Contribution of M-opsin-based color vision to refractive development in mice.

M-opsin, encoded by opn1mw gene, is involved in green-light perception of mice. The role of M-opsin in emmetropization of mice remains uncertain. To answer the above question, 4-week-old wild-type (WT) mice were exposed to white light or green light (460-600 nm, a peak at 510 nm) for 12 weeks. Refractive development was estimated biweekly. After treatment, retinal function was assessed using electroretinogram (ERG). Dopamine (DA) in the retina was evaluated by high-performance liquid chromatography, M-opsin and S-opsin protein levels by Western blot and ELISA, and mRNA expressions of opn1mw and opn1sw by RT-PCR. Effects of M-opsin were further verified in Opn1mw-/- and WT mice raised in white light for 4 weeks. Refractive development was examined at 4, 6, and 8 weeks after birth. The retinal structure was estimated through hematoxylin and eosin staining (H&E) and transmission electron microscopy (TEM). Retinal wholemounts from WT and Opn1mw-/- mice were co-immunolabeled with M-opsin and S-opsin, their distribution and quantity were then assayed by immunofluorescence staining (IF). Expression of S-opsin protein and opn1sw mRNA were determined by Western blot, ELISA, or RT-PCR. Retinal function and DA content were analyzed by ERG and liquid chromatography tandem-mass spectrometry (LC-MS/MS), respectively. Lastly, visual cliff test was used to evaluate the depth perception of the Opn1mw-/- mice. We found that green light-treated WT mice were more myopic with increased M-opsin expression and decreased DA content than white light-treated WT mice after 12-week illumination. No electrophysiologic abnormalities were recorded in mice exposed to green light compared to those exposed to white light. A more hyperopic shift was further observed in 8-week-old Opn1mw-/- mice in white light with lower DA level and weakened cone function than the WT mice under white light. Neither obvious structural disruption of the retina nor abnormal depth perception was found in Opn1mw-/- mice. Together, these results suggested that the M-opsin-based color vision participated in the refractive development of mice. Overexposure to green light caused myopia, but less perception of the middle-wavelength components in white light promoted hyperopia in mice. Furthermore, possible dopaminergic signaling pathway was suggested in myopia induced by green light.

Disparity between central and peripheral refraction inheritance in twins.

The last decades have witnessed a sudden increase in myopia incidence among youngsters that have been related to modern lifestyle along with the use of emerging technologies affecting visual exposure. Increasing exposures to known risk factors for myopia, such as time spent indoors, close-distance work, or low-light conditions are thought to be responsible for this public health issue. In most cases, development of myopia is secondary to a vitreous chamber enlargement, although the related mechanisms and the potential interaction between central and peripheral retinal area remain unclear. For a better understanding, we performed a classical twin study where objective refractive error along 70° of horizontal retinal arc was measured in 100 twin pairs of university students, 78% of which showed manifest myopia. We found the variance of shared environmental origin (range 0.34 to 0.67) explained most of the objective refractive error variance within central 42° of the retina (22° temporal to 19° nasal), whereas additive genetic variance (range 0.34 to 0.76) was predominant in the peripheral retinal areas measured. In this sample of millennial university students, with a large prevalence of myopia, environmental exposures were mostly responsible for inter-individual variation in the retinal horizontal area surrounding the macula, while their relative weight on phenotypic variance was gradually descending, and replaced by the variance of genetic origin, towards the retinal periphery.

RNA sequencing analysis of long non-coding RNA expression in ocular posterior poles of guinea pig myopia models.

