Alex W Hewitt

Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia

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Publications (180)1000.24 Total impact

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    ABSTRACT: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
    Diabetologia 07/2015; DOI:10.1007/s00125-015-3697-2 · 6.88 Impact Factor
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    ABSTRACT: P values associated with null hypothesis significance testing (NHST) are almost universal in the ophthalmic literature. A p value < 0.05 is traditionally considered as 'significant'. This concept may deflect further thought about the veracity of the results. P values influence the publishability of the data, and have flow-on effects for funding success and the direction of future research. Despite their importance, the problems inherent in p values have been recognized since their inception, and in more recent years have been increasingly highlighted in some scientific fields. In this review, we aim to bring the problems associated with p values and NHST to the attention of the ophthalmic research community. We do not offer a universal solution to the problem of determining the veracity of a scientific claim; however, we demonstrate the need for caution in interpreting "significant" p values by performing a Bayesian re-analysis of t-tests in the ophthalmic literature. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Ophthalmology 07/2015; DOI:10.1111/ceo.12570 · 1.95 Impact Factor
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    ABSTRACT: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Cross-sectional, case control study. White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
    Ophthalmology 06/2015; DOI:10.1016/j.ophtha.2015.05.004 · 6.17 Impact Factor
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    ABSTRACT: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency>5%). However, these studies typically ignore the large set of exonic variants whose minor allele frequency is usually low. In this study we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P=6.63x10(-10)) in WNT10A. This gene is 437kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study from Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland twin registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P=5.41x10(-5)). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 06/2015; DOI:10.1093/hmg/ddv211 · 6.68 Impact Factor
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    ABSTRACT: MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultra-high content platforms. We used extensive analytical tools to compute inter-and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical samples using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest.
    Scientific Reports 06/2015; 5. DOI:10.1038/srep10375 · 5.58 Impact Factor
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    ABSTRACT: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.
    Jama Ophthalmology 05/2015; DOI:10.1001/jamaophthalmol.2015.0980 · 3.83 Impact Factor
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    ABSTRACT: X-linked Retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Clinical and molecular characterisation of male and female individuals affected with XLRS in a consaguineous family. Consanguineous Eastern European-Australian family METHODS: Four clinically affected and nine unaffected family members were genetically and clinically characterised. DNA analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank (AIRDR). Clinical and molecular characterisation of the causative mutation in a consanguineous family with X-linked retinoschisis RESULTS: By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C>T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant whilst the males were hemizygous. Clinical and genetic characterisation of affected homozygous females in x-linked retinoschisis affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Ophthalmology 04/2015; DOI:10.1111/ceo.12541 · 1.95 Impact Factor
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    ABSTRACT: Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
    Human Molecular Genetics 04/2015; 24(13):3880-3892. DOI:10.1093/hmg/ddv128 · 6.68 Impact Factor
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    ABSTRACT: Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10(-217); non-Japanese: ORA allele = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.
    Nature Genetics 02/2015; 47(6). DOI:10.1038/ng.3226 · 29.65 Impact Factor
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    ABSTRACT: Mounting evidence suggests that individuals with schizophrenia have an underlying vulnerability to cardiovascular disease, and a recent study suggested that this vulnerability might be reflected in the retinal microvasculature. The purpose of this study was to test the hypothesis that the retinal microvessels reflect familial vulnerability to psychotic symptoms. Participants were 531 adolescent and young adult twins who took part in the Brisbane Longitudinal Twin Study and the Twins Eye Study in Tasmania. The twins had photographs taken of their retina when they were adolescents or young adults (M age=20.6years), and retinal vessel diameter was assessed using computer software. The twins completed an assessment of psychosis symptoms approximately six years later. We compared retinal venular diameters of individuals with one or more symptoms of psychosis (n=45), their unaffected co-twins (n=24), and controls (n=462). Individuals with one or more symptoms of psychosis had wider venules (standardized mean=0.29) than controls (standardized mean=-0.04; p=.03), and unaffected co-twins had venular diameters that were intermediate (standardized mean=0.13) between the two groups, suggesting that wide venules may represent a proxy marker of familial vulnerability to psychosis symptoms. Consistent with previous work, there were no differences in arteriolar diameter between individuals with and without symptoms of psychosis. Findings suggest that wide retinal venules may serve as a proxy marker of familial liability to psychosis symptoms. The pathophysiological mechanisms linking psychosis and cardiovascular disease may be operative from early in life, possibly at the level of the microvasculature. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; 164(1-3). DOI:10.1016/j.schres.2015.01.045 · 4.43 Impact Factor
