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Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

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.

Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access) Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

212 Background: The 2006 ASCO and the ESMO consensus statement on quality cancer care defined the delivery of multimodality treatment by a multidisciplinary team of appropriately skilled health professionals as an essential component of quality cancer care. Furthermore, MDCs have demonstrated improved survival in breast, head and neck, ovarian and colorectal cancers. Despite these advantages, health care systems struggle to implement and sustain MDCs due to the heavy burden imposed by the required work processes. We report on the large-scale utilization of a propriety quality measurement platform OncoLens to run MDCs across the country. Methods: Technology quality metrics were collected from the ongoing daily usage of the platform including cancer characteristics, care team utilization metrics, average attendance, quality metrics collected for accreditation and clinical trials matching on the OncoLens platform. Results: The virtual platform was accessible to around 8000 providers across the United States. In 2020, 13771 cases were discussed. Attendance of the required specialties for high quality care of Medical Oncology, Radiation Oncology, Surgery, Pathology and Radiology was attained, with the average conference attendance being 14. Race/ethnicity data on the cases revealed White (9197, 67%), Black (1817,13%), Hispanic (363,3%) and Other (2356,17%). Optional quality metrics were collected during discussions for CoC, NAPBC and NAPRC accreditation. These included NCCN guidelines discussed, Staging discussed, clinical trials discussed, Genetics discussion, palliative care discussion, rehabilitation services, reproductive counselling discussed, psychosocial counselling discussed, nutritional counselling discussed, reconstructive surgery discussion, tobacco cessation discussion across General and Site-specific conferences. Most of the case presentations were prospective. This format does enable cancer programs to collect quality metrics around Cancer program accreditation by the American College of Surgeons. 66% of patients discussed potentially matched to clinical trials during the discussion. Conclusions: A technology platform can assist cancer programs to collect quality metrics around cancer care. This gives them the ability to run data driven quality programs targeting specific quality metrics. Hispanics have a lower percentage of cases presented at MDC compared to other race/ethnicities. It is possible to have high quality discussions and attain metrics for Commission on Cancer accreditation utilizing a virtual platform.

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.

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

e13561 Background: Cancer centers in the US are required to discuss a minimum of 15% analytic cases and prospective presentation (minimum 80%) in the multidisciplinary case conference (tumor board, MDCC), per the Commission on Cancer accrediting standards. Tumor board discussion have been shown to improve treatment decision making and patient outcomes. These meetings were in person meetings in the Pre-COVID era. The COVID 19 pandemic and the subsequent requirements for social distancing forced hospitals to move most MDCCs to a virtual format. We report on the large scale utilization of a propriety Care-Coordination platform OncoLens to run MDCCs across the country. Methods: Technology quality metrics were collected from the ongoing daily usage of the platform including time characteristics, care team utilization metrics, average attendance, quality metrics collected for accreditation and clinical trials matching on the OncoLens platform. Results: The virtual platform was accessible to around 8000 providers across the United States. On average per month there were 250 virtual meetings with over 290,000 meeting minutes. Conferences ranged from 30 minutes to 4 hours. 75% of users used the web application 25% of users utilized their smart phones .System uptime was 99.99%. Hospitals were able to conduct General and Site specific conferences. Virtual attendance of the required specialties of Medical Oncology, Radiation Oncology, Surgery, Pathology and Radiology was attained, with the average conference attendance being 14. On average hospitals required 2 administrative training sessions. Most of the case presentations were prospective. This format does enable cancer programs to collect quality metrics around Cancer program accreditation by the American College of Surgeons. A wide variety of common and rare cancer types were discussed in the virtual format. 66% of patients discussed potentially matched to clinical trials during the discussion. Conclusions: The shift of MDCCs to a mostly virtual environment occurred quickly in response to the COVID 19 pandemic. It took an average of 2 training classes to get the cancer care team on board with the use of new technology. It is possible to have high quality discussions and attain metrics for Commission On Cancer accreditation utilizing a virtual platform.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 x 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, beta = -0.33 D, P = 3.6 x 10(-6); GJD2: rs524952 A allele, beta = -0.31 D, P = 1.68 x 10(-5); ZMAT4-SFRP1: rs2137277 A allele, beta = 20.47 D, P = 1.68 x 10(-4)), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 x 10(-3)-4.78 x 10(-4)). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 x 10(-8)), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.

Author version made available in accordance with the publisher's policy., Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia., Australian National Health and Medical Research Council.

To examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss.Retrospective, multicenter cohort study.A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe.Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss.Yearly change in VA.The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P0.0001) per year overall, but the rate varied according to baseline VA: (1) eyes with baseline VA ≥20/25 (N = 53) declined at a rate of approximately 1.0 line per year; (2) eyes with VA between 20/25 and 20/70 (N = 65) declined at a rate of approximately 0.9 lines per year; (3) eyes with VA between 20/70 and 20/200 (N = 163) declined at a rate of 0.2 lines per year; and (4) eyes with VA worse than 20/200 (n = 49) improved at a rate of 0.5 lines per year. Older age of onset was associated with slower VA loss: Patients with onset age30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years.Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.

The refractive errors, myopia and hyperopia, are optical defects of the visual system that can cause blurred vision. Uncorrected refractive errors are the most common causes of visual impairment worldwide. It is estimated that 2.5 billion people will be affected by myopia alone within the next decade. Experimental, epidemiological and clinical research has shown that refractive development is influenced by both environmental and genetic factors. Animal models have showed that eye growth and refractive maturation during infancy are tightly regulated by visually guided mechanisms. Observational data in human populations provide compelling evidence that environmental influences and individual behavioral factors play crucial roles in myopia susceptibility. Nevertheless, the majority of the variance of refractive error within populations is thought to be because of hereditary factors. Genetic linkage studies have mapped two dozen loci, while association studies have implicated more than 25 different genes in refractive variation. Many of these genes are involved in common biological pathways known to mediate extracellular matrix (ECM) composition and regulate connective tissue remodeling. Other associated genomic regions suggest novel mechanisms in the etiology of human myopia, such as mitochondrial-mediated cell death or photoreceptor-mediated visual signal transmission. Taken together, observational and experimental studies have revealed the complex nature of human refractive variation, which likely involves variants in several genes and functional pathways. Multiway interactions between genes and/or environmental factors may also be important in determining individual risks of myopia, and may help explain the complex pattern of refractive error in human populations.

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged

Purpose To investigate the heritability of intraocular pressure (IOP) and cup-to-disc ratio (CDR) in an older well-defined population. Design Family-based cohort study. Participants Through the population-based Salisbury Eye Evaluation study, we recruited 726 siblings (mean age, 74.7 years) in 284 sibships. Methods Intraocular pressure and CDR were measured bilaterally for all participants. The presence or absence of glaucoma was determined by a glacuoma specialist for all probands on the basis of visual field, optic nerve appearance, and history. The heritability of IOP was calculated as twice the residual between-sibling correlation of IOP using linear regression and generalized estimating equations after adjusting for age, gender, mean arterial pressure, race, self-reported diabetes status, and history of systemic steroid use. The heritability of CDR was calculated using the same model and adjustments as above, while also adjusting for IOP. Main Outcome Measures Heritability and determinants of IOP and CDR, and impact of siblings' glaucoma status on IOP and CDR. Results We estimated the heritability to be 0.29 (95% confidence interval [CI], 0.12–0.46) for IOP and 0.56 (95% CI, 0.35–0.76) for CDR in this population. Mean IOP in siblings of glaucomatous probands was statistically significantly higher than in siblings of normal probands (mean difference, 1.02 mmHg; P = 0.017). The mean CDR in siblings of glaucomatous probands was 0.07 (or 19%) larger than in siblings of glaucoma suspect referrals ( P = 0.045) and siblings of normal probands ( P = 0.004). Conclusions In this elderly population, we found CDR to be highly heritable and IOP to be moderately heritable. On average, siblings of glaucoma patients had higher IOPs and larger CDRs than siblings of nonglaucomatous probands.

Purpose To determine whether hyperopia aggregates in families in an older mixed-race population. Design Cross-sectional familial aggregation study using sibships. Methods We recruited 759 subjects (mean age, 73.4 years) in 241 families through the population-based Salisbury Eye Evaluation study. Subjects underwent noncycloplegic refraction if best-corrected visual acuity (BCVA) was ≤20/40, had lensometry to measure their currently worn spectacles if BCVA was >20/40 with spectacles, or were considered to be plano (refraction of zero) if the BCVA was >20/40 without spectacles. Preoperative refraction from medical records was used for bilaterally pseudophakic subjects. Results Utilizing hyperopia cutoffs from 1.00 to 2.50 diopters, age-, race-, and gender-adjusted odds ratios for hyperopia with an affected sibling ranged from 2.72 (95% confidence interval [CI], 1.84–4.01) to 4.87 (95% CI, 2.54–9.30). The odds of hyperopia increased with age until 75 years, after which they remained relatively constant. Black men were significantly less likely to be hyperopic than white men, white women, or black women. Conclusions Hyperopia appears to be under strong genetic control in this older population.

