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PurposeData on myopia progression during its entire course are scarce. The aim of this study is to investigate myopia progression in Europeans as a function of age and degree of myopia from first prescription to final refractive error.MethodsThe Drentse Refractive Error and Myopia Study assessed data from a branch of opticians in the Netherlands from 1985 onwards in a retrospective study. First pair of glasses prescribed was defined as a spherical equivalent of refraction (SER) ≤−0.5 D to ≥−3.0 D. Subjects with prescriptions at an interval of at least 1 year were included in the analysis.ResultsA total of 2555 persons (57.3% female) met the inclusion criteria. Those with first prescription before the age of 10 years showed the strongest progression (−0.50 D; IQR: −0.75 to −0.19) and a significantly (pConclusionOur trajectories of the natural course of myopia progression may serve as a guide for myopia management in European children. SER at 10 years is an important prognostic indicator and will help determine treatment intensity.

Contains fulltext : 243957.pdf (Publisher’s version ) (Open Access) PURPOSE: Primary open-angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. METHODS: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). RESULTS: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p

Contains fulltext : 238066.pdf (Publisher’s version ) (Open Access) PURPOSE: To compare treatment outcomes of treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) with bevacizumab as the first-line treatment, according to the guidelines of the Dutch Ophthalmological Society, with those treated first with either ranibizumab or aflibercept, as used in many other countries, all treated using a treat-and-extend strategy. METHODS: Data were obtained from the prospectively designed Fight Retinal Blindness! outcomes registry. The primary outcome was the mean change from baseline in visual acuity of all treated eyes, after 12, 24 and 36 months of treatment. Secondary outcomes were the number of injections, the number of visits and the rate of switching to a second anti-VEGF drug. RESULTS: The study included 703 treatment-naïve eyes with nAMD with 12 months follow-up, 373 eyes with 24 months follow-up, and 171 eyes with 36 months follow-up in the Netherlands, and 1131, 652, and 303 treatment-naïve eyes with respectively 12, 24, and 36 months of follow-up in all other countries. The change in visual acuity from baseline did not differ between the Netherlands and the other countries at any follow-up time. The median number of injections, visits and the proportion of eyes switching treatment was significantly higher in the Netherlands than in the other countries. CONCLUSION: Starting anti-VEGF treatment for nAMD with bevacizumab, as is mandatory in the Netherlands, delivers outcomes similar to those starting treatment with either ranibizumab or aflibercept, but at a cost of more frequent injections, and visits, and more frequent switching treatment to a second drug.

Aims The contribution of sex hormones to micro- and macrovascular damage might differ among women and men. In particular, little is known about the association between sex hormones and small vessel disease. Therefore, we examined the association of total oestradiol, total testosterone, free-androgen index (FAI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione levels with micro- and macrovascular diseases. Methods and results This cross-sectional study included 2950 women and 2495 men from the population-based Rotterdam Study. As proxy of microvascular damage, we measured diameters of retinal arterioles and venules. Markers of macrovascular damage included carotid intima-media thickness and carotid plaque, coronary artery calcification (CAC), and peripheral artery disease. Linear and logistic regression models were used and adjusted for age, cardiovascular risk factors, and years since menopause. Associations with microvasculature: In women, total testosterone [mean difference per 1-unit increase in natural-log transformed total testosterone (95% confidence interval, CI): 2.59 (0.08–5.09)] and androstenedione [4.88 (1.82–7.95)] and in men DHEAS [2.80 (0.23–5.37)] and androstenedione [5.83 (2.19–9.46)] were associated with larger venular caliber. Associations with markers of large vessel disease: In women, higher total testosterone [−0.29 (−0.56 to −0.03)], FAI [−0.33 (−0.56 to −0.10)], and androstenedione levels [−0.33 (−0.64 to −0.02)] were associated with lower CAC burden and FAI [odds ratio (95% CI): 0.82 (0.71–0.94)] was associated with lower prevalence of plaque. Conclusion A more androgenic profile was associated with more microvascular damage in both women and men. Among women, however, higher androgen levels were also associated with less macrovascular damage. Our findings suggest that androgens might have distinct effects on the vasculature, depending on the vascular bed and stages of the atherosclerosis process.

