Identification of Rare Variants Involved in High Myopia Unraveled by Whole Genome Sequencing.

Purpose: Myopia (nearsightedness) is a condition in which a refractive error (RE) affects vision. Although common variants explain part of the genetic predisposition (18%), most of the estimated 70% heritability is missing. Here, we investigate the contribution of rare genetic variation because this might explain more of the missing heritability in the more severe forms of myopia. In particular, high myopia can lead to blindness and has a tremendous impact on a patient and at the societal level. The exact molecular mechanisms behind this condition are not yet completely unraveled, but whole genome sequencing (WGS) studies have the potential to identify novel (rare) disease genes, explaining the high heritability. Design: Cross-sectional study performed in the Netherlands. Participants: We investigated 159 European patients with high myopia (RE > -10 diopters). Methods: We performed WGS using a stepwise filtering approach and burden analysis. The contribution of common variants was calculated as a genetic risk score (GRS). Main Outcome Measures: Rare variant burden, GRS. Results: In 25% (n = 40) of these patients, there was a high (> 75th percentile) contribution of common predisposing variants; that is, these participants had higher GRSs. In 7 of the remaining 119 patients (6%), deleterious variants in genes associated with known (ocular) disorders, such as retinal dystrophy disease (prominin 1 [PROM1]) or ocular development (ATP binding cassette subfamily B member 6 [ABCB6], TGFB induced factor homeobox 1 [TGIF1]), were identified. Furthermore, without using a gene panel, we identified a high burden of rare variants in 8 novel genes associated with myopia. The genes heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) (proportion in study population vs. the Genome Aggregation Database (GnomAD) 0.14 vs. 0.03, P = 4.22E-17), RNA binding motif protein 20 (RBM20) (0.15 vs. 0.06, P = 4.98E-05), and MAP7 domain containing 1 (MAP7D1) (0.19 vs. 0.06, P = 1.16E-10) were involved in the Wnt signaling cascade, melatonin degradation, and ocular development and showed most biologically plausible associations. Conclusions: We found different contributions of common and rare variants in low and high grade myopia. Using WGS, we identified some interesting candidate genes that could explain the high myopia phenotype in some patients. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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.

Prevalence of Myopic Macular Features in Dutch Individuals of European Ancestry With High Myopia.

IMPORTANCE: High myopia incidence and prevalence is increasing worldwide, and the visual burden caused by myopia is expected to rise accordingly. Studies investigating the occurrence of myopic complications in individuals of European ancestry with high myopia are scarce, hampering insights into the frequency of myopic retinal complications in European individuals and their visual burden. OBJECTIVE: To assess the frequency of myopic macular features in individuals of European ancestry with high myopia. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis of the Dutch Myopia Study (MYST) and individuals with high myopia from the Rotterdam Study (RS) included 626 patients with high myopia (spherical equivalent of refractive error [SER] ≤-6 diopters [D] or axial length [AL] ≥26 mm) who underwent an extensive ophthalmic examination including multimodal retinal imaging. In addition to this combination of a population-based cohort study and mix-based high myopia study, a systematic literature review was also performed to compare findings with studies of individuals of Asian ancestry. EXPOSURES: High myopia, age, and AL. MAIN OUTCOMES AND MEASURES: Frequency of myopic macular and optic disc features: tessellated fundus, myopic macular degeneration (MMD), staphyloma, peripapillary intrachoroidal cavitation, peripapillary atrophy (PPA), and "plus" lesions (choroidal neovascularization, Fuchs spot, and lacquer cracks). RESULTS: The mean (SD) SER of the combined study population (MYST and RS) was -9.9 (3.2) D; the mean (SD) age was 51.4 (15.1) years, and 387 (61.8%) were women. The prevalence of MMD was 25.9% and increased with older age (P for trend <.001), lower SER (odds ratio [OR], 0.70; 95% CI, 0.65-0.76; P < .001), and higher AL (OR, 2.53; 95% CI, 2.13-3.06; P < .001). Choroidal neovascularization or Fuchs spot was present in 2.7% (n = 17), both lesions in 0.3% (n = 2), and lacquer cracks in 1.4% (n = 9). Staphyloma, PPA, and MMD were highly prevalent in visual impaired and blind eyes (frequency was 73.9% [20 of 27], 90.5% [19 of 21], and 63.0% [17 of 27] of unilateral blind eyes for MMD, staphyloma, and PPA, respectively). Seven previous studies in Asian populations reported a variable MMD frequency ranging from 8.3% to 64%, but frequencies were similar for comparable risk profiles based on age and SER. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of a highly myopic Dutch population of European ancestry, myopic retinal features were frequent; were associated with age, SER, and AL; and occurred in all visually severely impaired eyes. The absence of treatment options for most of these retinal complications emphasizes the need for effective strategies to prevent high myopia.

