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Purpose We identified families with autosomal dominant optic atrophy (ADOA), determined the number and type of OPA1 mutations, and investigated the phenotypic variation and penetrance in ADOA Australian pedigrees. Design Cross-sectional genetics study. Methods Probands were identified on the basis of characteristic clinical features of ADOA. We screened the OPA1 gene using single-strand conformational polymorphism, heteroduplex analysis (SSCP/HA), or by direct sequencing. Penetrance for pedigrees in which a mutation of OPA1 had been identified was calculated initially using all recruited individuals, and subanalysis was performed using only those families for which there was total recruitment of siblings. Results A total of 406 patients from 17 pedigrees were recruited, and OPA1 mutations were identified in 11/17 (65%) of these. The mean age at clinical examination was 38.2 ± 19.9 years (median age, 35 years; range, four to 83 years). The median best-corrected visual acuity in OPA1- mutation carriers was 20/70 (range, 20/16 to hand movements [HM]). The penetrance in Australian ADOA pedigrees in the families with complete sibling recruitment was 82.5%. On the other hand, overall penetrance for all individuals harboring an OPA1 mutation was 88%. Conclusions OPA1 mutations were identified in 11/17 (65%) of the ADOA pedigrees in this study. The penetrance in our cohort was lower than originally described (82.5% vs 98%) but higher than some recent studies since the availability of genotyping. It is anticipated that this figure would be even lower as more asymptomatic individuals are identified. There are likely to be other genetic and environmental modifiers influencing disease penetrance.

Glaucoma, which is a complex heterogeneous disease, presents an ideal case for genetic investigation. Primary open-angle glaucoma (POAG) is the commonest subtype and will be the focus of this review. When detected early, POAG is amenable to therapeutic intervention. Unfortunately, current population-based clinical screening lacks efficacy. If individuals with a genetic predisposition for developing POAG can be identified, then efficient and cost-effective population-based screening programs could be designed. Although considerable inroads have been made in understanding the natural history of POAG caused by mutations in the myocilin and optineurin genes, other POAG genes accounting for most cases remain to be identified. This review explores the genetic mechanisms that have been unequivocally linked to the glaucomatous process and then discusses potential avenues for future breakthroughs.

To determine whether there is a difference in disease severity between familial and sporadic primary open-angle glaucoma (POAG).A cross-sectional study design compared the distribution of Glaucoma Inheritance Study in Tasmania (GIST) severity scores of patients with genealogically confirmed familial POAG and those with sporadic POAG. The GIST severity scores provide a combined weighting of glaucoma severity based on findings from visual field defects and optic disc analysis, with and without intraocular pressure. A Poisson regression analysis, t test, and chi(2) tests were performed.One thousand twelve (59.5%) of 1700 subjects had familial glaucoma. The mean +/- SD age at examination was greater in the sporadic POAG group compared with the familial group (72.6 +/- 10.3 years vs 70.6 +/- 12.6 years; P = .001). The family group was significantly younger at diagnosis than the sporadic group (mean +/- SD, 61.4 +/- 13.0 years vs 64.0 +/- 12.6 years; P.001). The GIST severity scores were significantly skewed toward greater disease severity in the familial group compared with the sporadic group (P.001).Identifying individuals at risk of severe POAG will be more successful if screening programs are developed with appropriate weighting toward those with a positive family history of the disease.

PURPOSE. A classic twin study was performed to determine the heritability of central corneal thickness (CCT), an important parameter in glaucoma assessment. METHODS. The concordance of CCT between monozygotic (MZ) and dizygotic (DZ) twins was compared. A total of 256 twin pairs (131 MZ and 125 DZ) were recruited from three centers: the Twin Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Twins U.K. Adult Registry held at St. Thomas’ Hospital in London. As part of an extensive ophthalmic evaluation, CCT was measured by ultrasound pachymetry. Structural equation modeling with the Mx program (Department of Psychiatry, Medical College of Virginia, Richmond, VA) was used to determine the heritability of CCT. RESULTS. The mean age of subjects was 38 years (range, 8 – 81). The mean CCT of all eyes examined was 544.5 37.3 m (SD). The CCT measurements correlated more highly in MZ twins than in DZ twins, with intraclass correlation coefficients of 0.95 and 0.52, respectively, suggesting a strong genetic influence. A model of additive genetic and unique environmental effects provided the best fit, yielding a heritability of 0.95 (95% confidence interval [CI], 0.93– 0.96) with the remaining variation being attributable to unique environmental factors. CONCLUSIONS. In this study of Australian and U.K. twins, genetic factors were shown to be of major importance in CCT, with a