Purpose: To detect the differential expression of long non-coding RNAs (lncRNAs) in the ocular posterior poles of two guinea pig myopia models and explore the pathogenic role of lncRNAs in myopia. Methods: Form-deprived myopia (FDM) and lens-induced myopia (LIM) models were induced in guinea pig right eyes by wearing a translucent latex balloon head mask and a -10.00 diopter (D) lens, respectively. Ocular biometric parameters were measured biweekly. At 6 weeks after the induction of myopia, the guinea pig eyeballs were processed for hematoxylin and eosin staining to examine the ocular morphology. The ocular posterior poles from the normal control, FDM, and LIM groups were collected to analyze the differential expression of lncRNAs between the groups with high-throughput RNA sequencing (RNA-seq). Further, the lncRNA-mRNA colocation network was delineated to predict the functions of the differentially expressed lncRNAs. Last, Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the colocated mRNAs of the differentially expressed lncRNAs. Additionally, the expression of the most differentially expressed lncRNAs in the myopia-induced eyes and the contralateral eyes was validated with quantitative real-time PCR (qPCR). Results: Compared with the normal controls and the contralateral eyes, the myopia-induced eyes in the FDM and LIM groups exhibited decreased scleral and choroidal thicknesses, reduced refraction, and increased ocular axial length but without changes in the corneal curvature radius at 6 weeks after myopia was induced. RNA-seq showed that 372 and 247 lncRNAs were differentially expressed in the FDM and LIM groups, respectively, in comparison to the normal counterparts. There were 380 differentially expressed lncRNAs in the LIM group compared to the FDM group. The GO and KEGG analyses showed that the colocated mRNAs of the differentially expressed lncRNAs were enriched in cellular components such as the extracellular matrix (ECM) structural constituent; in molecular functions such as kinase activity, metabolism, and growth; as well as in pathways including ECM-receptor interaction, glycosaminoglycan degradation, and mucin type O-Glycan biosynthesis. The expression patterns of the selected lncRNAs were verified with qPCR. Conclusions: High-throughput RNA-seq revealed previously undescribed lncRNA expression profiling in guinea pig FDM and LIM models. These results may shed light on the molecular pathogenesis of myopia and provide clues for interventional targets for this highly prevalent visual disorder.

Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia.

BACKGROUND: Population studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. METHODS: Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). We used RNA-seq to analyze gene expression in the retinae of these mice and reconstruct genetic networks and signaling pathways underlying refractive eye development. We also utilized genome-wide gene-based association analysis to identify mouse genes and pathways associated with myopia in humans. RESULTS: Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from - 21.2 diopters (D) in 129S1/svlmj mice to + 22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from - 5.6 D in NZO/HILtJ mice to - 20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with myopia in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. CONCLUSIONS: Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different vertebrate species. These results identify major signaling pathways involved in refractive eye development and provide attractive targets for the development of anti-myopia drugs.

Possible Causes of Discordance in Refraction in Monozygotic Twins: Nearwork, Time Outdoors and Stochastic Variation.

Purpose: To evaluate the impact of differences in nearwork and time spent outdoors on difference in refraction in monozygotic (MZ) twins. Methods: Data on MZ twins aged 7 to 18 years from the Guangzhou Twin Eye Study were used in this analysis. A standard questionnaire was administered by personal interview to estimate time spent on nearwork and time spent outdoors. Spherical equivalent (SE) was measured by autorefraction under cycloplegia. The interaction between age and nearwork or time spent outdoors was also estimated. Results: A total of 490 MZ twin pairs (233 male and 257 female) were eligible in this analysis, the mean age was 13.14 ± 2.49. In the mixed-effects model, nearwork difference was a risk factor of discordance in myopic SE (ß = -0.11 diopter (D)/h, P = 0.009), the overall association between time outdoors difference and SE discordance was not significant (ß = -0.89 (D)/h, P = 0.120) although an interaction between time spent outdoors difference and age was detected (ß = 0.07 (D)/h, P = 0.002). Furthermore, difference in nearwork and time outdoors explained about 1.8% and 2.5% of the variation in SE discordance, respectively. Conclusions: Given the very marked genetic similarity of MZ twins, and the small effects of known risk factors on SE discordance, we suggest that the SE discordance across MZ twins largely results from stochastic variations at the genomic or epigenetic levels, or from uncollected environmental factors.

Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth.

Myopia (nearsightedness) is the most common eye disorder, which is rapidly becoming one of the leading causes of vision loss in several parts of the world because of a recent sharp increase in prevalence. Nearwork, which produces hyperopic optical defocus on the retina, has been implicated as one of the environmental risk factors causing myopia in humans. Experimental studies have shown that hyperopic defocus imposed by negative power lenses placed in front of the eye accelerates eye growth and causes myopia, whereas myopic defocus imposed by positive lenses slows eye growth and produces a compensatory hyperopic shift in refractive state. The balance between these two optical signals is thought to regulate refractive eye development; however, the ability of the retina to recognize the sign of optical defocus and the composition of molecular signaling pathways guiding emmetropization are the subjects of intense investigation and debate. We found that the retina can readily distinguish between imposed myopic and hyperopic defocus, and identified key signaling pathways underlying retinal response to the defocus of different signs. Comparison of retinal transcriptomes in common marmosets exposed to either myopic or hyperopic defocus for 10 days or 5 weeks revealed that the primate retina responds to defocus of different signs by activation or suppression of largely distinct pathways. We also found that 29 genes differentially expressed in the marmoset retina in response to imposed defocus are localized within human myopia quantitative trait loci (QTLs), suggesting functional overlap between genes differentially expressed in the marmoset retina upon exposure to optical defocus and genes causing myopia in humans. These findings identify retinal pathways involved in the development of myopia, as well as potential new strategies for its treatment.