Phenotypic Consequences of the GJD2 Risk Genotype in Myopia Development.

Purpose: To study the relatively high effect of the refractive error gene GJD2 in human myopia, and to assess its relationship with refractive error, ocular biometry and lifestyle in various age groups. Methods: The population-based Rotterdam Study (RS), high myopia case-control study MYopia STudy, and the birth-cohort study Generation R were included in this study. Spherical equivalent (SER), axial length (AL), axial length/corneal radius (AL/CR), vitreous depth (VD), and anterior chamber depth (ACD) were measured using standard ophthalmologic procedures. Biometric measurements were compared between GJD2 (rs524952) genotype groups; education and environmental risk score (ERS) were calculated to estimate gene-environment interaction effects, using the Synergy index (SI). Results: RS adults carrying two risk alleles had a lower SER and longer AL, ACD and VD (AA versus TT, 0.23D vs. 0.70D; 23.79 mm vs. 23.52 mm; 2.72 mm vs. 2.65 mm; 16.12 mm vs. 15.87 mm; all P < 0.001). Children carrying two risk alleles had larger AL/CR at ages 6 and 9 years (2.88 vs. 2.87 and 3.00 vs. 2.96; all P < 0.001). Education and ERS both negatively influenced myopia and the biometric outcomes, but gene-environment interactions did not reach statistical significance (SI 1.25 [95% confidence interval {CI}, 0.85-1.85] and 1.17 [95% CI, 0.55-2.50] in adults and children). Conclusions: The elongation of the eye caused by the GJD2 risk genotype follows a dose-response pattern already visible at the age of 6 years. These early effects are an example of how a common myopia gene may drive myopia.

IMI 2021 Yearly Digest.

Purpose: The International Myopia Institute (IMI) Yearly Digest highlights new research considered to be of importance since the publication of the first series of IMI white papers. Methods: A literature search was conducted for articles on myopia between 2019 and mid-2020 to inform definitions and classifications, experimental models, genetics, interventions, clinical trials, and clinical management. Conference abstracts from key meetings in the same period were also considered. Results: One thousand articles on myopia have been published between 2019 and mid-2020. Key advances include the use of the definition of premyopia in studies currently under way to test interventions in myopia, new definitions in the field of pathologic myopia, the role of new pharmacologic treatments in experimental models such as intraocular pressure-lowering latanoprost, a large meta-analysis of refractive error identifying 336 new genetic loci, new clinical interventions such as the defocus incorporated multisegment spectacles and combination therapy with low-dose atropine and orthokeratology (OK), normative standards in refractive error, the ethical dilemma of a placebo control group when myopia control treatments are established, reporting the physical metric of myopia reduction versus a percentage reduction, comparison of the risk of pediatric OK wear with risk of vision impairment in myopia, the justification of preventing myopic and axial length increase versus quality of life, and future vision loss. Conclusions: Large amounts of research in myopia have been published since the IMI 2019 white papers were released. The yearly digest serves to highlight the latest research and advances in myopia.

The Complications of Myopia: A Review and Meta-Analysis.

