s refractive error. Invest Ophthalmol Vis Sci. 2002;43:3633-3640.
21. Baird PN, Schache M, Dirani M. The GEnes in Myopia (GEM) study in understanding the aetiology of refractive errors. Prog Retin Eye Res. 2010;29:520-542.
22. Hornbeak DM, Young TL. Myopia genetics: a review of current research and emerging trends. Curr Opin Ophthalmol. 2009;20:356-362.
23. Jacobi FK, Pusch CM. A decade in search of myopia genes. Front Biosci (Landmark Ed). 2010;15:359-372.
24. Stambolian D. Genetic susceptibility and mechanisms for refractive error. Clin Genet. 2013;84:102-108.
25. Fan Q, Barathi VA, Cheng CY, et al. Genetic variants on chromosome 1q41 influence ocular axial length and high myopia. PLoS Genet. 2012;8:e1002753.
26. Li YJ, Goh L, Khor CC, et al. Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore Chinese. Ophthalmology. 2011;118:368-375.
27. Li Z, Qu J, Xu X, et al. A genome-wide association study reveals association between common variants in an intergenic region of 4q25 and high-grade myopia in the Chinese Han population. Hum Mol Genet. 2011;20:2861-2868.
28. Nakanishi H, Yamada R, Gotoh N, et al. A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1. PLoS Genet. 2009;5:e1000660.
29. Shi Y, Qu J, Zhang, D, et al. Genetic variants at 13q12.12 are associated with high myopia in the Han Chinese population. Am J Hum Genet. 2011;88:805-813.
30. Chen KC, His E, Hu CY, Chou WW, Liang CL, Juo SH. MicroRNA-328 may influence myopia development by mediating the PAX6 gene. Invest Ophthalmol Vis Sci. 2012;53:2732-2739.
31. Liu R, Hu M, He JC, et al. The effects of monochromatic illumination on early eye development in rhesus monkeys. Invest Ophthalmol Vis Sci. 2014;55:1901-1909.
32. Solouki AM, Verhoeven VJ, van Dujin CM, et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet. 2010;42:897-901.
33. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet. 2010;42:902-905.
34. Verhoeven VJ, Hysi PG, Saw SM, et al. Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium. Hum Genet. 2012;131:1467-1480.
35. Deans MR, Volgyi B, Goodenough DA, Bloomfield SA, Paul DL. Connexin36 is essential for transmission of rodmediated visual signals in the mammalian retina. Neuron. 2002;36:703-712.
36. Guldenagel M, Ammermuller J, Feigenspan A, et al. Visual transmission deficits in mice with targeted disruption of the gap junction gene connexin36. J Neurosci. 2001;21:6036-6044.
37. Kihara AH, Paschon V, Cardoso CM, et al. Connexin36, an essential element in the rod pathway, is highly expressed in the essentially rodless retina of Gallus gallus. J Comp Neurol. 2009;512:651-663.
38. Striedinger K, Petrasch-Parwez E, Zoidl G, et al. Loss of connexin36 increases retinal cell vulnerability to secondary cell loss. Eur J Neurosci. 2005;22:605-616.
39. Fernandez-Medarde A, Barhoum R, Riquelme R, et al. RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations. J Neurochem. 2009;110:641-652.
40. Tonini R, Mancinelli E, Balestrini M, et al. Expression of Ras-GRF in the SK-N-BE neuroblastoma accelerates retinoicacid- induced neuronal differentiation and increases the functional expression of the IRK1 potassium channel. Eur J Neurosci. 1999;11:959-966.
41. Verhoeven VJ, Hysi PG, Wojciechowski R, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45(3):314-318.
42. Kiefer AK, Tung JY, Do CB, et al. Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia. PLoS Genet. 2013;9:e1003299.
43. Wojciechowski R, Hysi PG. Focusing in on the complex genetics of myopia. PLoS Genet. 2013;9, e1003442.
44. Hawthorne FA, Young TL. Genetic contributions to myopic refractive error: insights from human studies and supporting evidence from animal models. Exp Eye Res. 2013;114: 141-149.
45. Cooke Bailey JN, Sobrin L, Pericak-Vance MA, Haines JL, Hammond CJ, Wiggs JL. Advances in the genomics of common eye diseases. Hum Mol Genet. 2013;22:R59-65.
46. Shi Y, Li Y, Zhang D, et al. Exome sequencing identifies ZNF644 mutations in high myopia. PLoS Genet. 2011;7:e1002084.
47. Tran-Viet KN, Powell C, Barathi VA, et al. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am J Hum Genet. 2013;92:820-826.
48. Aldahmesh MA, Khan AO, Alkuraya H, et al. Mutations in LRPAP1 are associated with severe myopia in humans. Am J Hum Genet. 2013;93:313-320.
49. Kaprio J. Twins and the mystery of missing heritability: the contribution of gene-environment interactions. J Intern Med. 2012;272:440-448.
50. Pan CW, Ramamurthy D, Saw SM. Worldwide prevalence and risk factors for myopia. Ophthalmic Physiol Opt. 2012;32:3-16.