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Müller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions.

INVOLVEMENT OF MULTIPLE MOLECULAR PATHWAYS IN THE GENETICS OF OCULAR REFRACTION AND MYOPIA.

PURPOSE: The prevalence of myopia has increased dramatically worldwide within the last three decades. Recent studies have shown that refractive development is influenced by environmental, behavioral, and inherited factors. This review aims to analyze recent progress in the genetics of refractive error and myopia. METHODS: A comprehensive literature search of PubMed and OMIM was conducted to identify relevant articles in the genetics of refractive error. RESULTS: Genome-wide association and sequencing studies have increased our understanding of the genetics involved in refractive error. These studies have identified interesting candidate genes. All genetic loci discovered to date indicate that refractive development is a heterogeneous process mediated by a number of overlapping biological processes. The exact mechanisms by which these biological networks regulate eye growth are poorly understood. Although several individual genes and/or molecular pathways have been investigated in animal models, a systematic network-based approach in modeling human refractive development is necessary to understand the complex interplay between genes and environment in refractive error. CONCLUSION: New biomedical technologies and better-designed studies will continue to refine our understanding of the genetics and molecular pathways of refractive error, and may lead to preventative and therapeutic measures to combat the myopia epidemic.

The refractive state of the eye in Icelandic horses with the Silver mutation.

BACKGROUND: The syndrome Multiple Congenital Ocular Anomalies (MCOA) is a congenital eye disorder in horses. Both the MCOA syndrome and the Silver coat colour in horses are caused by the same missense mutation in the premelanosome protein (PMEL) gene. Horses homozygous for the Silver mutation (TT) are affected by multiple ocular defects causing visual impairment or blindness. Horses heterozygous for the Silver mutation (CT) have less severe clinical signs, usually cysts arising from the ciliary body iris or retina temporally. It is still unknown if the vision is impaired in horses heterozygous for the Silver mutation. A recent study reported that Comtois horses carrying the Silver mutation had significantly deeper anterior chambers of the eye compared to wild-type horses. This could potentially cause refractive errors. The purpose of the present study was to investigate if Icelandic horses with the Silver mutation have refractive errors compared to wild-type horses. One hundred and fifty-two Icelandic horses were included in the study, 71 CT horses and five TT horses. All horses were genotyped for the missense mutation in PMEL. Each CT and TT horse was matched by a wild-type (CC) horse of the same age ± 1 year. Skiascopy and a brief ophthalmic examination were performed in all horses. Association between refraction and age, eye, genotype and sex was tested by linear mixed-effect model analysis. TT horses with controls were not included in the statistical analyses as they were too few. RESULTS: The interaction between age and genotype had a significant impact on the refractive state (P = 0.0001). CT horses older than 16 years were on average more myopic than wild-type horses of the same age. No difference in the refractive state could be observed between genotypes (CT and CC) in horses younger than 16 years. TT horses were myopic (-2 D or more) in one or both eyes regardless of age. CONCLUSION: Our results indicate that an elderly Icelandic horse (older than 16 years) carrying the Silver mutation is more likely to be myopic than a wild-type horse of the same age.