Purpose To quantify the risk for age-related cortical cataract and posterior subcapsular cataract (PSC) associated with having an affected sibling after adjusting for known environmental and personal risk factors. Design Sibling cohort study. Participants Participants in the ongoing Salisbury Eye Evaluation (SEE) study (n = 321; mean age, 78.1±4.2 years) and their locally resident siblings (n = 453; mean age, 72.6±7.4 years) were recruited at the time of Rounds 3 and 4 of the SEE study. Intervention/testing methods Retroillumination photographs of the lens were graded for the presence of cortical cataract and PSC with the Wilmer grading system. The residual correlation between siblings' cataract grades was estimated after adjustment for a number of factors (age; gender; race; lifetime exposure to ultraviolet-B light; cigarette, alcohol, estrogen, and steroid use; serum antioxidants; history of diabetes; blood pressure; and body mass index) suspected to be associated with the presence of cataract. Results The average sibship size was 2.7 per family. Multivariate analysis revealed the magnitude of heritability (h 2 ) for cortical cataract to be 24% (95% CI, 6%–42%), whereas that for PSC was not statistically significant (h 2 4%; 95% CI, 0%–11%) after adjustment for the covariates. The model revealed that increasing age, female gender, a history of diabetes, and black race increased the odds of cortical cataract, whereas higher levels of provitamin A were protective. A history of diabetes and steroid use increased the odds for PSC. Conclusions This study is consistent with a significant genetic effect for age-related cortical cataract but not PSC.

The prevalence of angle-closure glaucoma (ACG) is greater for Eskimos/Inuit than it is for any other ethnic group in the world. Although it has been suggested that this prevalence may be due to a population tendency toward shallower anterior chamber angles, available evidence for other populations such as Chinese with high rates of ACG has not consistently demonstrated such a tendency.A reticule, slit-lamp, and standard Goldmann one-mirror goniolens were used to make measurements in the anterior chamber (AC) angle according to a previously reported protocol for biometric gonioscopy (BG) (Ophthalmology 1999;106:2161-7). Measurements were made in all four quadrants of one eye among 133 phakic Alaskan Eskimos aged 40 years and older. Automatic refraction, dilated examination of the anterior segment and optic nerve, and A-scan measurements of AC depth, lens thickness, and axial length were also carried out for all subjects.Both central and peripheral AC measurements for the Eskimo subjects were significantly lower than those previously reported by us for Chinese, blacks, and whites under the identical protocol. Eskimos also seemed to have somewhat more hyperopia. There were no differences in biometric measurements between men and women in this Eskimo population. Angle measurements by BG seemed to decline more rapidly over life among Eskimos and Chinese than blacks or whites. Although there was a significant apparent decrease in AC depth, increase in lens thickness, and increase in hyperopia with age among Eskimos, all of these trends seemed to reverse in the seventh decade and beyond.Eskimos do seem to have shallower ACs than do other racial groups. Measurements of the AC angle seem to decline more rapidly over life among Eskimos than among blacks or whites, a phenomenon also observed by us among Chinese, another group with high ACG prevalence. This apparent more rapid decline may be due to a cohort effect with higher prevalence of myopia and resulting wider angles among younger Eskimos and Chinese.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

PURPOSE. Three loci defined by single nucleotide polymorphisms (SNPs) rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 between the PCMTD1 and ST18 genes, recently have been associated with primary angle closure glaucoma (PACG). We explored the genetic association of these SNPs with subtypes of primary angle closure in a South Indian population. METHODS. The study included three case definitions: primary angle closure/primary angle closure glaucoma (PAC/PACG, N ¼ 180); primary angle closure suspect (PACS, N ¼ 171), and a combined any-angle closure group. Controls consisted of 411 individuals from South India. Genotyping for all three SNPs was performed using the TaqMan allelic discrimination assay. Genetic association was estimated using a v 2 test statistics and logistic regression. RESULTS. Among the three studied SNPs, significant genetic association was identified for rs1015213 in the PAC/PACG (P ¼ 0.002) and any-angle closure (P ¼ 0.003) analyses. However, no significant genetic association was seen when in PACS subjects (P ¼ 0.052). SNPs rs3753841 and rs11024102 showed no evidence of genetic association with angleclosure phenotypes (P > 0.05) in South Indian participants. CONCLUSIONS. In our study, rs1015213 (located in the intergenic region between PCMTD1 and ST18) was associated significantly with PAC/PACG, confirming prior reports of an association between this region and angle closure glaucoma. Further work with a larger sample size is necessary to confirm the importance of COL11A1 and PLEKHA7 in the pathogenesis of glaucoma.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P, This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