Purpose To describe the phenotype of an individual homozygous for the common Gln368STOP myocilin mutation and to discuss the other family members. Design Cascade screening was performed for Australian families that had been identified as having the myocilin Gln368STOP mutation. Methods Recruited subjects underwent comprehensive clinical examination and mutation analysis for the Gln368STOP myocilin mutation by direct sequencing. Results One 49-year-old woman was found to be homozygous for the mutation. Her maximal recorded intraocular pressure was 17 mm Hg. Bilateral optic disk examination revealed small, healthy optic discs. Automated perimetry testing was normal. Conclusions Neither the individual homozygous for the Gln368STOP myocilin mutation nor her younger heterozygous siblings displayed any signs suggestive of glaucoma. One of the two heterozygous parents did manifest glaucoma. Although there is the possibility of the homozygous individual developing glaucoma in the future, she does not manifest a phenotype that is more severe than usual.

Aims: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract. Methods: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model. Results: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals. Conclusion: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p.

Background: Central corneal thickness (CCT) has been found to be a powerful predictor for the development of glaucoma in patients with ocular hypertension. This study aimed to determine whether CCT was also related to glaucoma severity. Methods: The vertical cup/disc ratio (VCDR) was used as a single objective measure of glaucoma severity. Vertical cup diameters and vertical disc diameters were measured using a graticule attached to a 60 D Volk lens, in consecutive patients presenting to a single ophthalmologist. Measurements were corrected for magnification. The difference between corrected VCDR and 95% probability of VCDR normality was compared to CCT, which was measured with an ultrasonic pachymeter. Results: During the study period 554 eyes from 281 patients with glaucoma were reviewed. The mean CCT was 519.0 µm, with the mean corrected VCDR being 0.71. A univariate linear regression model revealed that an increase of 10 µm in CCT resulted in a 0.009 decrease in the difference between true VCDR and the predicted normal VCDR. The R2 value for the regression was 0.04 (P

Over the past decade with the spread of the internet, the means by which patients seek health information has dramatically changed. In 2005, an analysis of approximately 6000 adults in the USA revealed that over 60% of internet users searched for health information online, with only approximately 10% using a physician as their initial source of health-related information.1 While the use of online resources to obtain primary health information has some concerning aspects, it also has potential public health benefits. For example, it is possible to detect emerging …

IMPORTANCE Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. OBJECTIVE To perform a clinical and genetic investigation of a large white family with autosomal dominant nanophthalmos. DESIGN, SETTING, AND PARTICIPANTS Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase-polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available individuals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated individuals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. MAIN OUTCOMES AND MEASURES Nanophthalmos status. RESULTS Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white individuals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. CONCLUSIONS AND RELEVANCE A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.

PURPOSE To investigate the association between serum vitamin D levels and myopia in young adults. METHODS A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D₃ (25(OH)D₃) concentrations were determined using mass spectrometry. The association between serum 25(OH)D₃ concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. RESULTS Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D₃ concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D₃ concentration was associated with higher risk of having myopia (odds ratio [OR] for

Glaucoma, the worldwide leading cause of irreversible blindness, is characterized by progressive degeneration of the optic nerve and loss of retinal ganglion cells. Research into glaucoma pathogenesis has been hampered by difficulties in isolating and culturing retinal ganglion cells in vitro. However, recent improvements in laboratory techniques have enabled the generation of a variety of mature cell types from pluripotent stem cells, including retinal ganglion cells. Indeed, stem cell-based approaches have the potential to revolutionize the field by providing an unlimited source of cells for replacement therapies and by enabling development of in vitro disease models for drug screening and research. Consequently, research aimed at directing pluripotent stem cells to differentiate into retinal ganglion cells has expanded dramatically during the past decade, resulting in significant advances in technique and efficiency. In this paper, we review the methodology for retinal ganglion cell differentiation from pluripotent stem cells of both mouse and human origin and summarize how these techniques have opened up new avenues for modelling glaucoma. Generation of stem cell–derived retinal ganglion cells will have significant translational values, providing an in vitro platform to study the mechanisms responsible for pathogenesis and for drug screening to improve treatment options, as well as for the development of cell therapies for optic neuropathies such as glaucoma.