Changes in ocular biometry and anterior chamber parameters after pharmacologic mydriasis and peripheral iridotomy in primary angle closure suspects / Cambios en la biometría ocular y los parámetros de la cámara anterior tras midriasis farmacológica e iridotomía periférica en sospechas de cierre angular primario

Purpose: The aim of this study was to evaluate the effects of pharmacologic mydriasis and Peripheral Iridotomy (PI) on ocular biometry and anterior chamber parameters in primary angle closure suspects. Methods: In this prospective interventional case series, 21 primary angle closure suspects were enrolled. Intraocular pressure, refraction, ocular biometry (Lenstar, LS900), and anterior chamber parameters (Pentacam HR) were measured at four occasions: before PI (before and after mydriasis with phenylephrine) and two weeks after PI (before and after mydriasis). The study was conducted on both eyes and only one eye per patient, in random, was included in the analysis. Results: The mean age of the participants was 60±7 years and 17 (81%) were female. There were no significant differences in intraocular pressure, refraction, keratometry, biometric and anterior chamber parameters between groups, except for anterior chamber volume, which showed increments with PI and mydriasis. The corresponding values for anterior chamber volume were as follows: 88.2±13.7mm3 before PI, undilated; 106.3±18.8 before PI, dilated; 99.0±14.6 after PI, undilated, and 107.4±16.5 after PI, dilated (P<0.001). Conclusions: This study showed no change in the ocular biometric and anterior chamber parameters including iridocorneal angle after PI and/or pharmacologic mydriasis except for increments in anterior chamber volume. This factor has the potential to be used as a numerical proxy for iris position in evaluating and monitoring patients with primary angle closure suspects after PI (AU)

Objetivo: El objetivo de este estudio fue el de evaluar los efectos de la midriasis farmacológica y la iridotomía periférica (IP) en la biometría ocular y los parámetros de la cámara anterior en las sospechas de cierre angular primario. Métodos: En esta serie de casos intervencional prospectiva, se incluyó a 21 sospechas de cierre angular primario. Se realizaron las mediciones siguientes: presión intraocular, refracción, biometría ocular (Lenstar, LS900), y parámetros de la cámara anterior (Pentacam HR) en cuatro ocasiones, antes de la IP (antes y después de la midriasis con fenilefrina) y dos semanas después de la IP (antes y después de la midriasis). El estudio se realizó en ambos ojos, incluyéndose en el análisis un solo ojo por paciente de manera aleatoria. Resultados: La edad media de los participantes fue de 60±7 años, de los cuales 17 eran mujeres (81%). No se hallaron diferencias significativas en cuanto a presión intraocular, refracción, queratometría, parámetros biométricos y de la cámara anterior entre los grupos, exceptuando el volumen de la cámara anterior, que reflejó incrementos con la IP y la midriasis. Los valores correspondientes para el volumen de la cámara anterior fueron los siguientes: 88.2±13,7mm3antes de la IP, sin dilatación; 106.3±18,8 antes de la IP, con dilatación; 99.0±14,6 tras la IP, sin dilatación, y 107.4±16,5 tras la IP, con dilatación (P<0,001). Conclusiones: El presente estudio no reflejó cambios en los parámetros biométricos oculares y de la cámara anterior, incluyendo el ángulo iridocorneal tras la IP y/o midriasis farmacológica, exceptuando los incrementos del volumen de la cámara anterior. Este factor tiene el potencial de ser utilizado como indicador numérico de la posición del iris al evaluar y supervisar a los pacientes con sospechas de cierre angular primario tras IP (AU)

Genetics of Refraction and Myopia.

Both genetic and environmental factors play roles in the development of refractive errors. Identification of genes involved in refractive errors may help in elucidating the underlying molecular mechanism related to both genetic defects and environmental pressure. Recent development of techniques for genome wide analysis provides unique opportunity in dissecting the genetic basis related to refractive errors. This chapter tries to give a brief overview on the recent progress of genetic study of refractive errors, especially myopia.

[Characteristics of refractive status of mutant Lumican transgenic mice].

