IMI Risk Factors for Myopia

Risk factor analysis provides an important basis for developing interventions for any condition. In the case of myopia, evidence for a large number of risk factors has been presented, but they have not been systematically tested for confounding. To be useful for designing preventive interventions, risk factor analysis ideally needs to be carried through to demonstration of a causal connection, with a defined mechanism. Statistical analysis is often complicated by covariation of variables, and demonstration of a causal relationship between a factor and myopia using Mendelian randomization or in a randomized clinical trial should be aimed for. When strict analysis of this kind is applied, associations between various measures of educational pressure and myopia are consistently observed. However, associations between more nearwork and more myopia are generally weak and inconsistent, but have been supported by meta-analysis. Associations between time outdoors and less myopia are stronger and more consistently observed, including by meta-analysis. Measurement of nearwork and time outdoors has traditionally been performed with questionnaires, but is increasingly being pursued with wearable objective devices. A causal link between increased years of education and more myopia has been confirmed by Mendelian randomization, whereas the protective effect of increased time outdoors from the development of myopia has been confirmed in randomized clinical trials. Other proposed risk factors need to be tested to see if they modulate these variables. The evidence linking increased screen time to myopia is weak and inconsistent, although limitations on screen time are increasingly under consideration as interventions to control the epidemic of myopia

When do myopia genes have their effect? Comparison of genetic risks between children and adults

Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged 25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10–25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated; and in adults 20 loci were associated. Association with GRS increased with age; β = 0.0016 per risk allele (P = 2 × 10–8) in <10 years, 0.0033 (P = 5 × 10–15) in 10- to 25-year-olds, and 0.0048 (P = 1 × 10–72) in adults. Genes with strongest effects (LAMA2, GJD2) had an early effect that increased with age. Our results provide insights on the age span during which myopia genes exert their effect. These insights form the basis for understanding the mechanisms underlying high and pathological myopia

Association of anthropometric measures across the life-course with refractive error and ocular biometry at age 15 years

YesBackground A recent Genome-wide association meta-analysis (GWAS) of refractive error reported shared genetics with anthropometric traits such as height, BMI and obesity. To explore a potential relationship with refractive error and ocular structure we performed a life-course analysis including both maternal and child characteristics using data from the Avon Longitudinal Study of Parents and Children cohort. Methods Measures collected across the life-course were analysed to explore the association of height, weight, and BMI with refractive error and ocular biometric measures at age 15 years from 1613children. The outcome measures were the mean spherical equivalent (MSE) of refractive error (dioptres), axial length (AXL; mm), and radius of corneal curvature (RCC; mm). Potential confounding variables; maternal age at conception, maternal education level, parental socio-economic status, gestational age, breast-feeding, and gender were adjusted for within each multi-variable model. Results Maternal height was positively associated with teenage AXL (0.010 mm; 95% CI: 0.003, 0.017) and RCC (0.005 mm; 95% CI: 0.003, 0.007), increased maternal weight was positively associated with AXL (0.004 mm; 95% CI: 0.0001, 0.008). Birth length was associated with an increase in teenage AXL (0.067 mm; 95% CI: 0.032, 0.10) and flatter RCC (0.023 mm; 95% CI: 0.013, 0.034) and increasing birth weight was associated with flatter RCC (0.005 mm; 95% CI: 0.0003, 0.009). An increase in teenage height was associated with a lower MSE (− 0.007 D; 95% CI: − 0.013, − 0.001), an increase in AXL (0.021 mm; 95% CI: 0.015, 0.028) and flatter RCC (0.008 mm; 95% CI: 0.006, 0.010). Weight at 15 years was associated with an increase in AXL (0.005 mm; 95% CI: 0.001, 0.009). Conclusions At each life stage (pre-natal, birth, and teenage) height and weight, but not BMI, demonstrate an association with AXL and RCC measured at age 15 years. However, the negative association between refractive error and an increase in height was only present at the teenage life stage. Further research into the growth pattern of ocular structures and the development of refractive error over the life-course is required, particularly at the time of puberty

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

The genetics of myopia

Myopia is the most common eye condition worldwide and its prevalence is increasing. While changes in environment, such as time spent outdoors, have driven myopia rates, within populations myopia is highly heritable. Genes are estimated to explain up to 80% of the variance in refractive error. Initial attempts to identify myopia genes relied on family studies using linkage analysis or candidate gene approaches with limited progress. More genome-wide association study (GWAS) approaches have taken over, ultimately resulting in the identification of hundreds of genes for refractive error and myopia, providing new insights into its molecular machinery. These studies showed myopia is a complex trait, with many genetic variants of small effect influencing retinal signaling, eye growth and the normal process of emmetropization. The genetic architecture and its molecular mechanisms are still to be clarified and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed.We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes.To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression.The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth

Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study

Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors

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