To assess the correlations between retinal nerve fiber layer (RNFL) thickness measured with scanning laser polarimetry and visual field (VF) sensitivity in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).Prospective, comparative, observational cases series.Fifty patients with POAG and 56 patients with PACG were examined using scanning laser polarimetry with variable corneal compensation (GDx VCC; Laser Diagnostic Technologies, Inc.) and Humphrey VF analyzer (Carl Zeiss Meditec, Inc.) between August 2005 and July 2006 at Taipei Veterans General Hospital. Correlations between RNFL thickness and VF sensitivity, expressed as mean sensitivity in both decibel and 1/Lambert scales, were estimated by the Spearman rank correlation coefficient (r(s)) and multivariate median regression models (pseudo R(2)). The correlations were determined globally and for 6 RNFL sectors and their corresponding VF regions.The correlation between RNFL thickness and mean sensitivity (in decibels) was weaker in the PACG group (r(s) = 0.38; P = .004; pseudo R(2) = 0.17) than in the POAG group (r(s) = 0.51; P.001; pseudo R(2) = .31), but the difference in the magnitude of correlation was not significant (P = .42). With Bonferroni correction, the structure-function correlation was significant in the superotemporal (r(s) = 0.62), superonasal (r(s) = 0.56), inferonasal (r(s) = 0.53), and inferotemporal (r(s) = 0.50) sectors in the POAG group (all P.001), whereas it was significant only in the superotemporal (r(s) = 0.53) and inferotemporal (r(s) = 0.48) sectors in the PACG group (both P.001). The results were similar when mean sensitivity was expressed as 1/Lambert scale.Both POAG and PACG eyes had moderate structure-function correlations using scanning laser polarimetry. Compared with eyes with POAG, fewer RNFL sectors have significant structure-function correlations in eyes with PACG.

Myopia is the leading cause of visual impairment in nearly all population-based studies of ocular disease, and correction of refractive error consumed over $12 billion per year in the United States 10 years ago, even before the recent surge in refractive surgery.1 In some populations of east Asia, studies suggest that the prevalence of myopia may exceed 80% among young persons,2 and there is some evidence that rates may be increasing rapidly.3 There is also evidence for a recent increase in the prevalence of myopia in populations such as Eskimos, in whom myopia was rare only a few generations ago.4 Such apparent rapid changes in the prevalence of myopia within defined populations argue for strong environmental influences in the development of myopia. For example, much evidence exists that implicates near work as an important determinant of myopia.5–10 Nevertheless, there is also considerable evidence that myopia is under genetic control. Studies have consistently shown strong correlations between the refractive errors of first-degree relatives.11–13 Twin studies by Hammond et al.,14 Teikari et al.,15,16 and Lyhne et al.17 have suggested that the heritability—that is, the proportion of the population variance under genetic control—for refraction may exceed 80%. It is therefore likely that the development of myopia is mediated by both environmental and genetic risk factors. At least four chromosomal locations18–22 have been linked to high (that is, in excess of 5 D) myopia. No such loci had been identified for moderate myopia (1–5 D), which comprises some 80% of myopia among American adults,23 until a recent report by Stambolian et al.24 who found significant genetic linkage of myopia to a region on chromosome 22 in an Ashkenazi Jewish population. Moreover, in a genome-wide scan of 221 dizygotic twin pairs, Hammond et al.25 reported significant linkage signals to multiple genetic loci when analyzing refractive error as a quantitative trait. Their highest linkage peak was observed at chromosomal location 11p13 while evidence for linkage was also noted at regions 3q26, 8p23, and 4q12. The relative paucity of evidence for linkage in lower levels of refractive error, compared with high myopia, is partly because high myopia may be more likely to present in an autosomal dominant fashion,22 whereas the genetics of lower refractive errors may be more complex and multifactorial. Nevertheless, Farbrother et al.26 argue that even high myopia phenotypes are unlikely to be inherited in an autosomal dominant fashion and that a multifactorial etiology is more likely. In view of the high prevalence (some 20 million American adults23) and the resultant significant impact on the health economy in the cost of spectacles, contact lenses, and refractive surgery, it certainly seems that moderate myopia is deserving of genetic study to elucidate its fundamental mechanisms, which may or may not be the same as those of high myopia. Using linear regression models and generalized estimating equations (GEEs), we estimated the heritability of refractive error in a population-based sample of elderly sibships in eastern Maryland. We also used logistic regression models to calculate the odds of myopia in siblings of myopic individuals compared with siblings of nonmyopes, using four thresholds to define myopia.