OBJECTIVE: To investigate the change of refractive status in transgenic mice with mutant Lumican (bright proteoglycan) gene at different ages. METHODS: Experimental Study. Fifty-four 3-week-old with mutant Lumican gene (cDNA 596T > C) mice (27 male and 27 female) were randomly divided into 9 groups (n = 6, half male and half female) by random number table. One group (3-week-old) was randomly chosen and measured the refractive status by retinoscopy after mydriasis. Measurement of other groups were repeated the method above respectively in the fourth, fifth, sixth, eighth, tenth, twelfth, sixteenth, and twentieth week. Differences of diopter between right and left eye and between male and female were compared within each group by paired t test. The differences of mice's diopters in different age were compared by Kruskal-Wallis H test. Pairwise comparisons were acquired by Mann-Whitney U test. RESULTS: There were no statistic difference of diopters between binoculus: The mice's diopters of right and left eyes were respective measured in the twentieth week (1.50 ± 0.45) D and (1.25 ± 0.42) D (t = -0.889, P > 0.05), The mice's diopters of right and left eyes were respective measured in the third week (-2.50 ± 2.59) D and (-2.50 ± 4.32) D (t = 0.000, P > 0.05); There were no statistic difference of diopters between different genders: The mice's diopters of female and male were respective measured in the third week (-0.5 ± 3.83) D and (-4.17 ± 1.94) D, (t = 2.079, P > 0.05), The mice's diopters of female and male were respective measured in the twelfth week (1.50 ± 0.84) D and (1.50 ± 1.87) D (t = 0.000, P > 0.05); Analysis of binocular diopters revealed significant differences among nine groups (H = 20.910, P < 0.05). Diopters measured in the third week (-2.50 ± 3.40D) and the sixth week (+3.25 ± 2.67) D had statistical difference (Z = -3.259, P < 0.001). There were no statistical significance between other groups (P > 0.001). CONCLUSIONS: Characteristics of diopters gathered from mice with Lumican gene mutation at different weeks are summarized as follows: Myopia could be observed in the third week. And this situation of myopia was gradually transformed into hyperopia with aging. The maximum hyperopic diopter was observed at 6th-week-old mice. From the eighth to twentieth week, the degree of hyperopic diopter gradually decreased and stabilized.

Genetic effects on refraction and correlation with hemodynamic variables: a twin study.

Spherical equivalent (SE) has not been linked to increased cardiovascular morbidity. Methods: 132 Hungarian twins(age 43.3±16.9 years) underwent refraction measurements (Huvitz MRK-3100 Premium AutoRefractokeratometer)and oscillometry (TensioMed Arteriograph). Results: Heritability analysis indicated major role for genetic components in the presence of right and left SE (82.7%, 95%CI, 62.9 to 93.7%, and 89.3%, 95%CI, 72.8 to 96.6%),while unshared environmental effects accounted for 17% (95%CI, 6.3% to 37%), and 11% (95%CI, 3.4% to 26.7%)of variations adjusted for age and sex. Bilateral SE showed weak age-dependent correlations with augmentation index (AIx), aortic pulse wave velocity (r ranging between 0.218 and 0.389, all p < 0.01), aortic systolic blood pressure and pulse pressure (r between 0.188 and 0.289, p < 0.05). Conclusions: These findings support heritability of spherical equivalent, which does not coexist with altered hemodynamics (e.g. accelerated arterial aging).Accordingly, SE and the investigated hemodynamic parameters seem neither phenotypically nor genetically associated.

Distribution and heritability of peripheral eye length in Chinese children and adolescents: the Guangzhou Twin Eye Study.

PURPOSE: Peripheral eye length (PEL) provides a measure of overall eye shape, which may play a role in the development of myopia. The current study explores the distribution and heritability of PEL, relative PEL (RPEL, defined as PEL minus axial eye length) and relative ratio PEL (RRPEL, defined as PEL divided by axial eye length) in Chinese children and adolescents. METHODS: Subjects included both male and female youths participating in the Guangzhou Twin Eye Study. Eye length was measured by partial coherence laser interferometry axially, 40° temporally (PEL-T(40)) and 40° nasally (PEL-N(40)). Structural equation modeling (SEM) was used to estimate the relative contribution of genetic and environmental factors on PEL, RPEL, and RRPEL, adjusting for age and sex. RESULTS: We examined 104 monozygotic (MZ) and 54 dizygotic (DZ) twins aged 8 to 20 years old. The intraclass correlation coefficients were 0.89 for PEL-T(40), 0.92 for PEL-N(40), 0.80 for RPEL-T(40), 0.73 for RPEL-N(40), 0.77 for RRPEL-T(40), and 0.73 for RRPEL-N(40) in MZ pairs, and 0.52, 0.50, 0.39, 0.58, 0.37, and 0.58 in DZ pairs, respectively. The best fit adjusted models estimated that additive genetic effects accounted for approximately 86.2%, 89.8%, 79.9%, 75.5%, 77.1%, and 74.5% of the variance for the above mentioned traits, respectively, while dominant genetic effects and shared environmental factors were negligible. CONCLUSIONS: Additive genetic effects had a substantial influence on phenotypic variation in PEL and RPEL, suggesting genetic rather than environmental factors play a major role in determining eye shape.

