Whole exome sequence analysis in 51 624 participants identifies novel genes and variants associated with refractive error and myopia.

Refractive errors are associated with a range of pathological conditions, such as myopic maculopathy and glaucoma, and are highly heritable. Studies of missense and putative loss of function (pLOF) variants identified via whole exome sequencing (WES) offer the prospect of directly implicating potentially causative disease genes. We performed a genome-wide association study for refractive error in 51 624 unrelated adults, of European ancestry, aged 40-69 years from the UK and genotyped using WES. After testing 29 179 pLOF and 495 263 missense variants, 1 pLOF and 18 missense variants in 14 distinct genomic regions were taken forward for fine-mapping analysis. This yielded 19 putative causal variants of which 18 had a posterior inclusion probability >0.5. Of the 19 putative causal variants, 12 were novel discoveries. Specific variants were associated with a more myopic refractive error, while others were associated with a more hyperopic refractive error. Association with age of onset of spectacle wear (AOSW) was examined in an independent validation sample (38 100 early AOSW cases and 74 243 controls). Of 11 novel variants that could be tested, 8 (73%) showed evidence of association with AOSW status. This work identified COL4A4 and ATM as novel candidate genes associated with refractive error. In addition, novel putative causal variants were identified in the genes RASGEF1, ARMS2, BMP4, SIX6, GSDMA, GNGT2, ZNF652 and CRX. Despite these successes, the study also highlighted the limitations of community-based WES studies compared with high myopia case-control WES studies.

Whole exome sequencing of known eye genes reveals genetic causes for high myopia.

High myopia [refractive error ≤ -6 diopters (D)] is a heterogeneous condition, and without clear accompanying features, it can be difficult to pinpoint a genetic cause. This observational study aimed to evaluate the utility of whole exome sequencing (WES) using an eye disorder gene panel in European patients with high myopia. Patients with high myopia were recruited by ophthalmologists and clinical geneticists. Clinical features were categorized into isolated high myopia, high myopia with other ocular involvement or with systemic involvement. WES was performed and an eye disorder gene panel of ~500 genes was evaluated. Hundred and thirteen patients with high myopia [mean (SD) refractive error - 11.8D (5.2)] were included. Of these, 53% were children younger than 12 years of age (53%), 13.3% were aged 12-18 years and 34% were adults (aged > 18 years). Twenty-three out of 113 patients (20%) received a genetic diagnosis of which 11 patients displayed additional ocular or systemic involvement. Pathogenic variants were identified in retinal dystrophy genes (e.g. GUCY2D and CACNA1F), connective tissue disease genes (e.g. COL18A1 and COL2A1), non-syndromic high myopia genes (ARR3), ocular development genes (e.g. PAX6) and other genes (ASPH and CNNM4). In 20% of our high myopic study population, WES using an eye gene panel enabled us to diagnose the genetic cause for this disorder. Eye genes known to cause retinal dystrophy, developmental or syndromic disorders can cause high myopia without apparent clinical features of other pathology.

Early onset X-linked female limited high myopia in three multigenerational families caused by novel mutations in the ARR3 gene.

This study describes the clinical spectrum and genetic background of high myopia caused by mutations in the ARR3 gene. We performed an observational case series of three multigenerational families with high myopia (SER≤-6D), from the departments of Clinical Genetics and Ophthalmology of a tertiary Dutch hospital. Whole-exome sequencing (WES) with a vision-related gene panel was performed, followed by a full open exome sequencing. We identified three Caucasian families with high myopia caused by three different pathogenic variants in the ARR3 gene (c.214C>T, p.Arg72*; c.767+1G>A; p.?; c.848delG, p.(Gly283fs)). Myopia was characterized by a high severity (<-8D), an early onset (<6 years), progressive nature, and a moderate to bad atropine treatment response. Remarkably, a female limited inheritance pattern was present in all three families accordant with previous reports. The frequency of a pathogenic variant in the ARR3 gene in our diagnostic WES cohort was 5%. To conclude, we identified three families with early onset, therapy-resistant, high myopia with a female-limited inheritance pattern, caused by a mutation in the ARR3 gene. The singular mode of inheritance might be explained by metabolic interference due to X-inactivation. Identification of this type of high myopia will improve prompt myopia treatment, monitoring, and genetic counseling.

Design, implementation and initial findings of COVID-19 research in the Rotterdam Study: leveraging existing infrastructure for population-based investigations on an emerging disease.

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.