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

Item does not contain fulltext 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.

To identify risk factors for axial length (AL) elongation and incident school myopia.Population-based prospective birth-cohort study.Four thousand seven hundred thirty-four children examined at 6 and 9 years of age from the Generation R Study in Rotterdam, The Netherlands.Axial length and corneal radius (CR) were measured with an IOLMaster 500 and daily life activities and demographic characteristics were obtained by questionnaire. Three thousand three hundred sixty-two children (71%) were eligible for cycloplegic refractive error measurements. Linear regression models on AL elongation were used to create a risk score based on the regression coefficients resulting from environmental and ocular factors. The predictive value of the prediction score for myopia (≤-0.5 diopter) was estimated using receiver operating characteristic curves. To test if regression coefficients differed for baseline AL-to-CR ratio, interaction terms were calculated with baseline AL-to-CR ratio and environmental factors.Axial length elongation and incident myopia.From 6 to 9 years of age, average AL elongation was 0.21±0.009 mm/year and myopia developed in 223 of 2136 children (10.4%), leading to a myopia prevalence at 9 years of age of 12.0%. Seven parameters were associated independently (P0.05) with faster AL elongation: parental myopia, 1 or more books read per week, time spent reading, no participation in sports, non-European ethnicity, less time spent outdoors, and baseline AL-to-CR ratio. The discriminative accuracy for incident myopia based on these risk factors was 0.78. Axial length-to-CR ratio at baseline showed statistically significant interaction with number of books read per week (P0.01) and parental myopia (P0.01). Almost all predictors showed the highest association with AL elongation in the highest quartile of AL-to-CR ratio; incidental myopia in this group was 24% (124/513).Determination of a risk score can help to identify school children at high risk of myopia. Our results suggest that behavioral changes can offer protection particularly in these children.

Contains fulltext : 205478.pdf (Publisher’s version ) (Open Access) PURPOSE: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. METHODS: 5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. RESULTS: Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9-9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (beta 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. CONCLUSIONS: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height.

PURPOSE: To assess the age-specific proportion of visual impairment in patients with pseudoxanthoma elasticum (PXE) and to compare this with foveal abnormality and similar data of late age-related macular degeneration patients. METHODS: Cross-sectional data of 195 patients with PXE were reviewed, including best-corrected visual acuity and imaging. The World Health Organisation criteria were used to categorize bilateral visual impairment. These results were compared with similar data of 131 patients with late age-related macular degeneration from the Rotterdam study. RESULTS: Overall, 50 PXE patients (26.0%) were visually impaired, including 21 (11%) with legal blindness. Visual functioning declined with increasing age. In patients older than 50 years, 37% was visually impaired and 15% legally blind. Foveal choroidal neovascularization was found in 84% of eyes with a best-corrected visual acuity lower than 20/70 (0.30) and macular atrophy in the fovea in 16%. In late age-related macular degeneration patients, 40% were visually impaired and 13% legally blind. Visual impairment started approximately 20 years later as compared with PXE patients. CONCLUSION: Visual impairment and blindness are frequent in PXE, particularly in patients older than 50 years. Although choroidal neovascularization is associated with the majority of vision loss, macular atrophy is also common. The proportion of visual impairment in PXE is comparable with late age-related macular degeneration but manifests earlier in life.