The investigation of the genetic basis of refractive error and myopia entered a new stage with the introduction of genome-wide association studies (GWAS). Multiple GWAS on many ethnic groups have been published over the years, providing new insight into the genetic architecture and pathophysiology of refractive error. This is a review of the GWAS published to date, the main lessons learned, and future possible directions of genetic studies of myopia and refractive error.

PURPOSE: To investigate age-related trends in refractive, corneal, and internal astigmatism and to assess the association between internal astigmatism and lens opacity in an elderly Chinese population. METHODS: A population-based study was conducted among 1360 inhabitants aged 65 years and older in Taipei, Taiwan. Participants underwent measurements of refraction, corneal dioptric power, and slit lamp biomicroscopy with lens grading. A total of 2084 eyes were included in power vector analyses of Cartesian astigmatism (J(0)) and oblique astigmatism (J(45)) components of refractive, corneal, and internal astigmatism. RESULTS: The crude prevalence of refractive astigmatism (defined as ≥0.75 diopters) was 73.0% based on the right eyes and 76.4% based on the left eyes. The vector values in both refractive J(0) and corneal J(0) tended to be more negative with increasing age (P < 0.001), indicating the trend toward against-the-rule (ATR) astigmatism. Corneal J(0) alone accounted for 54% of the variability in refractive J(0). Refractive J(45) increased with age in the right eyes (P < 0.001) and decreased slightly with age in the left eyes (P = 0.012). Cortical opacity was associated with internal J(0) (P = 0.025), but the association was weak. CONCLUSIONS: Astigmatism affects approximately three quarters of the Chinese population aged 65 years and older in Taiwan. With increasing age, the prevalence of astigmatism increases, and refractive and corneal astigmatism shift toward ATR. Continuous corneal changes appear to be responsible for the age trend in refractive astigmatism. The severity of lens opacity plays only a minor role in the change of internal astigmatism.