Purpose To investigate in Australian patients with glaucoma and normal controls the prevalence and associated phenotype of the WDR36 D658G mutation, which has previously been suggested to be a disease-causing mutation in pedigrees with primary open-angle glaucoma (POAG). Design Case-control study. Methods Two hundred forty-nine individuals with POAG and 217 age-matched control subjects were recruited through the Glaucoma Inheritance Study in Tasmania, Australia. Genomic DNA was amplified by polymerase chain reaction by intronic primers. The presence of the D658G variant was detected by Bgl I restriction enzyme digestion. Results The D658G variant was identified in four POAG cases (1.6%) and four control subjects (1.8%) (χ 2 = 0.04, P = .84). No control subject with the variant had a family history of glaucoma. Conclusions The WDR36 D658G is a neutral variant in the Australian population. Further populations should be carefully assessed for this variant before concluding that WDR36 is a glaucoma gene.

PurposeA recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.MethodPatients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.ResultsAfter adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.ConclusionThe present results support the initial GWAS findings, and confirm the SNP's contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.

Glaucoma is a major cause of blindness in the world. Recent genome-wide association studies (GWAS) have identified common genetic variants for glaucoma, but still a significant heritability gap remains. We hypothesized that copy number variants (CNVs) might influence part of the susceptibility to glaucoma or its related quantitative endophenotypes.THIS STUDY EXAMINED THE ASSOCIATION BETWEEN CNVS AND INTRAOCULAR PRESSURE (IOP), THE MAJOR MODIFIABLE RISK FACTOR FOR PRIMARY OPEN-ANGLE GLAUCOMA (POAG), IN THREE POPULATION PANELS OF EUROPEAN ANCESTRY: the TwinsUK cohort (n = 1047), the Australian Twin Eye Study (n = 561), and the Wellcome Trust Case-Control Consortium 2 (WTCCC2)/Blue Mountains Eye Study (BMES) (n = 1660). We also used PCR-based assays to investigate a locus of interest that we found associated with IOP in a POAG case-control panel of European ancestry from London, United Kingdom.WE IDENTIFIED ASSOCIATIONS BETWEEN IOP AND TWO CNV REGIONS IN THE TWINSUK COHORT: 5q21.2 (P = 0.003) overlapping the gene RAB9BP1 and 12p13.3 (P = 0.03) overlapping the genes SLC2A14 and SLC2A3. The Australian Twin Eye Study and BMES both replicated the 5q21.2 CNV association and direction of effect (P = 0.001 and P = 0.02, respectively). A meta-analysis across all the cohorts showed that presence of a copy number change at this locus increased IOP by 1.56 mm Hg (P = 1.24 × 10(-6)). In the case-control study, the 5q21.2 CNV locus did not show association with high-pressure (≥21 mm Hg) POAG cases.The 5q21.2 CNV locus could represent a novel locus controlling IOP. Interestingly, this IOP locus is located in close vicinity to the previously widely replicated GLC1G linkage locus for glaucoma, for which subsequent studies have not reached consensus on the causal gene.