textabstractPURPOSE. To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations. METHODS. Multiethnic cohort study (N ¼ 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N ¼ 27; cone-rod dystrophy [CRD], N ¼ 1; and macular dystrophy, N ¼ 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299þ5_1299þ8del variant in macular dystrophy patients. RESULTS. We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was 0.84 6 0.44 ln(deg2 ) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs ¼ 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was 57 6 17 lm per year (P < 0.01) (n ¼ 14) or 3.69% 6 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299þ5_1299þ8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant. CONCLUSIONS. We report on EYS-associated macular dystrophy, extending the spectrum of EYSassociated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Objective Reticular pseudodrusen (RPD), a key feature of age-related macular degeneration (AMD), are poorly detected by human experts on standard color fundus photography (CFP) and typically require advanced imaging modalities such as fundus autofluorescence (FAF). The objective was to develop and evaluate the performance of a novel multimodal, multitask, multiattention (M3) deep learning framework on RPD detection. Materials and Methods A deep learning framework (M3) was developed to detect RPD presence accurately using CFP alone, FAF alone, or both, employing >8000 CFP-FAF image pairs obtained prospectively (Age-Related Eye Disease Study 2). The M3 framework includes multimodal (detection from single or multiple image modalities), multitask (training different tasks simultaneously to improve generalizability), and multiattention (improving ensembled feature representation) operation. Performance on RPD detection was compared with state-of-the-art deep learning models and 13 ophthalmologists; performance on detection of 2 other AMD features (geographic atrophy and pigmentary abnormalities) was also evaluated. Results For RPD detection, M3 achieved an area under the receiver-operating characteristic curve (AUROC) of 0.832, 0.931, and 0.933 for CFP alone, FAF alone, and both, respectively. M3 performance on CFP was very substantially superior to human retinal specialists (median F1 score = 0.644 vs 0.350). External validation (the Rotterdam Study) demonstrated high accuracy on CFP alone (AUROC, 0.965). The M3 framework also accurately detected geographic atrophy and pigmentary abnormalities (AUROC, 0.909 and 0.912, respectively), demonstrating its generalizability. Conclusions This study demonstrates the successful development, robust evaluation, and external validation of a novel deep learning framework that enables accessible, accurate, and automated AMD diagnosis and prognosis.

To investigate the association between smartphone use and refractive error in teenagers using the Myopia app.Cross-sectional population-based study.A total of 525 teenagers 12 to 16 years of age from 6 secondary schools and from the birth cohort study Generation R participated.A smartphone application (Myopia app; Innovattic) was designed to measure smartphone use and face-to-screen distance objectively and to pose questions about outdoor exposure. Participants underwent cycloplegic refractive error and ocular biometry measurements. Mean daily smartphone use was calculated in hours per day and continuous use as the number of episodes of 20 minutes on screen without breaks. Linear mixed models were conducted with smartphone use, continuous use, and face-to-screen distance as determinants and spherical equivalent of refraction (SER) and axial length-to-corneal radius (AL:CR) ratio as outcome measures stratified by median outdoor exposure.Spherical equivalent of refraction in diopters and AL:CR ratio.The teenagers on average were 13.7 ± 0.85 years of age, and myopia prevalence was 18.9%. During school days, total smartphone use on average was 3.71 ± 1.70 hours/day and was associated only borderline significantly with AL:CR ratio (β = 0.008; 95% confidence interval [CI], -0.001 to 0.017) and not with SER. Continuous use on average was 6.42 ± 4.36 episodes of 20-minute use without breaks per day and was associated significantly with SER and AL:CR ratio (β = -0.07 [95% CI, -0.13 to -0.01] and β = 0.004 [95% CI, 0.001-0.008], respectively). When stratifying for outdoor exposure, continuous use remained significant only for teenagers with low exposure (β = -0.10 [95% CI, -0.20 to -0.01] and β = 0.007 [95% CI, 0.001-0.013] for SER and AL:CR ratio, respectively). Smartphone use during weekends was not associated significantly with SER and AL:CR ratio, nor was face-to-screen distance.Dutch teenagers spent almost 4 hours per day on their smartphones. Episodes of 20 minutes of continuous use were associated with more myopic refractive errors, particularly in those with low outdoor exposure. This study suggested that frequent breaks should become a recommendation for smartphone use in teenagers. Future large longitudinal studies will allow more detailed information on safe screen use in youth.

Importance: Treatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking. Objective: To determine long-term enlargement of GA. Design, Setting, and Participants: In this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020. Main Outcomes and Measures: Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. Results: Of 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm2(95% CI, 3.11-4.67). Enlargement rate varied widely between persons (0.02 to 4.05 mm2per year), with a mean of 1.09 mm2per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P =.01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. Conclusions and Relevance: In this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy..