Heritability of corneal refraction and corneal astigmatism: a population-based twin study among 66- to 79-year-old female twins.

PURPOSE: To examine the heritability of corneal refraction power (CR) and corneal astigmatism (AST) in older women. METHODS: Corneal refraction and AST were measured by IOL master in 52 monozygotic (MZ) and 47 dizygotic (DZ) female twin pairs aged 66-79 years. The relative contribution of genetic and environmental factors to individual differences in CR was estimated by applying an independent pathway model to the twin data and AST by intraclass correlations (ICC). RESULTS: For the right eye, mean CR was 44.58 dioptres (D) (standard deviation (SD) ±1.28) When comparing CR of the right and left eye between MZ and DZ, no significant difference was found. Mean AST was 0.77 D (SD ±0.44) with no differences observed either between the MZ and the DZ individuals, or between the left and the right eyes. ICCs between the sisters for CR were, for the right eye, 0.882 and 0.378 for MZ and DZ, respectively, and for the left eye 0.855 and 0.358. For AST of the right eye, the ICCs were 0.533 and 0.096 for the MZ and DZ pairs, respectively, and for the left eye, the MZ and DZ correlations were 0.396 and 0.299. Quantitative genetic modelling showed that 81% of the variance in CR could be explained by genetic factors, additive genetic factors explaining 62% (95% confidence interval [CI] 44% -86%) and dominant genetic effect 19% (95% CI 7-49%) of the variance in CR. Different models were constructed to explain the heredity of AST. None of these models gave meaningful results, although the ICC values for MZ were higher than those for DZ. CONCLUSIONS: Most of the variance in CR among older Finnish women could be explained by genetic factors.

Genetic variants near PDGFRA are associated with corneal curvature in Australians.

PURPOSE: Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 × 10(-8)) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. Results of initial genomewide association studies (GWAS) for CC in Australians were also reported. METHODS: Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia, were genotyped using genomewide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis. RESULTS: Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genomewide significance threshold of 5 × 10(-8). The SNP with strongest association was rs2444240 (P = 3.658 × 10(-7)), which is 31 kb upstream to the TRIM29 gene. CONCLUSIONS: A significant role of the PDGFRA gene in determining corneal curvature in the Australian population was confirmed in this study, also highlighting the putative association of the TRIM29 locus with CC.

Heritability of peripheral refraction in Chinese children and adolescents: the Guangzhou Twin Eye study.

PURPOSE: To estimate the heritability of peripheral refraction in Chinese children and adolescents. METHODS: The authors examined 72 monozygotic (MZ) twins and 48 dizygotic (DZ) twins aged 8 to 20 years from a population-based twin registry. Temporal and nasal peripheral refraction, each 40° from the visual axis, and axial refraction were measured using an autorefractor. Relative peripheral refractive error (RPRE) was defined as the peripheral refraction minus the axial refraction. Heritability was assessed by structural equation modeling after adjustment for age and sex. RESULTS: The mean and SD of temporal refraction (T(40)), nasal refraction (N(40)), RPRE-T(40), RPRE-N(40), and T(40)-N(40) asymmetry were -0.27 ± 2.0 D, 0.36 ± 2.19 D, 1.18 ± 1.39 D, 1.80 ± 1.69 D, and -0.62 ± 1.58 D, respectively. The intraclass correlations for T(40) refraction, N(40) refraction, RPRE-T(40), RPRE-N(40), and T(40)-N(40) asymmetry were 0.87, 0.83, 0.65, 0.74, and 0.58 for MZ pairs and 0.49, 0.42, 0.30, 0.41, and 0.32 for DZ pairs, respectively. A model with additive genetic and unique environmental effects was the most parsimonious, with heritability values estimated as 0.84, 0.76, 0.63, 0.70, and 0.55, respectively, for the peripheral refractive parameters. CONCLUSIONS: Additive genetic effects appear to explain most of the variance in peripheral refraction and relative peripheral refraction when adjusting for the effects of axial refraction.

Image defocus and altered retinal gene expression in chick: clues to the pathogenesis of ametropia.