Central corneal thickness (CCT) is one of the most heritable of all quantitative human traits.1 Accurate pachymetry is now standard of care in the clinical assessment of a number of ocular conditions. Since the publication of the Ocular Hypertension Treatment Study findings, CCT measurement has assumed an important role in glaucoma care.1 Additionally, corneal thinning is a key feature in the corneal ectasias and an accurate assessment of CCT is crucial prior to refractive surgery.1 As such, investigating the molecular underpinnings for CCT will have important ramifications both for associated diseases and in other quantitative trait mapping.1 Unfortunately, heritability estimates do not directly reflect the underlying genetic architecture and, similar to other complex traits, a number of loci have now been directly implicated in CCT. Recently, a genome-wide association study (GWAS) of more than 20,000 people identified 26 loci associated with CCT.2 Gao et al.'s work3 directly replicates and extends our understanding of one of these loci. A previously associated region at chromosome 9q34 contains two annotated genes (RXRA, COL5A1) that border a putative transcript (LOC100506532). Interestingly Gao et al.,3 through GWAS, identified a statistically significant signal at this locus in their cohort, and by conditional analysis of the top single nucleotide polymorphism (rs3118515), implicated a variant within LOC100506532 as conferring the major genetic effect in this region. Through RT-PCR, they then demonstrated that LOC100506532 is expressed in the human cornea. Despite the successful implication of many loci, one of the major ongoing challenges of GWAS interpretation is deciphering the "causative" variants from merely associated "marker" variants. Gao et al.'s work3 highlights the utility of refining loci through GWAS in people of non-Northern European ancestry. The use of Latino individuals, recruited through the Los Angeles Latino Eye Study, sheds important light on the role of the "RXRA-COL5A1" locus in determining CCT. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

This article appeared in a journal published by Elsevier Ltd. Under Elsevier's copyright, mandated authors are not permitted to make work available in an institutional repository., Purpose To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to-disc ratio (VCDR) also are associated with open-angle glaucoma (OAG). Design Retrospective case-control genetic association study. Methods A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia. Results Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 x 10-06; odds ratio, 1.38; 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 x 10-05; odds ratio, 0.74; 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG. Conclusions The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG., Australian National Health & Medical Research Council

Background: Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field. Methods: Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry. Results: The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.761025). We replicated this finding in the GIST cohort (p = 7.361023, and in the pooled sample (p = 6.661027) and in a meta-analysis of both the US and GIST datasets (1.361026, OR 2.17 (1.58–2.98 for the PRO allele). Conclusions: These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients., NHMRC: This study was supported by National Institutes of Health/National Eye Institute grants: R01EY015872 (Wiggs), R01EY015473 (Pasquale), P30EY014104 (Wiggs), Research to Prevent Blindness (Wiggs, Pasquale, Realini), the Harvard Glaucoma Center of Excellence (Wiggs, Pasquale), The Massachusetts Lions Eye Research Fund (Wiggs, Pasquale), National Health & Medical Research Council Project grant 229960, the Ophthalmic Research Institute of Australia, and Glaucoma Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Purpose. We sought to determine whether conjunctival ultraviolet autofluorescence (UVAF), a biomarker of outdoor light exposure, is associated with myopia. Methods. We performed a cross-sectional study on Norfolk Island and recruited individuals aged ≥15 years. Participants completed a sun-exposure questionnaire and underwent noncycloplegic autorefraction. Conjunctival UVAF used a specially adapted electronic flash system fitted with UV-transmission filters (transmittance range 300-400 nm, peak 365 nm) as the excitation source. Temporal and nasal conjunctival UVAF was measured in both eyes using computerized photographic analysis with the sum referred to as "total UVAF." Results. In 636 participants, prevalence of myopia decreased with an increasing quartile of total UVAF (P trend = 0.002). Median total UVAF was lower in subjects with myopia (spherical equivalent [SE] ≤ -1.0 diopter [D]) than participants without myopia: 16.6 mm 2 versus 28.6 mm 2, P = 0.001. In the multivariable model that adjusted for age, sex, smoking, cataract, height and weight, UVAF was independently associated with myopia (SE ≤ -1.0 D): odds ratio (OR) for total UVAF (per 10 mm 2) was 0.81, 95% confidence interval (CI) 0.69 to 0.94, P = 0.007. UVAF was also significantly associated with myopia when analysis was restricted to subjects

We thank Sabour and Ghassemi for their interest in our recent publication.1 Clearly the assessment of validity and reliability is important when developing a novel tool to objectively measure ocular ultraviolet radiation exposure. The concordance correlation coefficient (CCC) was used in our study because it provides a robust …

