The Role of Educational Attainment in Refraction: The Genes in Myopia (GEM) Twin Study

PURPOSE. Educational attainment has been proposed as one of the most consistent environmental risk factors associated with myopia. The Genes in Myopia (GEM) twin study is the first myopia twin study to determine the relative genetic contribution in educational attainment as well as assessing the shared genetic and environmental factors between educational attainment and refraction through structural equation modeling. METHODS. All twins from Victoria aged 18 years or older were invited to participate in this study through the Australian Twin Registry (ATR). Each twin completed a general questionnaire, and a comprehensive eye examination was undertaken. Education level was categorized to provide a level of attainment. RESULTS. A total of 612 twin pairs with a mean age of 52.36 years were examined. Higher educational attainment was significantly associated with a more myopic refraction (r ϭ Ϫ0.21, P Ͻ 0.01), with educational attainment explaining 4.41% of the total variance in refraction. Findings from the GEM twin study found that genes (additive genetic effects) explained 69% of the variance in educational attainment and common and unique environmental factors accounted for 20% and 11% of the variance, respectively. Of the genetic influences on refraction, 3.2% were common with those influencing educational attainment. CONCLUSIONS. The GEM twin study has shown that educational attainment is strongly influenced by genes, and therefore this risk factor should not solely be considered as an environmental risk factor. The same genetic factors that influence an individual's educational attainment may also be involved in the development of refractive error. (Invest Ophthalmol Vis Sci. 2008; 49:534 -538) DOI:10.1167/iovs.07-1123 A pproximately 20% to 25% of individuals in Western populations have myopia or near-sightedness, 1,2 with the prevalence being much higher (80%) in urbanized areas of Asia. 6 Major evidence to support a genetic contribution to myopia has come from twin studies and family-based linkage studies. Several twin studies 7-10 have collectively provided evidence to support a major genetic component, with concordance for myopia between identical (monozygotic) twins (r Ͼ 0.80) approximately twice that for myopia in nonidentical (dizygotic) twins (r Ͻ 0.4). As such, heritability estimates from twin studies range from 60% to 90% for refraction 8 More recently, family-based linkage studies have identified at least 14 myopia loci (MYP1 to -14) associated with all forms of myopia. 12 So far, no gene(s) have been significantly associated with myopia in these regions. Several environmental risk factors have been implicated as playing a role in myopia including intelligence and, most frequently, near-work activity. 14 -16 For instance, a recent study by Saw et al. 16 Nonetheless, considering myopia is complex in nature, it is essential to understand whether such risk factors are purely environmental or whether they share a common genetic basis with myopia. First, the etiology of these risk factors must be elucidated. For instance, what combination of social, cultural, environmental or genetic influences constitutes an individual's educational attainment? Considering the difficulty of obtaining accurate measures of near-work activity retrospectively, it is common for studies to use educational attainment as a surrogate measure for near work in studies of myopia. 17 Studies into educational attainment have reported heritability estimates reaching as high as 60%. 10 The use of twin studies is an effective tool in exploring gene-environment interactions (the magnitude of the effect of a genetic variant caused by a change in the environment) by quantifying the genetic component in disease while accounting for environmental factors in the same individuals. Jinks and Fulker 22 introduced a test to detect gene-environment interactions in disease through the analysis of MZ twin pairs. A gene-environment interaction is indicated when absolute differences (MZ twin 1 Ϫ MZ twin 2 ϭ environment effects) for any measure of interest in MZ twin pairs are significantly associated with the corresponding sums (MZ twin 1 ϩ MZ twin From th

Comprehensive Analysis of Copy Number Variation of Genes at Chromosome 1 and 10 Loci Associated with Late Age Related Macular Degeneration

Copy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored. We analyzed the two major AMD risk-associated regions on chromosome 1q32 and 10q26 for CNVs using Multiplex Ligation-dependant Probe Amplification. The analysis targeted nine genes in these two key regions, including the Complement Factor H (CFH) gene, the 5 CFH-related (CFHR) genes representing a known copy number “hotspot”, the F13B gene as well as the ARMS2 and HTRA1 genes in 387 cases of late AMD and 327 controls. No copy number variation was detected at the ARMS2 and HTRA1 genes in the chromosome 10 region, nor for the CFH and F13B genes at the chromosome 1 region. However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38×10−12) OR = 0.31, CI-0.95 (0.23–0.44), for both neovascular disease (nAMD) (p = 8.3×10−9) OR = 0.36 CI-0.95 (0.25–0.52) and geographic atrophy (GA) (p = 1.5×10−6) OR = 0.36 CI-0.95 (0.25–0.52) compared to controls. In addition, a significant association with deletion of CFHR1-4 was identified only in patients who presented with bilateral GA (p = 0.02) (OR = 7.6 CI-0.95 1.38–41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease