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Author summary The thickness of the inner retinal layers is one of the biomarkers for glaucoma, the leading cause of irreversible blindness globally. Here we utilised the large-scale of the UK Biobank and the images of the retina it contains to look for genetic variants that effect the thickness of the inner retina. We find many variants associated with this variable, but surprisingly only one that also affects glaucoma. Further analysis shows that glaucoma and genetically determined inner retinal thickness are not on the same genetic pathway and it is rather the change of thickness over time that is indicative of the disease. This is important as it invites the potential for the discovered variants to be used as a representation of baseline thickness in the clinic in the future. We also show that foveal hypoplasia, the lack of the normal valley-like shape of the central retina, is present at a population level in a mild form and is affected by three variants that also affect visual acuity. This is an interesting discovery as foveal hypoplasia was previously thought of as an outcome of rare Mendelian disease.

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. This cohort study assesses whether the incidence of rhegmatogenous retinal detachment has changed over recent years and whether this change is associated with an altered prevalence of rhegmatogenous retinal detachment risk factors in the Netherlands. Question What is the incidence of primary rhegmatogenous retinal detachment (RRD) in the Netherlands and has it changed over recent years? Findings In this cohort study, 4447 individuals in the Netherlands underwent surgery for RRD in 2016, resulting in an incidence of 26.2 per 100 000 inhabitants, an increase of 44% compared with similar data from 2009. Over the same period, an increase in myopia prevalence in a Dutch population-based cohort study was observed. Meaning In the Netherlands, an increase in RRD incidence may be associated with a simultaneous myopic shift in the population.

PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field

Contains fulltext : 235455.pdf (Publisher’s version ) (Open Access) PURPOSE: To determine the long-term longitudinal axial length changes in myopic and hyperopic adults with an iris-fixated phakic intraocular lens (pIOL). METHODS: The medical records of patients aged ≥18 years with myopia or hyperopia who were treated with pIOL implantation between 1996 and 2011 for refractive correction with a minimum follow-up of 5 years after pIOL implantation were analyzed. The main outcome measure was change in ocular axial length over time. RESULTS: 149 eyes of 149 myopic patients and 27 hyperopic eyes of 27 patients were included in this study. Mean patient age was 37.1 ± 10.4 years (35% male) in the myopic group and 39.4 ± 9.4 years (4% male) in the hyperopic group. The eyes of the myopic patients showed a significant mean increase in axial length of 0.45 ± 0.61 mm after a mean follow-up time of 144 ± 38 months (p

Refractive errors, in particular myopia, are a leading cause of morbidity and disability world-wide. Genetic investigation can improve understanding of the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 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 (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating 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 make possible predicting refractive error and the development of personalized myopia prevention strategies in the future., Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes.Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium.Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study.Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional β values; a lifestyle score was constructed based on smoking and diet.Intermediate and late AMD.The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from -3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold.Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.

To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD.Case-control study.Individuals (n = 4740) from 5 European cohorts.We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis.Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations.We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (96%) and for the rare variants (99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P0.001) and individuals without AMD (P0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy.This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

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.

Contains fulltext : 220949.pdf (Publisher’s version ) (Open Access) The Rotterdam Study is an ongoing prospective cohort study that started in 1990 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. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

Contains fulltext : 225467.pdf (Publisher’s version ) (Closed access) PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Purpose: To develop and validate a deep learning model for automatic segmentation of geographic atrophy (GA) in color fundus images (CFIs) and its application to study growth rate of GA. Participants: 409 CFIs of 238 eyes with GA from the Rotterdam Study (RS) and the Blue Mountain Eye Study (BMES) for model development, and 5,379 CFIs of 625 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. Methods: A deep learning model based on an ensemble of encoder-decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated GA in CFIs from RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was further applied to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. Results: The model obtained an average Dice coefficient of 0.72 $\pm$ 0.26 on the BMES and RS. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders' consensus measures. Eight automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement and perimeter) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of around 12 mm$^{2}$, after which growth rate stabilizes or decreases. Conclusion: The presented deep learning model allowed for fully automatic and robust segmentation of GA in CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate., Comment: 22 pages, 3 tables, 4 figures, 1 supplemental figure

Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype.Retrospective analysis of cross-sectional data.Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database.Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to the complement, lipid metabolism, or extracellular matrix (ECM) pathways and ARMS2 also were included, and genetic risk scores (GRSs) for each of those 3 pathways were calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype, or both for each subgroup was determined with 10-fold cross-validated areas under the receiver operating characteristic curve (cvAUCs), and the agreement between predicted and actual subgroup membership was assessed with calibration plots.Identification and characterization of GA subgroups based on their phenotype and genotype.Cluster analyses identified 3 subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy, and few drusen (any type); and subgroup 3 showed a high ARMS2 and ECM GRS, RPD, and extrafoveal atrophy. A high discriminative ability existed between subgroups for the genotype (cvAUC, ≥0.94), and a modest discriminative ability existed for the phenotype (cvAUC,0.65), with good calibration.We identified 3 GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.

