Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.

Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.

Associations of Children's Close Reading Distance and Time Spent Indoors with Myopia, Based on Parental Questionnaire.

Purpose: To study the association of parents' reports about their children's near work and outdoor habits with myopia in their children. Methods: Data from a questionnaire study conducted in 1983 among Finnish schoolchildren were reanalyzed. Vision screening had been performed for all the schoolchildren (n = 4961) in the 1st, 5th, and 8th grades (7-, 11-, and 15-year-olds) in an area of Central Finland. The questionnaire, including information about myopia, was returned by 4305 (86.7%) participants. Items concerned parents' estimates of their child's habitual reading distance, time spent indoors as compared with age peers, daily near work, outdoors time, and parents' myopia. The associations of myopia with these factors were studied. Results: Myopia prevalence in those with a habitual close reading distance vs. others was 14.3% vs. 2.1%, 28.7% vs. 13.1% and 45.8% vs. 24.7% for the 7-, 11- and 15-year-olds (p < 0.001 in all age-groups). Myopia prevalence in children reported by their parents as spending more time indoors than age peers was 10.9% vs. 2.8% (p < 0.001), 25.0% vs. 14.7% (p = 0.004) and 41.9% vs. 25.7% (p < 0.001) in the three age groups. Myopia prevalence among those reported as spending both more time indoors and reading at a close distance vs. others was 44.2% vs. 11.9% (Fisher's exact t-test, p < 0.001). In the multiple logistic regression models, parental myopia almost doubled the risk of myopia in the 11- and 15-year-olds. ORs (95% CI) for myopia adjusted for parental myopia and sex were for close reading distance 7.381 (4.054−13.440), 2.382 (1.666−3.406), 2.237 (1.498−3.057), (p < 0.001), and for more time spent indoors, 3.692 (1.714−7.954), p = 0.001, 1.861 (1.157−2.992), p = 0.010), 1.700 (1.105−2.615), p = 0.016, in the three age groups. Conclusion: Children, especially 7-year-olds, reported by their parents as having a close reading distance and spending a lot of time indoors were associated with a higher risk for myopia.

Commonly occurring genetic polymorphisms with a major impact on the risk of nonsyndromic strabismus: replication in a sample from Finland.

PURPOSE: To replicate associations between polymorphisms in the WRB and TSPAN10 genes and strabismus in an independent Finnish cohort and to calculate their population attributable risk. METHODS: Polymorphisms in the WRB (rs2244352) and TSPAN10 (rs6420484) genes were investigated in individuals from the FinnGen study group who had one of three categories of strabismus, with clinical diagnoses of (1) "strabismus-all subtypes" (3,515 cases and 173,384 controls), (2) "convergent concomitant strabismus" (ICD-10 code H50.0; 737 cases and 170,976 controls), and (3) "divergent concomitant strabismus" (ICD-10 code H50.1; 1,059 cases and 170,976 controls). RESULTS: The WRB polymorphism was associated with "all subtypes" of strabismus (OR = 1.08; P = 0.008) and divergent strabismus (OR = 1.11; P = 0.046) but not with convergent strabismus (P = 0.41). The WRB polymorphism had a population attributable risk of 3.4% for all strabismus subtypes and 4.7% for divergent strabismus. The TSPAN10 polymorphism was associated with all three strabismus phenotypes: "all subtypes" (OR = 1.08; P = 0.002), convergent strabismus (OR = 1.19; P = 0.001) and divergent strabismus (OR = 1.20; P =7.21E-05). The population attributable risk for the TSPAN10 polymorphism was 6.0% for any strabismus, 13.3% for convergent strabismus, and 13.9% for divergent strabismus. CONCLUSIONS: Genetic association with strabismus was replicated in a Finnish cohort for two common polymorphisms. Under the assumption that these polymorphisms are independent of other risk factors, they are responsible for up to 20% of isolated cases of strabismus in Finland, similar to estimates in other European populations.

Associations of near work time, watching TV, outdoors time, and parents' myopia with myopia among school children based on 38-year-old historical data.