Purpose: To determine the risk between degree of myopia and myopic macular degeneration (MMD), retinal detachment (RD), cataract, open angle glaucoma (OAG), and blindness. Methods: A systematic review and meta-analyses of studies published before June 2019 on myopia complications. Odds ratios (OR) per complication and spherical equivalent (SER) degree (low myopia SER < -0.5 to > -3.00 diopter [D]; moderate myopia SER ≤ -3.00 to > -6.00 D; high myopia SER ≤ -6.00 D) were calculated using fixed and random effects models. Results: Low, moderate, and high myopia were all associated with increased risks of MMD (OR, 13.57, 95% confidence interval [CI], 6.18-29.79; OR, 72.74, 95% CI, 33.18-159.48; OR, 845.08, 95% CI, 230.05-3104.34, respectively); RD (OR, 3.15, 95% CI, 1.92-5.17; OR, 8.74, 95% CI, 7.28-10.50; OR, 12.62, 95% CI, 6.65-23.94, respectively); posterior subcapsular cataract (OR, 1.56, 95% CI, 1.32-1.84; OR, 2.55, 95% CI, 1.98-3.28; OR, 4.55, 95% CI, 2.66-7.75, respectively); nuclear cataract (OR, 1.79, 95% CI, 1.08-2.97; OR, 2.39, 95% CI, 1.03-5.55; OR, 2.87, 95% CI, 1.43-5.73, respectively); and OAG (OR, 1.59, 95% CI, 1.33-1.91; OR, 2.92, 95% CI, 1.89-4.52 for low and moderate/high myopia, respectively). The risk of visual impairment was strongly related to longer axial length, higher myopia degree, and age older than 60 years (OR, 1.71, 95% CI, 1.07-2.74; OR, 5.54, 95% CI, 3.12-9.85; and OR, 87.63, 95% CI, 34.50-222.58 for low, moderate, and high myopia in participants aged >60 years, respectively). Conclusions: Although high myopia carries the highest risk of complications and visual impairment, low and moderate myopia also have considerable risks. These estimates should alert policy makers and health care professionals to make myopia a priority for prevention and treatment.

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

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.

Evidence That Emmetropization Buffers Against Both Genetic and Environmental Risk Factors for Myopia.

Purpose: To test the hypothesis that emmetropization buffers against genetic and environmental risk factors for myopia by investigating whether risk factor effect sizes vary depending on children's position in the refractive error distribution. Methods: Refractive error was assessed in participants from two birth cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) (noncycloplegic autorefraction) and Generation R (cycloplegic autorefraction). A genetic risk score for myopia was calculated from genotypes at 146 loci. Time spent reading, time outdoors, and parental myopia were ascertained from parent-completed questionnaires. Risk factors were coded as binary variables (0 = low, 1 = high risk). Associations between refractive error and each risk factor were estimated using either ordinary least squares (OLS) regression or quantile regression. Results: Quantile regression: effects associated with all risk factors (genetic risk, parental myopia, high time spent reading, low time outdoors) were larger for children in the extremes of the refractive error distribution than for emmetropes and low ametropes in the center of the distribution. For example, the effect associated with having a myopic parent for children in quantile 0.05 vs. 0.50 was as follows: ALSPAC: age 15, -1.19 D (95% CI -1.75 to -0.63) vs. -0.13 D (-0.19 to -0.06), P = 0.001; Generation R: age 9, -1.31 D (-1.80 to -0.82) vs. -0.19 D (-0.26 to -0.11), P < 0.001. Effect sizes for OLS regression were intermediate to those for quantiles 0.05 and 0.50. Conclusions: Risk factors for myopia were associated with much larger effects in children in the extremes of the refractive error distribution, providing indirect evidence that emmetropization buffers against both genetic and environmental risk factors.

Determining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma.

Purpose: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). Methods: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. Results: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. Conclusions: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

Interaction between lifestyle and genetic susceptibility in myopia: the Generation R study.