Contains fulltext : 200463.pdf (Publisher’s version ) (Open Access) A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction.

Contains fulltext : 193421.pdf (Publisher’s version ) (Open Access) PURPOSE: To generate percentile curves of axial length (AL) for European children, which can be used to estimate the risk of myopia in adulthood. METHODS: A total of 12 386 participants from the population-based studies Generation R (Dutch children measured at both 6 and 9 years of age; N = 6934), the Avon Longitudinal Study of Parents and Children (ALSPAC) (British children 15 years of age; N = 2495) and the Rotterdam Study III (RS-III) (Dutch adults 57 years of age; N = 2957) contributed to this study. Axial length (AL) and corneal curvature data were available for all participants; objective cycloplegic refractive error was available only for the Dutch participants. We calculated a percentile score for each Dutch child at 6 and 9 years of age. RESULTS: Mean (SD) AL was 22.36 (0.75) mm at 6 years, 23.10 (0.84) mm at 9 years, 23.41 (0.86) mm at 15 years and 23.67 (1.26) at adulthood. Axial length (AL) differences after the age of 15 occurred only in the upper 50%, with the highest difference within the 95th percentile and above. A total of 354 children showed accelerated axial growth and increased by more than 10 percentiles from age 6 to 9 years; 162 of these children (45.8%) were myopic at 9 years of age, compared to 4.8% (85/1781) for the children whose AL did not increase by more than 10 percentiles. CONCLUSION: This study provides normative values for AL that can be used to monitor eye growth in European children. These results can help clinicians detect excessive eye growth at an early age, thereby facilitating decision-making with respect to interventions for preventing and/or controlling myopia.

Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

Key Points Question What are the genotypic and phenotypic characteristics of patients with early-onset drusen maculopathy? Findings In this case-control study, patients with early-onset drusen maculopathy were frequently carriers of rare genetic variants in the complement factor H gene and were characterized by the presence of a large macular drusen area and lower genetic risk scores compared with patients with age-related macular degeneration. Meaning Sequencing of the complement factor H gene is important in considering future treatments targeting the complement system in patients with early-onset drusen maculopathy. Furthermore, the presence of a large macular drusen area supports the severe phenotype in these patients, who may be at high risk of developing geographic atrophy or choroidal neovascularization., This case-control study evaluates genotypic and phenotypic characteristics of patients with early-onset drusen maculopathy., Importance Early-onset drusen maculopathy (EODM) is a severe disease and can lead to advanced macular degeneration early in life; however, genetic and phenotypic characteristics of individuals with EODM are not well studied. Objective To identify genotypic and phenotypic characteristics of individuals with EODM. Design, Setting, and Participants This case-control study collected data from the European Genetic Database from September 2004 to October 2019. A total of 89 patients with EODM diagnosed at 55 years or younger and 91 patients with age-related macular degeneration (AMD) diagnosed at 65 years or older were included. Exposures Coding regions of CFH, CFI, C3, C9, CFB, ABCA4, PRPH2, TIMP3, and CTNNA1 genes were sequenced, genetic risk scores (GRS) were calculated based on 52 AMD-associated variants, and phenotypic characteristics on color fundus photographs were analyzed comparing patients with EODM and AMD. Main Outcomes and Measures GRS, frequency of rare genetic complement variants, and phenotypic characteristics. Results This case-control study included 89 patients with EODM (mean [SD] age, 51.8 [8.7] years; 58 [65.2%] were female) and 91 patients with AMD (mean [SD] age, 77.6 [6.1] years; 45 [49.5%] female). At a mean (SD) age of 56.4 (7.3) years, 40 of 89 patients with EODM (44.9%) were affected by geographic atrophy or choroidal neovascularization. A lower GRS was observed in patients with EODM compared with patients with AMD (1.03 vs 1.60; P = .002), and 27 of 89 patients with EODM (30.3%) carried rare variants in the CFH gene compared with 7 of 91 patients with AMD (7.7%). Carriership of a rare CFH variant was associated with EODM (odds ratio, 7.2; 95% CI, 2.7-19.6; P