Clear vision requires that images formed by incident light are focused at the eye's retinal plane. The maintenance of clear, focused, vision (i.e., emmetropia) through adulthood depends on a precise and complex regulation of eye shape during ocular development. This regulation ensures that the eye's focal and anatomic lengths are aligned. Any discrepancy between the position of the retina and the eye's focal point results in the spherical refractive errors myopia and hyperopia. In myopia, images of distant objects formed by the eye's optical system focus anterior to the retinal plane, causing blurred distance vision. In its functional opposite, hyperopia, these images focus behind the retina (in the unaccommodating eye). Hyperopia is associated with blurred near vision. Myopia and hyperopia are fundamentally qualitative definitions. However, the degree of departure from perfect focus can be quantified as the refractive error. Typically, refractive error represents the dioptric power of optical lenses necessary to achieve proper distance correction. By convention, negative values of refractive error (in diopters, D) represent myopia, whereas positive values represent hyperopia. Although there is a broad scientific consensus that environmental and behavioral factors influence refractive development and the genesis of myopia, genetic epidemiologic studies have consistently shown that the distribution of ocular refraction within populations is largely determined by genetics. Heritability estimates for refraction are usually very high across a wide spectrum of ethnic groups despite various intraethnic prevalences of myopia and myopigenic environmental influences. For example, we reported the heritability of refractive error in an adult Old Order Amish (AMISH) population to be 70%.1 High heritabilities are remarkably consistent across studies with estimates reported for Caucasian Americans,1–3 Europeans,4–7 and African Americans,3 ranging between 60% and 90%. Structurally, myopia is caused by an excessive axial length of the eye relative to its optical power.8 Hence, myopic eyes tend to be longer than nonmyopic eyes.8 The converse is true of hyperopia (i.e., hyperopic eyes are comparatively shorter than emmetropic and myopic eyes). Anatomically, these variations in axial length are due primarily to differences within the posterior (or vitreous) chamber, which occupies the bulk of the eye's volume. Although the molecular signal for blur-induced differential eye growth is thought to originate from within the retina, ocular elongation must occur via the growth of the outer tunic of the eye: the sclera. In mammals, the sclera is a fibrous connective tissue composed mainly of extracellular collagen, which accounts for up to 90% of the sclera's dry weight (Zorn N, et al. IOVS 1992;33:ARVO Abstract 1811). The majority (i.e., up to 99%) of scleral collagen is of the type I variety, although low levels of other collagen subtypes have also been found (Norton TT, et al. IOVS 1995;36:ARVO Abstract 3517). The structural organization of the scleral extracellular matrix (ECM) depends largely on the cellular activity of fibroblasts, the main ECM-producing cells in the sclera. The degradation of the ECM that occurs during scleral remodeling in eye growth and myopization (i.e., myopia development) is partially regulated through members of a major family of zinc- and calcium-dependent endopeptidases: the matrix metalloproteinases (MMPs) (see Rada et al.9 for a review). In humans, the MMP gene family comprises 23 distinct genes distributed across the genome; 9 MMP genes are located in a cluster at 11q22.2. The MMPs play numerous important roles in regulating cell–matrix composition in connective tissue and have been implicated in normal developmental processes and the pathogenesis of a variety of diseases.10,11 The expression of MMPs is generally low in tissues and is induced during active ECM remodeling.12 MMP regulation is mostly achieved at the transcriptional level but can occur at multiple stages. Activation of latent zymogens must occur for the MMPs to gain their proteolytic activity. Once activated, MMPs can be inactivated by multiple mechanisms, including direct interactions with one of four tissue inhibitors of matrix metalloproteinases (TIMPs).12 Given the important role of MMPs in ECM composition and remodeling, genetic variations in MMP genes are potential candidates for refractive error heritability and susceptibility to myopia. Indeed, a recent candidate gene study of older British adults reported statistically significant genetic associations between MMP3 and MMP9 polymorphisms and common myopia.13 We hypothesize that genetic polymorphisms in MMP and/or TIMP genes contribute to intrapopulation variations of refractive error measured as a quantitative trait. In the present study, we conducted family-based association analyses of genetic polymorphisms within MMP and TIMP candidate regions that included: MMP1, -2, -3, -7, -8, -9, -10, -12, -13, -14, -20, and -27, as well as TIMP1, -2, -3, and -4. These candidate regions were chosen to include genes whose homologs have shown differential expression in animal myopia models,14–17 as well as polymorphisms within a cluster of nine MMP genes situated at 11q22.2. Analyses were conducted on a subset of individuals from 63 Orthodox Ashkenazi Jewish (ASHK) and 55 Old Order Amish (AMISH) American families participating in the Myopia Family Study. We found statistically significant genetic associations between two single-nucleotide polymorphisms (SNPs), rs1939008 and rs9928731, and refractive error in the AMISH, but not the ASHK; rs1939008 is located between MMP1 and MMP10, and rs9928731 is located within MMP2.

To determine the heritability of refractive error and familial aggregation of myopia and hyperopia in an elderly Old Order Amish (OOA) population.Nine hundred sixty-seven siblings (mean age, 64.2 years) in 269 families were recruited for the Amish Eye Study in the Lancaster County area of Pennsylvania. Refractive error was determined by noncycloplegic manifest refraction. Heritability of refractive error was estimated with multivariate linear regression as twice the residual sibling-sibling correlation after adjustment for age and gender. Logistic regression models were used to estimate the sibling recurrence odds ratio (OR(s)). Myopia and hyperopia were defined with five different thresholds.The age- and gender-adjusted heritability of refractive error was 70% (95% CI: 48%-92%) in the OOA. Age and gender-adjusted OR(s) and sibling recurrence risk (lambda(s)), with different thresholds defining myopia ranged from 3.03 (95% CI: 1.58-5.80) to 7.02 (95% CI: 3.41-14.46) and from 2.36 (95% CI: 1.65-3.19) to 5.61 (95% CI: 3.06-9.34). Age and gender-adjusted OR(s) and lambda(s) for different thresholds of hyperopia ranged from 2.31 (95% CI: 1.56-3.42) to 2.94 (95% CI: 2.04-4.22) and from 1.33 (95% CI: 1.22-1.43) to 1.85 (95% CI: 1.18-2.78), respectively. Women were significantly more likely than men to have hyperopia. There was no significant gender difference in the risk of myopia.In the OOA, refractive error is highly heritable. Hyperopia and myopia aggregate strongly in OOA families.