The cornea is a transparent structure that permits the refraction of light into the eye. Evidence from a range of studies indicates that central corneal thickness (CCT) is strongly genetically determined. Support for a genetic component comes from data showing significant variation in CCT between different human ethnic groups. Interestingly, these studies also appear to show that skin pigmentation may influence CCT. To validate these observations, we undertook the first analysis of CCT in an oculocutaneous albinism (OCA) and Ugandan cohort, populations with distinct skin pigmentation phenotypes. There was a significant difference in the mean CCT of the OCA, Ugandan and Australian-Caucasian cohorts (Ugandan: 517.3±37 µm; Caucasian: 539.7±32.8 µm, OCA: 563.3±37.2 µm; p

PURPOSE: To develop a fully automated algorithm (AP) to perform a volumetric measure of the optic disc using conventional stereoscopic optic nerve head (ONH) photographs, and to compare algorithm-produced parameters with manual photogrammetry (MP), scanning laser ophthalmoscope (SLO) and optical coherence tomography (OCT) measurements. METHODS: One hundred twenty-two stereoscopic optic disc photographs (61 subjects) were analyzed. Disc area, rim area, cup area, cup/disc area ratio, vertical cup/disc ratio, rim volume and cup volume were automatically computed by the algorithm. Latent variable measurement error models were used to assess measurement reproducibility for the four techniques. RESULTS: AP had better reproducibility for disc area and cup volume and worse reproducibility for cup/disc area ratio and vertical cup/disc ratio, when the measurements were compared to the MP, SLO and OCT methods. CONCLUSION: AP provides a useful technique for an objective quantitative assessment of 3D ONH structures.

George Kitsos1, Zacharias Petrou2, Maria Grigoriadou3, John R Samples4, Alex W Hewitt5, Haris Kokotas3, Aglaia Giannoulia-Karantana3, David A Mackey6, Mary K Wirtz4, Marilita Moschou7, John PA Ioannidis8, Michael B Petersen31Department of Ophthalmology, University of Ioannina, School of Medicine, Ioannina, Greece; 2Department of Ophthalmology, General Hospital of Ioannina “G Chatzikosta”, Ioannina, Greece; 3Department of Genetics, Institute of Child Health, Athens, Greece; 4Department of Ophthalmology, Casey Eye Institute-OHS U, Portland, OR; 5Department of Ophthalmology, Flinders University, Adelaide, Australia; 6Center for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; 7Department of Ophthalmology, University of Athens, School of Medicine, Athens, Greece; 8Department Hygiene and Epidemiology, University of Ioannina, School of Medicine, Ioannina, GreeceBackground: Mutations in the MYOC gene have been shown to explain 5% of unrelated primary open angle glaucoma (POAG) in different populations. In particular, the T377M MYOC mutation has arisen at least three separate times in history, in Great Britain, India, and Greece. The purpose of this study is to investigate the distribution of the mutation among different population groups in the northwestern region of Greece.Materials and methods: We explored the distribution of the “Greek” T377M founder mutation in the Epirus region in Northwestern Greece, which could be its origin. Genotyping was performed in POAG cases and controls by PCR amplification of the MYOC gene, followed by digestion with restriction enzyme. Statistical analyses were performed by an exact test, the Kaplan–Meier method and the t-test.Results: In the isolated Chrysovitsa village in the Pindus Mountains, a large POAG family demonstrated the T377M mutation in 20 of 66 family members while no controls from the Epirus region (n = 124) carried this mutation (P < 0.001). Among other POAG cases from Epirus, 2 out of 14 familial cases and 1 out of 80 sporadic cases showed the mutation (P = 0.057). The probability of POAG diagnosis with advancing age among mutation carriers was 23% at age 40, and reached 100% at age 75. POAG patients with the T377M mutation were diagnosed at a mean age of 51 years (SD ± 13.9), which is younger than the sporadic or familial POAG cases: 63.1 (SD ± 11) and 66.8 (SD ± 9.8) years, respectively.Conclusions: The T377M mutation was found in high proportion in members of the Chrysovitsa family (30.3%), in lower proportion in familial POAG cases (14.2%) and seems rare in sporadic POAG cases (1.2%), while no controls (0%) from the Epirus region carried the mutation. Historical and geographical data may explain the distribution of this mutation within Greece and worldwide.Keywords: primary open angle glaucoma, GLC1C, myocilin, MYOC, founder mutation