PURPOSE: Because of the retina's role in refractive development, this study was conducted to analyze the retinal transcriptome in chicks wearing a spectacle lens, a well-established means of inducing refractive errors, to identify gene expression alterations and to develop novel mechanistic hypotheses about refractive development. METHODS: One-week-old white Leghorn chicks wore a unilateral spectacle lens of +15 or -15 D for 6 hours or 3 days. With total RNA from the retina/(retinal pigment epithelium, RPE), chicken gene microarrays were used to compare gene expression levels between lens-wearing and contralateral control eyes (n = 6 chicks for each condition). Normalized microarray signal intensities were evaluated by analysis of variance, using a false discovery rate of <10% as the statistical criterion. Selected differentially expressed genes were validated by qPCR. RESULTS: Very few retina/RPE transcripts were differentially expressed after plus lens wear. In contrast, approximately 1300 transcripts were differentially expressed under each of the minus lens conditions, with minimal overlap. For each condition, low fold-changes typified the altered transcriptome. Differentially regulated genes under the minus lens conditions included many potentially informative signaling molecules and genes whose protein products have roles in intrinsic retinal circadian rhythms. CONCLUSIONS: Plus or minus lens wear induce markedly different, not opposite, alterations in retina/RPE gene expression. The initial retinal responses to defocus are quite different from those when the eye growth patterns are well established, suggesting that different mechanisms govern the initiation and persistence or progression of refractive errors. The gene lists identify promising signaling candidates and regulatory pathways for future study, including a potential role for circadian rhythms in refractive development.

[Characterization of the biometric eye profile of a high myopic population: does high myopia correspond to a homogenous phenotype?]. / Caractérisation du profil biométrique oculaire d'une population myope fort: la myopie forte correspond-elle à un phénotype homogène?

PURPOSE: High myopia is a public health problem because of its high prevalence and is a major cause of blindness. The physiopathology of myopia remains unknown and mechanisms causing the disease are most probably complex, combining acquired environmental and genetic factors. The most recent data suggest that genetic determinisms of high myopia could be highly dependent on subject phenotype. The aim of this study was to analyse the ocular components of a high myopic population to verify whether high myopia corresponds to a homogeneous phenotype. PATIENTS AND METHODS: We analysed the biometric characteristics of 718 myopic eyes with a spherical equivalent of less than -5 diopters. The biometric parameters (corneal radius, axial length, and intraocular pressure) were compared controlling for sex and the degree of myopia. RESULTS: We found a difference between the phenotype of males and females. For men, axial length was the only determinant of the myopic phenotype, whereas for women, the myopic phenotype was determined by axial length and corneal radius. This difference between the phenotypes was more evident for myopia with a spherical equivalent greater than -10 diopters (moderate myopia). This difference between males and females disappeared in myopia less than -15 diopters. CONCLUSION: There are intersex differences considering the high myopia phenotype at a spherical equivalent less than -5 diopters. However, this difference disappears for extremely high myopia with a spherical equivalence of less than -15 diopters.

Heritability of spherical equivalent: a population-based twin study among 63- to 76-year-old female twins.

PURPOSE: To examine the heritability of spherical equivalent (SE) in older women. DESIGN: Population-based twin study. PARTICIPANTS: Ninety monozygotic (MZ) and 86 dizygotic (DZ) female twin pairs aged 63 to 76 years who were born from 1924 through 1937. METHODS: Ocular refraction was measured using an autorefractor and controlled by the subjective method. The contributions of genetic and environmental factors to individual differences in SE were estimated by applying an independent pathway model to twin data. MAIN OUTCOME MEASURES: Contribution of genetic and environmental effects to the variation in SE. RESULTS: Mean SE of the study population was 1.68 (standard deviation, ± 1.82) with no differences observed either between the MZ and the DZ individuals or between the left and the right eyes. The pairwise correlations were higher in the MZ sisters (intraclass correlation coefficient [ICC], 0.803 right eye and 0.807 left eye) than DZ sisters (ICC, 0.406 right eye and 0.435 left eye). Quantitative genetic modelling showed that 83% (95% confidence interval, 77%-87%) of the variance in SE could be explained by heritable factors. CONCLUSIONS: Additive genetic influences explained most of the individual differences in SE among older Finnish women.