PURPOSE: To study the prevalence and risk factors of myopia with data from a questionnaire study conducted in 1983 among Finnish school children. METHODS: School children (n = 4 961) from the 1st, 5th and 8th grades of school (7-, 11- and 15-year-olds) in Central Finland were screened for vision followed by a questionnaire, which was returned by 4 352 (87.7%) participants. Myopia was categorized based on the questionnaire. Items concerned daily time spent on near work and outdoor activities, excluding time spent at school, watching TV and parental myopia and the associations of myopia with these factors were studied. RESULTS: The prevalence of myopia was 3%, 15% and 27% among the 7-, 11- and 15-year-olds, and if daily near work at home was ≤1 hr, myopia prevalence was 0.5%, 3.3% and 17.6%, respectively. The adjusted risk of myopia for each daily near work hour was OR 1.476 (95% confidence interval 1.099-1.984, p = 0.010), OR 1.346 (1.170-1.584, p < 0.001) and OR 1.206 (1.076-1.352, p = 0.001), in the 3 age groups, respectively. The adjusted risk of myopia for each daily hour spent outdoors was OR 0.764 (0.648-0.900, p = 0.001) in the 11-year-olds and OR (0.840, 0.743-0.950, p = 0.005) in the 15-year-olds. Outdoors time prevented myopia at different levels of near work, although less at the highest levels, and near work increased risk of myopia with the level of outdoors time. If the ratio between near work and outdoors time was ≤0. 5 or >1.5, the prevalence of myopia was 1.4% versus 5.6%, 6.3% versus 24.7% and 15.9% versus 36.9%, among the 7-, 11- and 15-year-olds, respectively. The higher prevalence of myopia among the 11- and 15-year-old girls than boys was explained by more near work and less outdoor time among the girls. Having two myopic parents roughly doubled the risk of myopia compared to if one myopic parent in the 11- and 15-year-olds. CONCLUSIONS: Myopic parents, greater near work time, less outdoors time, a higher near work/outdoors ratio, and being a girl increased the risk of myopia. Myopia was rare in the 7- and 11-year-olds if daily near work at home did not exceed one hour or if the near work/outdoors ratio was not higher than 0.5. Outdoors time was associated with the prevalence of myopia at all levels of near work, although the association was weaker at the highest level.

Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia.

Purpose: Emmetropization requires coordinated scaling of the major ocular components, corneal curvature and axial length. This coordination is achieved in part through a shared set of genetic variants that regulate eye size. Poorly coordinated scaling of corneal curvature and axial length results in refractive error. We tested the hypothesis that genetic variants regulating eye size in emmetropic eyes are distinct from those conferring susceptibility to refractive error. Methods: A genome-wide association study (GWAS) for corneal curvature in 22,180 adult emmetropic individuals was performed as a proxy for a GWAS for eye size. A polygenic score created using lead GWAS variants was tested for association with corneal curvature and axial length in an independent sample: 437 classified as emmetropic and 637 as ametropic. The genetic correlation between eye size and refractive error was calculated using linkage disequilibrium score regression for approximately 1 million genetic variants. Results: The GWAS for corneal curvature in emmetropes identified 32 independent genetic variants (P < 5.0e-08). A polygenic score created using these 32 genetic markers explained 3.5% (P < 0.001) and 2.0% (P = 0.001) of the variance in corneal curvature and axial length, respectively, in the independent sample of emmetropic individuals but was not predictive of these traits in ametropic individuals. The genetic correlation between eye size and refractive error was close to zero (rg = 0.00; SE = 0.06; P = 0.95). Conclusions: These results support the hypothesis that genetic variants regulating eye size in emmetropic eyes do not overlap with those conferring susceptibility to myopia. This suggests that distinct biological pathways regulate normal eye growth and myopia development.

IMI Prevention of Myopia and Its Progression.

The prevalence of myopia has markedly increased in East and Southeast Asia, and pathologic consequences of myopia, including myopic maculopathy and high myopia-associated optic neuropathy, are now some of the most common causes of irreversible blindness. Hence, strategies are warranted to reduce the prevalence of myopia and the progression to high myopia because this is the main modifiable risk factor for pathologic myopia. On the basis of published population-based and interventional studies, an important strategy to reduce the development of myopia is encouraging schoolchildren to spend more time outdoors. As compared with other measures, spending more time outdoors is the safest strategy and aligns with other existing health initiatives, such as obesity prevention, by promoting a healthier lifestyle for children and adolescents. Useful clinical measures to reduce or slow the progression of myopia include the daily application of low-dose atropine eye drops, in concentrations ranging between 0.01% and 0.05%, despite the side effects of a slightly reduced amplitude of accommodation, slight mydriasis, and risk of an allergic reaction; multifocal spectacle design; contact lenses that have power profiles that produce peripheral myopic defocus; and orthokeratology using corneal gas-permeable contact lenses that are designed to flatten the central cornea, leading to midperipheral steeping and peripheral myopic defocus, during overnight wear to eliminate daytime myopia. The risk-to-benefit ratio needs to be weighed up for the individual on the basis of their age, health, and lifestyle. The measures listed above are not mutually exclusive and are beginning to be examined in combination.

Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia.

IMPORTANCE: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. OBJECTIVE: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. EXPOSURES: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of polygenic risk scores in replication samples. RESULTS: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). CONCLUSIONS AND RELEVANCE: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.

Update and guidance on management of myopia. European Society of Ophthalmology in cooperation with International Myopia Institute.

The prevalence of myopia is increasing extensively worldwide. The number of people with myopia in 2020 is predicted to be 2.6 billion globally, which is expected to rise up to 4.9 billion by 2050, unless preventive actions and interventions are taken. The number of individuals with high myopia is also increasing substantially and pathological myopia is predicted to become the most common cause of irreversible vision impairment and blindness worldwide and also in Europe. These prevalence estimates indicate the importance of reducing the burden of myopia by means of myopia control interventions to prevent myopia onset and to slow down myopia progression. Due to the urgency of the situation, the European Society of Ophthalmology decided to publish this update of the current information and guidance on management of myopia. The pathogenesis and genetics of myopia are also summarized and epidemiology, risk factors, preventive and treatment options are discussed in details.

Comparison of myopic progression in Finnish and Singaporean children.

PURPOSE: To compare 3-year myopic progression between Finnish and Singaporean children. METHODS: Myopic progression was compared between 9-year-old (mean age 9.7 ± 0.4 years, n = 92) and 11-year-old (mean age 11.7 ± 0.4 years, n = 144) Finnish (Finnish RCT) children and Singaporean children matched by age and refraction (SCORMMatched, n = 403) and 7- to 8-year-old Singaporean children matched only by refraction (SCORM Young, n = 186). Spherical equivalent (SE) was between -0.50 and -3.00 D. Refraction with cycloplegia was controlled annually for 3 years. Information on parental myopia, mother's education, time spent on near-work and outdoor time was gathered by parental questionnaire. RESULTS: Three-year myopic progression was -2.08 ± 0.96 D and -1.30 ± 0.69 D in the Finnish RCT and Singaporean SCORM Matched 9-year-olds, respectively, and -1.34 ± 0.78 D, and -0.52 ± 0.44 D in the 11-year-olds, respectively (p < 0.001 between all groups). Myopic progression was fastest (-2.69 ± 0.89 D) in the SCORM 7-year-olds and similar between the SCORM Matched 9-year-olds and Finnish RCT 11-year-olds (p = 0.55). The Finnish RCT and SCORM Matched children showed significant differences in both daily near-work time (1.8 ± 1.0 versus 3.4 ± 1.9 hours per day, p < 0.001) and outdoor time (2.6 ± 0.9 versus 0.5 ± 0.4 hours per day, p < 0.001). These differences did not, however, explain the differences in myopic progression between the groups. More time spent outdoors was associated with less myopic progression in the Finnish RCT (r = 0.17, p = 0.009) group only. In the whole materials, greater myopic progression was associated with younger age at baseline (p < 0.001), younger age was associated with mother's higher education (p < 0.001), and mothers higher education was associated with myopia in both parents (p < 0.001). CONCLUSION: Age at baseline was the most significant factor associated with myopic progression. However, at the same age and with the same initial refraction, the Finnish and Singaporean children showed different myopic progression. This result remains unexplained. Thus, age of myopia onset should be considered when comparing myopic progression between different samples and conducting treatment trials. Parental myopia may be a weak indicator of heredity of myopia.

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Heredity of interocular similarities in components of refraction: a population-based twin study among 66- to 79-year-old female twins.