51. French AN, Morgan IG, Mitchell P, Rose KA. Risk factors for incident myopia in Australian schoolchildren: The Sydney Adolescent Vascular and Eye Study. Ophthalmology. 2013;
52. Au Eong KG, Tay TH, Lim MK. Education and myopia in 110,236 young Singaporean males. Singapore Med J. 1993;34, 489-492.
53. Morgan I, Rose K. How genetic is school myopia? Prog Retin Eye Res. 2005;24:1-38.
54. He M, Zheng Y, Xiang F. Prevalence of myopia in urban and rural children in mainland China. Optom Vis Sci. 2009;86:40-44.
55. Sherwin JC, Reacher MH, Keogh RH, Khawaja AP, Mackey DA, Foster JP. The association between time spent outdoors and myopia in children and adolescents: a systematic review and meta-analysis. Ophthalmology. 2012;119:2141-2151.
56. French AN, Ashby RS, Morgan IG, Rose KA. Time outdoors and the prevention of myopia. Exp Eye Res. 2013;114:58-68.
57. Yi JH, Li RR. [Influence of near-work and outdoor activities on myopia progression in school children]. Zhongguo Dang Dai Er Ke Za Zhi. 2011;13:32-35.
58. Norton TT, Siegwart JT Jr. Light levels, refractive development, and myopia--a speculative review. Exp Eye Res. 2013;114:48-57.
59. Ashby RS, Schaeffel F. The effect of bright light on lens compensation in chicks. Invest Ophthalmol Vis Sci. 2010;51:5247-5253.
60. Feldkaemper M, Schaeffel F. An updated view on the role of dopamine in myopia. Exp Eye Res. 2013;114:106-119.
61. Ip JM, Saw SM, Rose KA, et al. Role of near work in myopia: findings in a sample of Australian school children. Invest Ophthalmol Vis Sci. 2008;49:2903-2910.
62. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology. 2008;115:1279-1285.
63. Hoogerheide J, Rempt F, Hoogenboom WP. Acquired myopia in young pilots. Ophthalmologica. 1971;163:209-215.
64. Smith EL 3rd, Hung LF, Huang J. Relative peripheral hyperopic defocus alters central refractive development in infant monkeys. Vision Res. 2009;49:2386-2392.
65. Verhoeven VJ, Buitendijk GH; Consortium for Refractive Error and Myopia (CREAM), et al. Education influences the role of genetics in myopia. Eur J Epidemiol. 2013;28:973-980.
66. Fan Q, Wojciechowski R, Kamran Ikram M, et al. Education influences the association between genetic variants and refractive error: a meta-analysis of five Singapore studies. Hum Mol Genet. 2014;23:546-554.
67. Wiesel TN, Raviola E. Myopia and eye enlargement after neonatal lid fusion in monkeys. Nature. 1977;266:66-68.
68. Troilo D, Judge SJ. Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus). Vision Res. 1993;33:1311-1324.
69. Marsh-Tootle WL, Norton TT. Refractive and structural measures of lid-suture myopia in tree shrew. Invest Ophthalmol Vis Sci. 1989;30:2245-2257.
70. Wallman J, Turkel J, Trachtman J. Extreme myopia produced by modest change in early visual experience. Science. 1978;201:1249-1251.
71. Hung LF, Crawford ML, Smith EL. Spectacle lenses alter eye growth and the refractive status of young monkeys. Nat Med. 1995;1:761-765.
72. Graham B, Judge SJ. The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus). Vision Res. 1999;39:189-206.
73. Schaeffel F, Glasser A, Howland HC. Accommodation, refractive error and eye growth in chickens. Vision Res. 1988;28:639-657.
74. Wallman J, Adams JI. Developmental aspects of experimental myopia in chicks: susceptibility, recovery and relation to emmetropization. Vision Res. 1987;27:1139-1163.
75. Diether S, Schaeffel F. Local changes in eye growth induced by imposed local refractive error despite active accommodation. Vision Res. 1997;37:659-668.
76. Charman WN, Radhakrishnan H. Peripheral refraction and the development of refractive error: a review. Ophthalmic Physiol Opt. 2010;30:321-338.
77. Liu Y, Wildsoet C. The effective add inherent in 2-zone negative lenses inhibits eye growth in myopic young chicks. Invest Ophthalmol Vis Sci. 2012;53:5085-5093.
78. Ashby R, Ohlendorf A, Schaeffel F. The effect of ambient illuminance on the development of deprivation myopia in chicks. Invest Ophthalmol Vis Sci. 2009;50:5348-5354.
79. Kroger RH, Wagner HJ. The eye of the blue acara (Aequidens pulcher, Cichlidae) grows to compensate for defocus due to chromatic aberration. J Comp Physiol. 1996;179:837-842.
80. Jiang L, Zhang S, Schaeffrel F, et al. Interactions of chromatic and lens-induced defocus during visual control of eye growth in guinea pigs (Cavia porcellus). Vision Res. 2014;94:24-32.
81. McBrien NA, Stell WK, Carr B. How does atropine exert its anti-myopia effects? Ophthalmic Physiol Opt. 2013;33:373-378.