MYOPIC PRESENTATION OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To increase insight into the myopic presentation of central serous chorioretinopathy (CSC) by comparing a large group of myopic patients with CSC with reference groups with only one of the diagnoses. METHODS: Myopic patients with CSC (spherical equivalent ≤-3D, n = 46), emmetropic patients with CSC (spherical equivalent -0.5 to 0.5 D, n = 83), and myopic, non-CSC patients (n = 50) were included in this multicenter cross-sectional study. Disease characteristics and imaging parameters, such as subfoveal choroidal thickness and indocyanine green angiography patterns, were compared between cases and reference groups. RESULTS: In myopic patients with CSC, median subfoveal choroidal thickness (286 µm [IQR 226-372 µm]) was significantly thicker than subfoveal choroidal thickness in myopic, non-CSC patients (200 µm [IQR 152-228 µm], P < 0.001) but thinner than emmetropic patients with CSC (452 µm [IQR 342-538 µm], P < 0.001). They also had pachyvessels in 70% of the eyes comparable with emmetropic CSC (76%, P = 0.70). Choroidal hyperpermeability was frequently present on indocyanine green angiography in both myopic and emmetropic CSC eyes. Need for treatment, treatment success, and recurrence rate were not significantly different between CSC groups. CONCLUSION: Myopic CSC presents with similar imaging and clinical characteristics as emmetropic CSC, apart from their thinner choroids. Keeping in mind the structural changes of myopia, other imaging characteristics could aid the diagnostic process.

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.

The Role of GJD2(Cx36) in Refractive Error Development.

Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 (GJD2) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2(Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2(Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2(Cx36) in refractive error development.

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.

Association analyses of rare variants identify two genes associated with refractive error.

PURPOSE: Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. METHODS: Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses. RESULTS: We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error. CONCLUSION: The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.

Association of Rhegmatogenous Retinal Detachment Incidence With Myopia Prevalence in the Netherlands.

Importance: The incidence of rhegmatogenous retinal detachment (RRD) is partly determined by its risk factors, such as age, sex, cataract surgery, and myopia. Changes in the prevalence of these risk factors could change RRD incidence in the population. Objective: To determine whether the incidence of RRD in the Netherlands has changed over recent years and whether this change is associated with an altered prevalence of RRD risk factors. Design, Setting, and Participants: This cohort study included data from all 14 vitreoretinal clinics in the Netherlands, as well as a large Dutch population-based cohort study. All patients who underwent surgical repair for a primary RRD in the Netherlands from January 1 to December 31, 2009, and January 1 to December 31, 2016, were analyzed, in addition to all participants in the population-based Rotterdam Study who were examined during these years. Analysis began February 2018 and ended November 2019. Exposures: RRD risk factors, including age, male sex, cataract extraction, and myopia. Main Outcomes and Measures: Age-specific RRD incidence rate in the Dutch population, as well as change in RRD incidence and risk factor prevalence between 2009 and 2016. Results: In 2016, 4447 persons (median [range] age, 61 [3-96] years) underwent surgery for a primary RRD within the Netherlands, resulting in an RRD incidence rate of 26.2 per 100 000 person-years (95% CI, 25.4-27.0). The overall RRD incidence rate had increased by 44% compared with similar data from 2009. The increase was observed in both phakic (1994 in 2009 to 2778 in 2016 [increase, 39%]) and pseudophakic eyes (1004 in 2009 to 1666 in 2016 [increase, 66%]), suggesting that cataract extraction could not solely account for the overall rise. Over the same period, the prevalence of mild, moderate, and severe myopia among persons aged 55 to 75 years had increased by 15.6% (881 of 4561 [19.3%] vs 826 of 3698 [22.3%]), 20.3% (440 of 4561 [9.6%] vs 429 of 3698 [11.6%]), and 26.9% (104 of 4561 [2.3%] vs 107 of 3698 [2.9%]), respectively, within the population-based Rotterdam Study. Conclusions and Relevance: In this study, an increase was observed in primary RRD incidence in the Netherlands over a 7-year period, which could not be explained by a different age distribution or cataract surgical rate. A simultaneous myopic shift in the Dutch population may be associated, warranting further population-based studies on RRD incidence and myopia prevalence.

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.

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.

Performance of Classification Systems for Age-Related Macular Degeneration in the Rotterdam Study.

Purpose: To compare frequently used classification systems for age-related macular degeneration (AMD) in their abilty to predict late AMD. Methods: In total, 9066 participants from the population-based Rotterdam Study were followed up for progression of AMD during a study period up to 30 years. AMD lesions were graded on color fundus photographs after confirmation on other image modalities and grouped at baseline according to six classification systems. Late AMD was defined as geographic atrophy or choroidal neovascularization. Incidence rate (IR) and cumulative incidence (CuI) of late AMD were calculated, and Kaplan-Meier plots and area under the operating characteristics curves (AUCs) were constructed. Results: A total of 186 persons developed incident late AMD during a mean follow-up time of 8.7 years. The AREDS simplified scale showed the highest IR for late AMD at 104 cases/1000 py for ages <75 years. The Rotterdam classification showed the highest IR at 89 cases/1000 py >75 years. The 3-Continent harmonization classification provided the most stable progression. Drusen area >10% ETDRS grid (hazard ratio 30.05, 95% confidence interval [CI] 19.25-46.91) was most prognostic of progression. The highest AUC of late AMD (0.8372, 95% CI: 0.8070-0.8673) was achieved when all AMD features present at baseline were included. Conclusions: Highest turnover rates from intermediate to late AMD were provided by the AREDS simplified scale and the Rotterdam classification. The 3-Continent harmonization classification showed the most stable progression. All features, especially drusen area, contribute to late AMD prediction. Translational Relevance: Findings will help stakeholders select appropriate classification systems for screening, deep learning algorithms, or trials.

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.

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.

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.

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.

Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.