PURPOSE: To examine genetic influences on interocular similarities in ocular refraction and components of refraction among elderly female twins. METHODS: Refraction was assessed in 94 monozygotic (MZ) and 74 dizygotic (DZ) female twins aged 66-78 years. Absolute values of interocular differences (Aniso variables) in spherical refraction (SR), refractive astigmatism (AST), spherical equivalent (SE), corneal refractive power (CR), corneal astigmatism (CAST), anterior chamber depth (ACD) and axial length (AL) were calculated. The differences between sisters in each of the Aniso variables were calculated and graded into two categories, best differentiating the groups, here isometropic and anisometropic values. The cut-offs for grading as isometropic were AnisoSR < 0.75 D, AnisoAST < 0.5 D, AnisoSE < 1.0 D, AnisoCR < 0.5 D, AnisoCAST < 0.50 D, AnisoACD < 0.1 mm and AniosAL < 0.1 mm. Genetic influences on these traits were investigated by comparing the prevalence of isometropic and anisometropic differences between the MZ and DZ pairs in the Aniso variables and the interrelationships between the Aniso variables. RESULTS: When the Aniso variables were treated as continuous, no significant differences were found between the MZ and DZ subjects. When the proportions of isometropic intratwinpair interocular differences in the Aniso variables in the MZ and DZ cotwins were compared, the prevalences (MZ/DZ) were AnisoSR: 68%/60%; AnisoAST: 66%/57%; AnisoSE: 87%/68%; AnisoCR: 83%/78%; AnisoCAST: 69%/35%; AnisoACD: 77%/63%; and AnisoAL: 76%/60%. The differences were statistically significant for Aniso SE (p = 0.035, Fisher's exact test) and CAST (p = 0.007). The greater homogeneity in the interocular differences between the MZ sisters supports the assumption that isometropia of different elements of refraction is genetically influenced and tending to continue up to older ages. In cases where AnisoSE was <1.0 D, higher CR in one eye was associated with shorter AL (r = -0.398, p < 0.001), thereby contributing to emmetropization, irrespective of zygosity. In the cases of AnisoSE ≥1 D, no similar influence on emmetropization was observed. The difference between sisters in AnisoSE was associated with the intratwinpair difference in Aniso AL, but not with the intratwinpair differences in AnisoCR, irrespective of zygosity. CONCLUSION: The higher prevalence of similarities in isometropia of the spherical equivalent and corneal astigmatism between the MZ pairs compared to DZ pairs is consistent with the view that genetic influences on the refractive elements of the eye, tending to isometropia, continue into older age. The interrelation between CR and AL tends to maintain isometropia of SE irrespective of zygosity.

Risk factors for high myopia: a 22-year follow-up study from childhood to adulthood.

PURPOSE: To determine the effect of the definition of high myopia on its prevalence and risk factors for high myopia. METHODS: A total of 240 myopic schoolchildren (119 boys and 121 girls) at the mean age of 10.9 years (range 8.8-12.8 years) were recruited to a randomized clinical trial of myopia treatment among children from 3rd- and 5th grades of school referred for an eye examination due to poor distant vision and having no previous spectacles. Clinical follow-ups, including refraction with cycloplegia, were conducted annually at 3 years [third follow-up here = clinical follow-up 1, (n = 237)], and thereafter twice at approximately 10-year intervals [clinical follow-ups 2 (n = 179) and 3, (n = 134)]. Additional refraction values between follow-ups 2 and 3 were received from ophthalmologists and opticians' prescriptions and records. The most recent adulthood refraction measure available was taken as the final refraction value for 204 (85%) of the original cohort [mean follow-up time (±standard deviation) 22.1 (±3.9) years]. Parental myopia, time spent on reading and close work, watching TV and outdoor activities were assessed with a questionnaire at the clinical follow-ups. The influence of different definitions of high myopia on its prevalence was analysed. The associations of different factors with high myopia were investigated. RESULTS: Mean spherical equivalent (SE) at baseline was -1.43 (±0.60) D, ranging from -0.38 D to -3.00 D. At follow-up end, mean SE of the more myopic eye was -5.29 (±1.95) D, ranging from -1.00 D to -11.25 D. High myopia prevalence with the definitions SE < -6.00 D in the right eye and SE ≤ -6.00 D or ≤-5.00 D in either eye was 24%, 32% and 52%, respectively. In this study, high myopia was defined as spherical equivalent (SE) ≤ -6.00 D in either eye. If both parents were myopic, the odds ratio (OR) of having high myopia was 3.9 (95% CI: 1.5-10.4). Younger age at baseline predicted higher prevalence of high myopia; baseline ages between 8.8 and 9.7 and between 11.9 and 12.8 years gave prevalences 65% and 7%. Higher myopia at baseline, higher myopic progression between the first follow-ups and more time spent on reading and close work as compared with time spent outdoors were associated with high myopia. CONCLUSION: About 32% of the children receiving first spectacles for myopia between ages of 8.8-12.8 years had high myopia (SE ≤ -6.00 D in either eye) in adulthood. Different definitions of high myopia ranging between -5 D and -6 D lead to large differences in prevalence. A generally accepted definition of high myopia is thus needed. Parental myopia, age at baseline, myopic progression during the first post onset year, and more time spent on reading and close work and less on outdoor activities in childhood were associated with adulthood high myopia.