82. Barathi VA, Beuerman RW. Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment. Mol Vis. 2011;17:680-692.
83. Arumugam B, McBrien NA. Muscarinic antagonist control of myopia: evidence for M4 and M1 receptor-based pathways in the inhibition of experimentally-induced axial myopia in the tree shrew. Invest Ophthalmol Vis Sci. 2012;53:5827-5837.
84. Zhu X, Wallman J. Opposite effects of glucagon and insulin on compensation for spectacle lenses in chicks. Invest Ophthalmol Vis Sci. 2009;50:24-36.
85. Fischer AJ, McGuire JJ, Schaeffel F, Stell WK. Light- and focus-dependent expression of the transcription factor ZENK in the chick retina. Nat Neurosci. 1999;2:706-712.
86. Ashby R, Kozulin P, Megaw PL, Morgan IG. Alterations in ZENK and glucagon RNA transcript expression during increased ocular growth in chickens. Mol Vis. 2010;16:639-649.
87. Mertz JR, Wallman J. Choroidal retinoic acid synthesis: a possible mediator between refractive error and compensatory eye growth. Exp Eye Res. 2000;70:519-527.
88. McFadden SA, Howlett MH, Mertz JR. Retinoic acid signals the direction of ocular elongation in the guinea pig eye. Vision Res. 2004;44:643-653.
89. Fang F, Pan M, Yan T, et al. The role of cGMP in ocular growth and the development of form-deprivation myopia in guinea pigs. Invest Ophthalmol Vis Sci. 2013;54:7887-7902.
90. Tao Y, Pan M, Liu S, et al. cAMP level modulates scleral collagen remodeling, a critical step in the development of myopia. PLoS One. 2013;8:e71441.
91. Rymer J, Wildsoet CF. The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Vis Neurosci. 2005;22:251-261.
92. Feng L, Eisenstat DD, Chiba S, Ishizaki Y, Gan L, Shibasaki K. Brn-3b inhibits generation of amacrine cells by binding to and negatively regulating DLX1/2 in developing retina. Neuroscience. 2011;195:9-20.
93. Wilson SI. Target practice: Zic2 hits the bullseye! EMBO J. 2010;29:3037-3038.
94. Srinivas M, Ng L, Liu H, Jia L, Forrest D. Activation of the blue opsin gene in cone photoreceptor development by retinoidrelated orphan receptor beta. Mol Endocrinol. 2006;20:1728-1741.
95. Liu H, Kim SY, Fu Y, et al. An isoform of retinoid-related orphan receptor beta directs differentiation of retinal amacrine and horizontal interneurons. Nat Commun. 2013;4:1813.
96. Iglesias AI, Springelkamp H, van der Linde H, et al. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet. 2014;23(5):1320-1332.
97. Nair KS, Hmani-Aifa M, Ali Z, et al. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nat Genet. 2011;43:579-584.
98. Patten SA, Jacobs-McDaniels NL, Zaouter C, Drapeau P, Albertson RC, Moldovan F. Role of Chd7 in zebrafish: a model for CHARGE syndrome. PLoS One. 2012;7:e31650.
99. Jiang X, Zhou Y, Xian L, Chen W, Wu H, Gao X. The mutation in Chd7 causes misexpression of Bmp4 and developmental defects in telencephalic midline. Am J Pathol. 2012;181:626-641.
100. Zhang Y, Liu Y, Ho C, Wildsoet CF. Effects of imposed defocus of opposite sign on temporal gene expression patterns of BMP4 and BMP7 in chick RPE. Exp Eye Res. 2013;109:98-106.
101. Driessen CA, Winkens HJ, Hoffmann K, et al. Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters. Mol Cell Biol. 2000;20:4275-4287.
102. Kim TS, Maeda A, Maeda T, et al. Delayed dark adaptation in 11-cis-retinol dehydrogenase-deficient mice: a role of RDH11 in visual processes in vivo. J Biol Chem. 2005;280:8694-8704.
103. Sakai Y, Luo T, McCaffery P, Hamada H, Drager UC. CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development. Dev Biol. 2004;276:143-157.
104. Wenzel A, Oberhauser V, Pugh EN Jr, et al. The retinal G protein-coupled receptor (RGR) enhances isomerohydrolase activity independent of light. J Biol Chem. 2005;280:29874-29884.
105. Ciolofan C, Li XB, Olson C, et al. Association of connexin36 and zonula occludens-1 with zonula occludens-2 and the transcription factor zonula occludens-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina. Neuroscience. 2006;140:433-451.
106. Xiao H, Chen X, Steele Jr EC. Abundant L-type calcium channel Ca(v)1.3 (alpha1D) subunit mRNA is detected in rod photoreceptors of the mouse retina via in situ hybridization. Mol Vis. 2007;13:764-771.
107. Pattnaik BR, Hughes BA. Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium. Am J Physiol Cell Physiol. 2012;302,C821-33.
108. Williams JA, Greenwood J, Moss SE. Retinal changes precede visual dysfunction in the complement factor H knockout mouse. PLoS One. 2013;8, e68616.