PURPOSE: It is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein. DESIGN: Case-control study. METHODS: STUDY POPULATION: Total of 302 patients with IRD. from 2 ophthalmogenetic centers in the Netherlands. REFERENCE POPULATION: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (N = 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression. RESULTS: Bipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P

Contains fulltext : 182318.pdf (Publisher’s version ) (Open Access) To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.

Item does not contain fulltext Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Item does not contain fulltext BACKGROUND: Parkinsonism is a common neurodegenerative syndrome in middle-aged and elderly persons. The etiology is multifactorial with a possible vascular contribution, but this has not been comprehensively studied. OBJECTIVE: To determine whether selected markers of subclinical vascular pathology are associated with the risk of all-cause parkinsonism in the general population. METHODS: We assessed a range of markers of subclinical vascular pathology (ankle-brachial index, carotid plaques and intima media thickness, retinal arteriolar and venular calibers) in 6199 persons from the population-based Rotterdam Study, who were free of parkinsonism and dementia at baseline. We followed these persons up till onset of parkinsonism, dementia, and death for 89,387 person-years until January 1, 2013. Hazard ratios (HRs) for all-cause parkinsonism and separately for Parkinson disease (PD) versus non-PD were estimated from competing risk regression models adjusting for potential confounders. RESULTS: During follow-up, we identified 211 cases of parkinsonism (110 had PD). None of the five markers of subclinical pathology was associated with all-cause parkinsonism. Only low ankle-brachial index was associated with a higher risk of non-PD parkinsonism (HR = 0.79, 95%CI: 0.68-0.92), but not with the risk of PD. CONCLUSION: We did not find a consistent pattern of associations between systemic vascular pathology markers with parkinsonism, suggesting that the potential involvement of vascular pathology is not prominent or needs further evaluation in studies with an even larger sample size.

Contains fulltext : 182194.pdf (Publisher’s version ) (Open Access) The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Item does not contain fulltext Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 x 10(-27)) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 x 10(-5)); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.

Item does not contain fulltext PURPOSE: To describe the phenotype and clinical course of patients with RPGR-associated retinal dystrophies, and to identify genotype-phenotype correlations. METHODS: A multicenter medical records review of 74 male patients with RPGR-associated retinal dystrophies. RESULTS: Patients had retinitis pigmentosa (RP; n = 52; 70%), cone dystrophy (COD; n = 5; 7%), or cone-rod dystrophy (CORD; n = 17; 23%). The median follow-up time was 11.6 years (range 0-57.1). The median age at symptom onset was 5.0 years (range 0-14 years) for patients with RP and 23.0 years (range 0-60 years) for patients with COD/CORD. The probability of being blind (best-corrected visual acuity

Purpose: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. Design: Prospective population-based cohort study. Methods: Four thousand two hundred and two participants from the Rotterdam Study ≥55 years of age who were free of AMD at baseline were included and followed up for 9.1 ± 5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox proportional hazards models that were adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. Results: Seven hundred fifty-four people developed incident AMD. Intake of the recommended amounts of vegetables (≥200 g/day), fruit (2×/day), and fish (2×/week) were 30.6%, 54.9%, and 12.5%, respectively. In particular, the intake of fish (2×/week) decreased the risk of incident AMD (hazard ratio 0.76 [95% confidence interval 0.60-0.97]). Intake of the recommended amounts of all 3 food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (hazard ratio 0.58 [95% confidence interval 0.36-0.93]). Younger age, higher income, and not smoking were associated with this food pattern, but the risk-lowering effects remained significant after additional adjustment for these factors. Conclusion: A diet of 200 grams per day of vegetables, fruit two times per day, and fish two times per week is associated with a significantly reduced risk of AMD.