A genome-wide association study of corneal astigmatism: The CREAM Consortium.

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Anisometropia of spherical equivalent and astigmatism among myopes: a 23-year follow-up study of prevalence and changes from childhood to adulthood.

PURPOSE: To study anisometropia of spherical equivalent and astigmatism from the onset of myopia at school age to adulthood. METHODS: A total of 240 myopic schoolchildren (mean age 10.9 years), with no previous spectacles, were recruited during 1983-1984 to a randomized 3-year clinical trial of bifocal treatment of myopia. Examinations with subjective cyclopedic refraction were repeated 3 years later (follow-up 1) for 238 subjects and thereafter at the mean ages of 23.2 (follow-up 2) and 33.9 years (follow-up 3) for 178 and 134 subjects. After exclusions, the 102 subjects who attended all three follow-ups were included in the analyses. Corneal refractive power and astigmatism and anterior chamber depth was measured with Pentacam topography and axial length with IOL master at study end. Prevalence and changes in anisometropia of spherical equivalent (AnisoSE) and astigmatism (AnisoAST) and their relationships with refractive and axial measures were studied. RESULTS: Mean (±SD) of spherical equivalent (SE), AnisoSE and AnisoAST increased from baseline to follow-up end from -1.44 ± 0.57 D to -5.11 ± 2.23 D, from 0.28 ± 0.30 D to 0.68 ± 0.69 D and from 0.14 ± 0.18 D to 0.37 ± 0.36 D, respectively. Prevalence of AnioSE, ≥1 D, increased from 5% to 22.6% throughout follow-up. Higher AnisoSE was associated with SE in the less myopic eye at baseline and at follow-up 1, and with SE in the more myopic eye in follow-ups 2 and 3 in adulthood. At study end, AnisoSE was associated with the interocular difference in axial length (AL) (r = 0.612, p < 0.001) but not with the interocular difference in corneal refraction (CR) (r = -0.122, p = 0.266). In cases of low AnisoSE(≤1.00 D), the negative correlation between the real interocular differences (value of right eye minus value of left eye) in CR and AL (r = -0.427, p < 0.001) decreased the influence of the interocular difference in AL on AnisoSE, causing emmetropization in AnisoSE. The interocular difference in corneal astigmatism was the main factor associated with AnisoAST (r = 0.231, p = 0.020). No significant relationship was found between AnisoAST and level of SE. CONCLUSION: Anisometropia of the spherical equivalent (AnisoSE) increased along with the myopic progression and at study end was mainly associated with the interocular difference in AL. AnisoAST was mainly explained by the interocular difference in corneal astigmatism. In cases with low AnisoSE (≤1.0 D), the interrelationship between CR and AL decreased AnisoSE causing emmetropization in AnisoSE.

Associations of reading posture, gaze angle and reading distance with myopia and myopic progression.

PURPOSE: To study the associations of habitual reading posture, gaze angle in reading and reading distance with myopia and changes in myopia among myopic children. METHODS: A total of 240 myopic schoolchildren (mean age 10.9 years), with no previous spectacles, were recruited during 1983-1984 to a randomized 3-year clinical trial of bifocal treatment of myopia. Three annual examinations with subjective cycloplegic refraction were conducted for 237-238 subjects. A further examination was conducted at the mean age of 23.2 years for 178 subjects. Habitual reading posture was elicited by questionnaire at study outset. Reading distance was measured with a Clement Clark accommodometer and gaze angle with an angle scale at baseline and all three annual follow-ups. Height was measured by a school nurse. The connections between the variables were studied with the standard statistical methods. RESULTS: Higher myopia was connected with shorter reading distance among girls at follow-ups 2 and 3, but not at the other examinations. The correlation of spherical equivalent with height was non-significant at each follow-up. Myopic progression across the whole follow-up was highest among those who read sitting down at baseline (-3.58 ± 1.75 D) and lowest among those who read face up lying down (-2.35 ± 1.53 D) (p = 0.021). Reading with eyes at a more downward angle was slightly connected with greater myopic progression (r = -0.166, p = 0.028). CONCLUSIONS: Reading in a sitting posture at myopia onset predicted the greatest myopic progression to adulthood and reading face up on one's back the lowest. Reading with eyes on turned more downwards was slightly connected with greater myopic progression.