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    ABSTRACT: The sequencing of the human genome, over a decade ago, was fundamental for developing personalised medicine. This is perhaps most apparent in the emergence of the direct-to-consumer (DTC) genetic testing market, which allows individuals to obtain information about their genetic profile and its many health and lifestyle implications. By circumventing the doctor-patient relationship, DTC genetic testing challenges the traditional model of healthcare delivery, and this raises concern among regulatory bodies worldwide. Genetics play an important role in the development of many eye diseases. However, little information is available describing the influence of the DTC industry in ophthalmology. In this review we examined DTC companies providing genetic test products for eye disease, giving a snapshot of the current market. Of all eye conditions, the majority of DTC companies provided susceptibility testing or risk assessment for age-related macular degeneration (AMD). For the 15 companies noted to offer products, we found considerable variation in the cost, scope and clarity of informational content of DTC genetic testing for ophthalmic conditions. The clinical utility of these tests currently remains in question and the AAO recommendations against routine testing for many conditions probably still apply. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Ophthalmology 02/2015; DOI:10.1111/ceo.12508 · 1.95 Impact Factor
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    ABSTRACT: Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7, and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n=8,105) we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β=0.44, p-value=1.87x10(-8), minor allele frequency=0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n=7,471) resulted in an effect size in the same direction that was significantly associated (β=0.16, p-value=0.04). The SNP was also significantly associated with POAG in two independent case-control studies (n=1,225 cases and n=4,117 controls; OR=1.53, p-value=1.99x10(-8)), especially with high-tension glaucoma (OR=1.66, p-value=2.81x10(-9); for normal-tension glaucoma OR=1.29, p-value=4.23x10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2, and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 01/2015; 24(9). DOI:10.1093/hmg/ddv027 · 6.68 Impact Factor
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    ABSTRACT: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. © 2015 WILEY PERIODICALS, INC.
    Genetic Epidemiology 01/2015; 39(3). DOI:10.1002/gepi.21886 · 2.95 Impact Factor
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    ABSTRACT: The regulation of miR-126 by rs4636297 single nucleotide polymorphism (SNP) has been implicated in the pathogenesis of neovascularisation by promoting vascular endothelial growth factor, suggesting it could be associated with sight threatening diabetic retinopathy (STDR), but has not been previously investigated or reported. A case control study of 531 individuals with diabetes was genotyped for the rs4636297 SNP, using the Sequenom iPLEX Gold chemistry. STDR included people with severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR). Association was tested using logistic regression analysis, adjusting for confounding variables. In an additive model, the A allele of rs4636297 SNP is significantly associated with STDR compared to people with none or mild diabetic retinopathy (DR) (odds ratio (OR) = 2.02, 95% confidence interval (CI) = 1.22-3.35, p = 0.006). The A allele of rs4636297, known to be the non-functional allele for post-translational regulation of miR-126, is associated with STDR. This finding suggests that this locus would be a potential therapeutic target for inhibiting the development of DR. © The Author(s) 2015.
    Diabetes & Vascular Disease Research 01/2015; 12(2). DOI:10.1177/1479164114560160 · 3.04 Impact Factor
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    ABSTRACT: Conjunctival UV autofluorescence (CUVAF) photography was developed to detect and characterize preclinical sunlight-induced ocular damage. Ocular sun exposure has been related to cases of pterygia and was recently negatively correlated with myopia. Hence, CUVAF has excellent potential as an objective biomarker of sun exposure. However, much variation in CUVAF has been observed, and the relative contributions of genes and environment to this variation have not yet been identified. To investigate sources of variation in CUVAF in relation to its potential clinical relevance. We performed a cross-sectional analysis of 3 population-based cohort studies in the general community, including the Twins Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Western Australian Pregnancy Cohort (Raine) Study. The twin studies were conducted between 2001 and 2009, and the 20-year follow-up of the Raine Study was completed between March 2010 and February 2012. We included genotypic and phenotypic data from 295 Australian families in the Tasmanian and Brisbane twin studies and from 661 participants in the 20-year follow-up of the Raine Study. We compared CUVAF levels in the 3 cohorts and performed a classic twin study to partition variation in CUVAF. We also conducted a genome-wide association analysis to identify specific genetic variants associated with CUVAF. The total area of CUVAF, heritability of CUVAF, and single-nucleotide polymorphisms (SNPs) associated with CUVAF from the genome-wide association study. Within twin cohorts, individuals living closer to the equator (latitude, 27.47° S) had higher levels of CUVAF compared with individuals from southern regions (latitude, 42.88° S) (median [interquartile range], 45.4 [26.8-68.5] vs 28.7 [15.0-42.3] mm2; P < .001). The variation in CUVAF explained by the additive genetic component was 0.37 (95% CI, 0.22-0.56), whereas the variation due to the common environment was 0.50 (95% CI; 0.29-0.71). The SNP rs1060043, located approximately 800 base pairs away from the SLC1A5 gene, a member of the solute carrier family 1, had a genome-wide significant association with a P value of 3.2 × 10-8. Gene-based analysis did not improve our power to detect association with other genes. Our findings confirm that, although a large environmental component to CUVAF (equivalent of sun exposure) exists, genes also play a significant role. We identified a SNP (rs1060043) as being significantly associated with CUVAF; replication of this finding in future studies is warranted.