Contains fulltext : 203178.pdf (Publisher’s version ) (Open Access) Purpose: To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. Methods: In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. Results: Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14-56) in the patients with arMD/arCRD, 26.2 years (range 18-40) in adRP, and 8.8 years (range 5-12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRP and arRP patients were frameshift and/or nonsense variants located far from the C-terminus. Conclusions: Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.

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 3 x 10(-3)) and a significant association between PRS for myopia and disc area (P = 1.59 3 x 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 x 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.

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. This multidisciplinary study focuses on several health outcomes including behaviour and cognition, body composition, eye development, growth, hearing, heart and vascular development, infectious disease and immunity, oral health and facial growth, respiratory health, allergy and skin disorders of children and their parents. Main exposures of interest include environmental, endocrine, genomic (genetic, epigenetic, microbiome), lifestyle related, nutritional and socio-demographic determinants. In total, 9778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Response at baseline was 61%, and general follow-up rates until the age of 10 years were around 80%. Data collection in children and their parents includes questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, lung function, Magnetic Resonance Imaging and biological sampling. Genome and epigenome wide association screens are available. Eventually, results from the Generation R Study contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

To investigate associations of adherence to the Mediterranean diet (MeDi) with incidence of advanced age-related macular degeneration (AMD; the symptomatic form of AMD) in 2 European population-based prospective cohorts.Prospective cohort study of the Rotterdam Study I (RS-I) and the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (Alienor) Study populations.Four thousand four hundred forty-six participants 55 years of age or older from the RS-I (The Netherlands) and 550 French adults 73 years of age or older from the Alienor Study with complete ophthalmologic and dietary data were included in the present study.Examinations were performed approximately every 5 years over a 21-year period (1990-2011) in RS-I and every 2 years over a 4-year period (2006-2012) in the Alienor Study. Adherence to the MeDi was evaluated using a 9-component score based on intake of vegetables, fruits, legumes, cereals, fish, meat, dairy products, alcohol, and the monounsaturated-to-saturated fatty acids ratio. Associations of incidence of AMD with MeDi were estimated using multivariate Cox proportional hazard models.Incidence of advanced AMD based on retinal fundus photographs.Among the 4996 included participants, 155 demonstrated advanced incident AMD (117 from the RS-I and 38 from the Alienor Study). The mean follow-up time was 9.9 years (range, 0.6-21.7 years) in the RS-I and 4.1 years (range, 2.5-5.0 years) in the Alienor Study. Pooling data for both the RS-I and Alienor Study, participants with a high (range, 6-9) MeDi score showed a significantly reduced risk for incident advanced AMD compared with participants with a low (range, 0-3) MeDi score in the fully adjusted Cox model (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P = 0.04 for trend).Pooling data from the RS-I and Alienor Study, higher adherence to the MeDi was associated with a 41% reduced risk of incident advanced AMD. These findings support the role of a diet rich in healthful nutrient-rich foods such as fruits, vegetables, legumes, and fish in the prevention of AMD.

Item does not contain fulltext Increasing evidence shows that thinner retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), assessed on optical coherence tomography (OCT), are reflecting global brain atrophy. Yet, little is known on the relation of these layers with specific brain regions. Using voxel-based analysis, we aimed to unravel specific brain regions associated with these retinal layers. We included 2,235 persons (mean age: 67.3 years, 55% women) from the Rotterdam Study (2007-2012) who had gradable retinal OCT images and brain magnetic resonance imaging (MRI) scans, including diffusion tensor (DT) imaging. Thicknesses of peripapillary RNFL and perimacular GCL were measured using an automated segmentation algorithm. Voxel-based morphometry protocols were applied to process DT-MRI data. We investigated the association between retinal layer thickness with voxel-wise gray matter density and white matter microstructure by performing linear regression models. We found that thinner RNFL and GCL were associated with lower gray matter density in the visual cortex, and with lower fractional anisotropy and higher mean diffusivity in white matter tracts that are part of the optic radiation. Furthermore, thinner GCL was associated with lower gray matter density of the thalamus. Thinner RNFL and GCL are associated with gray and white matter changes in the visual pathway suggesting that retinal thinning on OCT may be specifically associated with changes in the visual pathway rather than with changes in the global brain. These findings may serve as a basis for understanding visual symptoms in elderly patients, patients with Alzheimer's disease, or patients with posterior cortical atrophy.