Can HMG Co-A reductase inhibitors (“statins”) slow the progression of age-related macular degeneration? The Age-Related Maculopathy Statin Study (ARMSS)

Age-related macular degeneration (AMD) is responsible for the majority of visual impairment in the Western world. The role of cholesterol-lowering medications, HMG Co-A reductase inhibitors or statins, in reducing the risk of AMD or of delaying its progression has not been fully investigated. A 3-year prospective randomized controlled trial of 40 mg simvastatin per day compared to placebo in subjects at high risk of AMD progression is described. This paper outlines the primary aims of the Age-Related Maculopathy Statin Study (ARMSS), and the methodology involved. Standardized clinical grading of macular photographs and comparison of serial macular digital photographs, using the International grading scheme, form the basis for assessment of primary study outcomes. In addition, macular function is assessed at each visit with detailed psychophysical measurements of rod and cone function. Information collected in this study will assist in the assessment of the potential value of HMG Co-A reductase inhibitors (statins) in reducing the risk of AMD progression

Evaluating the Association Between Keratoconus and the Corneal Thickness Genes in an Independent Australian Population

PURPOSE. A recent genome-wide association study (GWAS) identified six loci associated with central corneal thickness that also conferred associated risk of keratoconus (KC). We aimed to assess whether genetic associations existed for these loci with KC or corneal curvature in an independent cohort of European ancestry. METHODS. In total, 157 patients with KC were recruited from public and private clinics in Melbourne, Australia, and 673 individuals without KC were identified through the Genes in Myopia study from Australia. The following six single-nucleotide polymorphisms (SNPs) that showed a statistically significant association with KC in a recent GWAS study were selected for genotyping in our cohort: rs4894535 (FNDC3B), rs1324183 (MPDZ-NF1B), rs1536482 (RXRA-COL5A1), rs7044529 (COL5A), rs2721051 (FOXO1), and rs9938149 (BANP-ZNF469). The SNPs were assessed for their association with KC or corneal curvature using logistic or linear regression methods, with age and sex included as covariates. Bonferroni corrections were applied to account for multiple testing. RESULTS. Genotyping data were available for five of the SNPs. Statistically significant associations with KC were found for the SNPs rs1324183 (P ¼ 0.001; odds ratio [OR], 1.68) and rs9938149 (P ¼ 0.010; OR, 1.47). Meta-analysis of previous studies yielded genomewide significant evidence of an association for rs1324183, firmly establishing it as a KC risk variant. None of the SNPs were significantly associated with corneal curvature. CONCLUSIONS. The SNPs rs1324183 in the MPDZ-NF1B gene and rs9938149 (between BANP and ZNF4659) were associated with KC in this independent cohort, but their association was via a non-corneal curvature route

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

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Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

BACKGROUND: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: OBJECTIVES: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. DESIGN: A proof of concept double-masked randomized controlled study. PARTICIPANTS: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile. INTERVENTION: Simvastatin 40 mg/day or placebo, allocated 1:1. MAIN OUTCOME MEASURES: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. CONCLUSION/SIGNIFICANCE: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Efficient photoionization for barium ion trapping using a dipole-allowed resonant two-photon transition

Two efficient and isotope-selective resonant two-photon ionization techniques for loading barium ions into radio-frequency (RF)-traps are demonstrated. The scheme of using a strong dipole-allowed transition at \lambda=553 nm as a first step towards ionization is compared to the established technique of using a weak intercombination line (\lambda=413 nm). An increase of two orders of magnitude in the ionization efficiency is found favoring the transition at 553 nm. This technique can be implemented using commercial all-solid-state laser systems and is expected to be advantageous compared to other narrowband photoionization schemes of barium in cases where highest efficiency and isotope-selectivity are required.Comment: 8 pages, 5 figure

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date

Association of Genetic Variation with Keratoconus

Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.Objective: To identify genetic susceptibility regions for keratoconus in the human genome.Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P -6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P -8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family

Data deposition: The data reported in this paper have been deposited as a National Center for Biotechnology Information BioProject (accession no. PRJNA401648). Author contributions: S.C. and E.E.E. designed research; S.C., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., T.A.G.-L., and R.K.W. performed research; S.C., J.H., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., F.G., A.J.R., R.H.G., T.A.G.-L., R.K.W., B.H.F.W., P.N.B., R.A., and E.E.E. contributed new reagents/analytic tools; S.C., B.J.N., J.H., and E.E.E. analyzed data; and S.C., B.J.N., and E.E.E. wrote the paper.Peer reviewedPublisher PD