Anisometropia of ocular refractive and biometric measures among 66- to 79-year-old female twins.

PURPOSE: To examine the prevalence of anisometropia of spherical refraction (AnisoSR), astigmatism (AnisoAST) and spherical equivalent (AnisoSE) and their associations with spherical refraction (SR), refractive astigmatism (AST), spherical equivalent (SE) and interocular differences of ocular biometric parameters among elderly female twins. METHODS: Refraction of 117 monozygotic (MZ) and 116 dizygotic (DZ) female twin subjects aged 66-79 years was assessed with an auto-refractor (Topcon AT) and controlled by subjective refraction. Corneal refraction, anterior chamber depth and axial length were measured with a Zeiss IOL Master. Participants with eyes operated for cataract or glaucoma were excluded, but the grade of nuclear opacity was not recorded. The associations between the absolute values of AnisoSR, AnisoAST and AnisoSE with SR, AST, SE, corneal refractive power (CR), corneal astigmatism (CAST), anterior chamber depth (ACD) and axial length (AL) and with their interocular differences were calculated. When calculating the interdependencies of the differences, the real and absolute differences between the right and left eye were used. RESULTS: Means ± standard deviations for AnisoSR, AnisoAST and AnisoSE were 0.67 ± 0.92 D, 0.42 ± 0.41 D and 0.65 ± 0.71 D, respectively. AnisoSR, AnisoAST and AnisoSE >1.0 D were present in 14.7%, 4.2% and 17.7% of cases, respectively. Anisometropia of spherical refraction (AnisoSR), AnisoAST and AnisoSE were higher the more negative the values of SR or SE. Hyperopic ametropia did not increase these anisometropia values. The correlations of AnisoSR and AnisoSE with the absolute values of interocular differences in CR and AL were non-significant. Using the real values of the interocular differences, the respective correlations were significant. The correlation between the real interocular differences in CR and AL was negative (r = -0.258, p < 0.001). Thus, the combined effect of the real interocular differences in CR and AL was a decrease in AnisoSR and AnisoSE (emmetropization). CONCLUSION: Higher AnisoSR and AnisoSE were associated with more myopic refraction and longer AL. Higher AnisoAST was associated with more negative SR and higher AST and CAST. The negative correlation between real interocular differences in CR and AL indicated their influence of emmetropization in AnisoSR and AnisoSE.

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

What is the influence of parents' myopia on their children's myopic progression? A 22-year follow-up study.

PURPOSE: To study the connection between parental myopia and their children's myopia from school age to adulthood. METHODS: Two hundred and forty myopic schoolchildren (119 boys, 121 girls, mean age 10.9 years) with no previous spectacles for myopia were recruited to a 3-year treatment trial with different use of spectacles. Follow-ups were performed at mean ages of 13.9, 23.7 and 33.2 years for 238, 176 and 170 subjects respectively. Subjective refraction was calibrated to the spherical equivalent at corneal level (SEcor). Corneal refractive power (CR) and axial length (AL) were measured. Parental myopia was assessed with a questionnaire and the children assigned accordingly to one of three hereditary groups: both parents myopic H++, one myopic parent = H+- and no myopic parents = H-. RESULTS: At baseline, no significant gender differences in age or SEcor were found in the different hereditary groups. Among girls, CR was significantly higher in hereditary group H++ (45.20 ± 1.08 D) than in group H+- (44.19 ± 1.28 D; p = 0.006) or H- (43.84 ± 1.18 D; p < 0.001). Among boys, the differences in CR between the hereditary groups were smaller and significant at follow-up 2 only. At follow-up end, among males, no significant differences between the hereditary groups were found in SEcor, CR, AL or myopic progression. Among females, myopic progression was 4.21 ± 1.81 D if one or both parents were myopic and -3.19 ± 1.36 D if neither parent was myopic (p = 0.035), but no significant difference was observed in AL. CONCLUSIONS: The main difference between the hereditary groups was higher CR and myopic progression among females with myopic parents than non-myopic parents, but with no significant difference in AL with respect to parental myopia at study end.