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10−10. The locus on chromosome 16 was associated with CCT with p = 8.95×10−11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population., Author Summary Central corneal thickness (CCT) is an important eye measurement. It has been considered as a prognosticator for the development of glaucoma, with a thin cornea potentially increasing the risk of developing a subtype known as open-angle glaucoma. CCT is highly heritable, yet its genetic determinants are poorly characterized. We have revealed two loci near gene FOXO1 and ZNF469 associated with CCT in this multi-stage genome-wide association study examining over 5,000 samples. It is of particular interest that, while rare mutations in ZNF469 cause Brittle Cornea Syndrome, more common variants near this gene also contribute to CCT variation in the general population. Furthermore, given the relation between CCT and glaucoma, results from our CCT studies will implement the search for the disease-susceptibility genes of glaucoma.

PURPOSE. Many ocular parameters show strong heritable tendencies. The significance of central corneal thickness (CCT) in the context of glaucoma has been the subject of much debate recently, but its heritability has not been extensively explored. This study was designed to investigate the parent-child heritability of CCT among groups who have CCT considered to be at the extreme ends of the normal range. METHODS. Index cases were recruited through a tertiary referral center if their CCT was greater than 578 mu m (thick) or less than 510 mu m (thin), representing +/- 1 SD from a previously published meta-analysis mean of 544 mu m (34 mu m SD). Subsequently, CCT was measured in all available family members of the index cases. Family units were then analyzed to establish the degree of heritability of CCT from parent to child. RESULTS. Thirty-three index cases were included in the analysis (10 > 1 SD and 23 > 1 SD from the meta-analysis CCT mean). The mean CCT of the children of index cases with a CCT more than 1 SD from the mean (n = 15) and less than 1 SD from the mean (n = 40) was 568 mu m (32 mu m SD) and 521 mu m (22 mu m SD), respectively (t = 6.14; P < 0.0001). The parent-child heritability estimate for CCT was h(2) = 0.68 (95% CI, 0.64-0.73). CONCLUSIONS. These results indicate that CCT shows strong parent-child heritability, with offspring likely to demonstrate CCT similar to the parental index case.

Purpose To estimate heritability and locate quantitative trait loci influencing axial length. Design Classic twin study of monozygotic and dizygotic twins reared together. Participants Eight hundred ninety-three individuals from 460 families were recruited through the Twin Eye Study in Tasmania and the Brisbane Adolescent Twin Study (BATS) and had ocular axial length measured. Methods Structural equation modeling on the entire sample was used to estimate genetic and environmental components of variation in axial length. Analysis of existing microsatellite marker genomewide linkage scan data was performed on 318 individuals from 142 BATS families. Main Outcome Measure Ocular axial length. Results The heritability estimate for axial length, adjusted for age and sex, in the full sample was 0.81. The highest multipoint logarithm of the odds (LOD) score observed was 3.40 (genomewide P = 0.0004), on chromosome 5q (at 98 centimorgans [cM]). Additional regions with suggestive multipoint LOD scores were also identified on chromosome 6 (LOD scores, 2.13 at 76 cM and 2.05 at 83 cM), chromosome 10 (LOD score, 2.03 at 131 cM), and chromosome 14 (LOD score, 2.84 at 97 cM). Conclusion Axial length, a major endophenotype for refractive error, is highly heritable and is likely to be influenced by one or more genes on the long arm of chromosome 5.

Objective To investigate whether structural differences of the optic nerve head are evident in young people who do not have manifest glaucoma but are known to carry myocilin mutations. Methods A case-control design was adopted. Subjects from Australian pedigrees known to have either the Gln368STOP myocilin mutation (cutoff age