Myopia is a refractive error of the eye caused by a complex interplay between nature and nurture. The aim of this study was to investigate whether environmental risk factors can influence the genetic effect in children developing myopia. A total of 3422 children participating in the birth-cohort study Generation R underwent an extensive eye examination at 9 years with measurements of refractive error and axial length corneal radius ratio (AL/CR). Environmental risk factors were evaluated using a questionnaire, and environmental risk scores (ERS) were calculated using backward regression analyses. Genetic risk scores (GRS) were calculated based on all currently known risk variants for myopia. Gene-environment interaction (G×E) was investigated using linear and logistic regression analyses. The predictive value of G×E and parental myopia was estimated using receiver operating characteristic curves. Myopia prevalence was 12%. Both GRS (P < 0.01) and ERS (P < 0.01) were significantly associated with myopia and AL/CR, as was G×E interaction (P < 0.01 for myopia; P = 0.07 for AL/CR). The predictive value of parental myopia was 0.67 (95% CI 0.65-0.70), similar to the values of GRS (0.67; 95% CI 0.64-0.70; P = 0.98) and ERS (0.69; 95% CI 0.66-0.72; P = 0.98). Adding G×E interaction significantly improved the predictive value to 0.73 (95% CI 0.70-0.75; P < 0.01). This study provides evidence that nature and nurture are equally important for myopia and AL/CR; however, the combination has the strongest influence. Since myopia genes are common in the population, adjustment of lifestyle should be a major focus in the prevention of myopia.

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.

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

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.

In vivo matching of postsynaptic excitability with spontaneous synaptic inputs during formation of the rat calyx of Held synapse.

KEY POINTS: Neurons in the medial nucleus of the trapezoid body of anaesthetized rats of postnatal day (P)2-6 showed burst firing with a preferred interval of about 100 ms, which was stable, and a second preferred interval of 5-30 ms, which shortened during development. In 3 out of 132 cases, evidence for the presence of two large inputs was found. In vivo whole-cell recordings revealed that the excitability of the principal neuron and the size of its largest synaptic inputs were developmentally matched. At P2-4, action potentials were triggered by barrages of small synaptic events that summated to plateau potentials, while at later stages firing depended on a single, large and often prespike-associated input, which is probably the nascent calyx of Held. Simulations with a Hodgkin-Huxley-like model, which was based on fits of the intrinsic postsynaptic properties, suggested an essential role for the low-threshold potassium conductance in this transition. ABSTRACT: In the adult, principal neurons of the medial nucleus of the trapezoid body (MNTB) are typically contacted by a single, giant terminal called the calyx of Held, whereas during early development a principal neuron receives inputs from many axons. How these changes in innervation impact the postsynaptic activity has not yet been studied in vivo. We therefore recorded spontaneous inputs and intrinsic properties of principal neurons in anaesthetized rat pups during the developmental period in which the calyx forms. A characteristic bursting pattern could already be observed at postnatal day (P)2, before formation of the calyx. At this age, action potentials (APs) were triggered by barrages of summating EPSPs causing plateau depolarizations. In contrast, at P5, a single EPSP reliably triggered APs, resulting in a close match between pre- and postsynaptic firing. Postsynaptic excitability and the size of the largest synaptic events were developmentally matched. The developmental changes in intrinsic properties were estimated by fitting in vivo current injections to a Hodgkin-Huxley-type model of the principal neuron. Our simulations indicated that the developmental increases in Ih , low-threshold K+ channels and leak currents contributed to the reduction in postsynaptic excitability, but that low-threshold K+ channels specifically functioned as a dampening influence in the near-threshold range, thus precluding small inputs from triggering APs. Together, these coincident changes help to propagate bursting activity along the auditory brainstem, and are essential steps towards establishing the relay function of the calyx of Held synapse.

Association of Axial Length With Risk of Uncorrectable Visual Impairment for Europeans With Myopia.

IMPORTANCE: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with structural changes of the retina and the globe because of elongation of the eye axis. How axial length-a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth-and myopia relate to the development of visual impairment over time is unknown. OBJECTIVES: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016. MAIN OUTCOMES AND MEASURES: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia. RESULTS: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from -25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of -6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of -6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high-risk areas. CONCLUSIONS AND RELEVANCE: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population.