    Jama Ophthalmology 01/2015; DOI:10.1001/jamaophthalmol.2014.5627 · 3.83 Impact Factor
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    ABSTRACT: PurposeAstigmatism is a common cause of refractive error and is known to vary in prevalence with age. Although the search for genes associated with spherical refractive errors (especially myopia) has met with limited success, current efforts to identify genetic variants implicated in astigmatism development have been less rewarding. We aimed to assess the association between astigmatism and age to identify appropriate age cut-offs for maximizing power in genetic studies of astigmatism.Methods We performed a cross-sectional analysis of right eye astigmatism data from four Australian-based eye studies comprising 3841 participants aged 5–90 years. Measurements were performed under cycloplegia using an autorefractor, and individuals with a history of cataract, refractive surgery or corneal pathology were excluded from the analysis. In addition to the magnitude and type (against-the-rule, with-the-rule, and oblique) of astigmatism, we calculated the vector components (J0, J45) and evaluated the association of these outcome measures with age.ResultsThe magnitude of refractive astigmatism (RA) remained relatively stable [mean ± SD (−0.44 D ± 0.50)] until individuals reached the age of 50, thereafter increasing in average magnitude by approximately 1.00 D for those subjects aged 90. In contrast, corneal astigmatism (CA) remained relatively stable from childhood until the age of 80 (−0.76 D ± 0.61). The prevalence of clinically significant RA (≥1.00 D) increased with age and was highest in those aged >70 years [55.1% (47.2–62.7%)]. Age was significantly associated with RA in adults [odds ratio (OR) = 1.04 per 1 year, p < 0.001]. A weaker relationship was observed between CA and age (OR = 1.007 per 1 year, p = 0.02).Conclusions We have confirmed the previously documented association between RA and age. Our results indicate that most of the observed change occurs after the age of 50, providing a recommended cut-off for participants in genetic studies of this refractive condition.
    Acta ophthalmologica 01/2015; DOI:10.1111/aos.12644 · 2.51 Impact Factor
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    ABSTRACT: Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.
    Nature Communications 01/2015; 6:6689. DOI:10.1038/ncomms7689 · 10.74 Impact Factor
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    ABSTRACT: 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. 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. 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.
    BMC Genomics 11/2014; 15(1):981. DOI:10.1186/1471-2164-15-981 · 4.04 Impact Factor
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    ABSTRACT: 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 <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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    ABSTRACT: Objective: Previous longitudinal studies suggest that depression and anxiety are associated with risk for cardiovascular disease. The aim of the present study was to test whether an association between depression and anxiety symptoms and retinal vessel caliber, an indicator of subclinical cardiovascular risk, is apparent as early as adolescence and young adulthood. Methods: Participants were 865 adolescents and young adults who participated in the Brisbane Longitudinal Twin Study and the Twin Eye Study in Tasmania. Participants completed an assessment of depression/anxiety symptoms (the Somatic and Psychological Health Report) when they were 16.5 years old (mean age), and they underwent retinal imaging, on average, 2.5 years later (range, 2 years before to 7 years after the depression/anxiety assessment). Retinal vessel caliber was assessed using computer software. Results: Depression and anxiety symptoms were associated with wider retinal arteriolar caliber in this sample of adolescents and young adults (β = 0.09, p = .016), even after adjusting for other cardiovascular risk factors (β = 0.08, p = .025). Multiple regression analyses revealed that affective symptoms of depression/anxiety were associated with retinal vessel caliber independently of somatic symptoms. Conclusions: Depression and anxiety symptoms are associated with measurable signs in the retinal microvasculature in early life, suggesting that pathological microvascular mechanisms linking depression/anxiety and cardiovascular disease may be operative from a young age.
    Psychosomatic Medicine 11/2014; 76(9). DOI:10.1097/PSY.0000000000000117 · 4.09 Impact Factor

Publication Stats

2k Citations
1,000.24 Total Impact Points


  • 2007–2015
    • Royal Victorian Eye and Ear Hospital
      Melbourne, Victoria, Australia
    • University of Iowa
      Iowa City, Iowa, United States
  • 2006–2015
    • University of Melbourne
      • • Centre for Eye Research Australia
      • • Department of Ophthalmology
      Melbourne, Victoria, Australia
  • 2005–2015
    • University of Tasmania
      • • School of Medicine
      • • Menzies Research Institute
      Hobart Town, Tasmania, Australia
  • 2012–2014
    • University of Western Australia
      • Lions Eye Institute
      Perth City, Western Australia, Australia
  • 2008–2014
    • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 2013
    • University of Washington Seattle
      • Cardiovascular Health Research Unit (CHRU)
      Seattle, Washington, United States
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
  • 2006–2013
    • Flinders University
      • Department of Ophthalmology
      Adelaide, South Australia, Australia
  • 2010
    • King's College London
      • Department of Twin Research and Genetic Epidemiology
      London, ENG, United Kingdom
  • 2005–2006
    • The Royal Hobart Hospital
      Hobart Town, Tasmania, Australia