Approximately 1 in 30 unselected patients with open-angle glaucoma (OAG) have a mutation in the myocilin gene. The purpose of this study was to describe the morphologic features of the optic nerve head (ONH) in myocilin glaucoma.A case-control design was adopted. Sixty-six patients heterozygous for a range of myocilin mutation (cases) were matched in disease severity to 105 patients with OAG known not to have a myocilin mutation (controls), using visual field findings. Quantifiable analysis of the ONH was undertaken of stereoscopic photographs, by using custom software with a z-screen. Subjective grading of the cup depth, lamina cribrosa pore shape and orientation, and the slope of the neuroretinal rim was performed by an examiner masked to the subject's mutation status. Mutation screening was conducted using either direct sequencing or single-stranded conformation polymorphism analysis.Patients with a myocilin mutation had glaucoma diagnosed earlier (P0.001) and had higher maximum recorded intraocular pressures (P0.001) than did the control OAG subjects. There was no significant (P0.05) difference in global disc area, global neuroretinal rim area, alpha-parapapillary atrophy, beta-parapapillary atrophy, slope of neuroretinal rim, or visible lamina cribrosa morphology between myocilin mutation carriers and patients with nonmyocilin glaucoma. Disc hemorrhages were identified more frequently in those without mutations (14/209 vs. 1/129), though this was not significant after correction for multiple hypothesis testing.No major structural or morphologic difference of the ONH was detected in pooled data from subjects who had myocilin mutations compared with data from individuals with nonmyocilin glaucoma.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited., Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Aberrant DNA methylation within the promoter of IL17RC in peripheral blood mononuclear cells has recently been reported in AMD. To validate this association, we examined DNA methylation of the IL17RC promoter in peripheral blood. First, we used Illumina Human Methylation450 Bead Arrays, a widely accepted platform for measuring global DNA methylation. Second, methylation status at multiple sites within the IL17RC promoter was determined by bisulfite pyrosequencing in two cohorts. Third, a methylation-sensitive quantitative PCR-based assay was performed on a subset of samples. In contrast to previous findings, we did not find evidence of differential methylation between AMD cases and age-matched controls. We conclude that hypomethylation within the IL17RC gene promoter in peripheral blood is not suitable for use as a clinical biomarker of AMD. This study highlights the need for considerable replication of epigenetic association studies prior to clinical application.

Background: The final common pathway for open angle glaucoma (OAG) is retinal ganglion cell apoptosis. Polymorphisms in p53, a major regulator of apoptosis, affect the efficiency of cell death induction. Association studies of p53 haplotypes and OAG have had conflicting results. Objective: To examine the association between p53 haplotypes and OAG in a larger white population than in previous reports, and extend the analysis to normal tension glaucoma. Methods: 345 unrelated people with OAG were recruited (283 subjects with high tension glaucoma and 62 with normal tension glaucoma) and compared with 178 age matched controls. Genomic DNA was analysed for the p53 codon 72 Arg/Pro polymorphism as well as for the presence or absence of a 16 bp intron 3 insertion. Results: In this white cohort no association was found between glaucoma (high or normal tension) and either sequence variant or haplotype. Conclusions: The p53 codon 72 Arg/Pro polymorphism is not associated with age of onset or severity of glaucoma.

The second author's name contained an error. Sim Xueling should be Xueling Sim. The correct citation is: Ikram MK, Sim X, Jensen RA, Cotch MF, Hewitt AW, et al. (2010) Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo. PLoS Genet 6(10): e1001184. doi:10.1371/journal.pgen.1001184.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Background Several individual studies have suggested that autosomal CpG methylation differs by sex both in terms of individual CpG sites and global autosomal CpG methylation. However, these findings have been inconsistent and plagued by spurious associations due to the cross reactivity of CpG probes on commercial microarrays. We collectively analysed 76 published studies (n = 6,795) for sex-associated differences in both autosomal and sex chromosome CpG sites. Results Overall autosomal methylation profiles varied substantially by study, and we encountered substantial batch effects. We accounted for these by conducting random effects meta-analysis for individual autosomal CpG methylation associations. After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing. In line with previous studies, average beta differences were small. Many of the most significantly associated CpG probes were new. Of note was differential CpG methylation in the promoters of genes thought to be involved in spermatogenesis and male fertility, such as SLC9A2, SPESP1, CRISP2, and NUPL1. Pathway analysis revealed overrepresentation of genes differentially methylated by sex in several broad Gene Ontology biological processes, including RNA splicing and DNA repair. Conclusions This study represents a comprehensive analysis of sex-specific methylation patterns. We demonstrate the existence of sex-specific methylation profiles and report a large number of novel DNA methylation differences in autosomal CpG sites between sexes. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-981) contains supplementary material, which is available to authorized users.