Purpose To investigate risk factors for the development and progression of diabetic retinopathy (DR) and long‐term visual outcomes in Dutch patients with type 1 diabetes mellitus (T1DM). Methods Cumulative incidences were calculated for DR, vision‐threatening DR (VTDR), defined as (pre)proliferative DR and diabetic macular oedema, and best‐corrected visual acuity (BCVA)

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 ? 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 ? 10(-5)). ? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Objective: To study the frequency and causes of visual impairment in relation to refractive error. Design: Population-based cohort study. Participants: A total of 6597 participants from Rotterdam Study I (baseline and 4 follow-up examinations) and 2579 participants from Rotterdam Study II (baseline and 2 follow-up examinations), all 55 years or older, were included. Methods: Participants underwent an extensive ophthalmic examination, including best-corrected visual acuity and objective refraction, fundus photography, visual field perimetry, and optical coherence tomography imaging of macula and optic disc. We calculated cumulative risks and odds ratios of visual impairment for various refractive error categories and determined causes by using all screening information as well as medical records. Main Outcome Measures: Unilateral and bilateral low vision (World Health Organization [WHO] criteria, VA = 0.05; United States (US) criteria, VA = 0.1) and blindness (WHO criteria, VA

Item does not contain fulltext Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the "missing" variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.

The choroid provides oxygen and nourishment to the outer retinal layers and is crucial for metabolic activity in the retina.1 Choroidal changes are associated with many eye diseases, such as age-related macular degeneration (AMD),2 age-related choroidal atrophy,3 central serous retinopathy,4 and choroiditis. It has been also reported that choroidal thickness increases during childhood and decreases during adulthood.5,6 Accurately and automatically measuring choroidal thickness is therefore of great interest. Spectral-domain optical coherence tomography (SD-OCT) provides a cross-sectional, three-dimensional (3D), microscale depiction of ocular tissues7 and clearly distinguishable retinal layers, as shown in Figure 1. However, without the use of enhanced depth imaging or image enhancement techniques, visualization of the choroid, including choroid–sclera junction, remains challenging (see Fig. 1). Due to the high backscatter by the retinal pigment epithelium layer (RPE), the intensity contrast in the choroid region can be insufficient for applying straightforward image analysis algorithms. Figure 1 In the standard clinically available SD-OCT scans, retinal layer structures are clear (red arrows), but the posterior choroidal boundary is difficult to distinguish (yellow arrow). At right, the surfaces from top to bottom are internal limiting membrane, ... Swept-source OCT (SS-OCT) allows increased scanning speed.8 In many SS-OCT prototype systems, a longer central wavelength (1060 vs. 840 nm in SD-OCT) is adopted to allow deeper penetration through the RPE. Consequently, the choroid–sclera boundary has higher contrast in SS-OCT (see Fig. 2). We and others have previously developed fully automated 3D algorithms for segmenting choroid on standard clinically available SD-OCT scans.9–14 In our approach, choroidal thickness was estimated by defining the Euclidian distance between the enveloping surfaces of a choroidal vasculature segmentation (see Fig. 3). Figure 2 Segmentation results from the previous method on clinically available SD-OCT image (Zeiss Cirrus; EDI mode was not used): (a) Original B-scan; (b) 3D choroidal vasculature segmentation; (c) the outer boundary of choroidal vasculature is estimated using ... Figure 3 Swept-source OCT and spectral-domain OCT show difference of intensity contrast around choroidal–scleral interface. An example of the difference of intensity contrast at the same location from the same eye in (a) SS-OCT image data and in (b) SD-OCT ... The purpose of this study was to develop and evaluate the validity of a fully automated 3D method capable of segmenting the choroid over the entire scan and quantifying choroidal thicknesses of the macula in both SS-OCT and SD-OCT image data of the same subjects, without a preceding vasculature segmentation step, so that choroidal thickness can be measured for each A-scan.

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets., Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

Item does not contain fulltext PURPOSE: To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. DESIGN: Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. METHODS: Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. RESULTS: In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. CONCLUSION: One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.