Alex W Hewitt

University of Melbourne, Melbourne, Victoria, Australia

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Publications (188)1022.97 Total impact

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    ABSTRACT: We demonstrate that a combination of Noggin, Dickkopf-1, Insulin Growth Factor 1 and basic Fibroblast Growth Factor, promotes the differentiation of human pluripotent stem cells into retinal pigment epithelium (RPE) cells. We describe an efficient one-step approach that allows the generation of RPE cells from both human embryonic stem cells and human induced pluripotent stem cells within 40-60 days without the need for manual excision, floating aggregates or imbedded cysts. Compared to methods that rely on spontaneous differentiation, our protocol results in faster differentiation into RPE cells. This pro-retinal culture medium promotes the growth of functional RPE cells that exhibit key characteristics of the RPE including pigmentation, polygonal morphology, expression of mature RPE markers, electrophysiological membrane potential and the ability to phagocytose photoreceptor outer segments. This protocol can be adapted for feeder, feeder-free and serum-free conditions. This method thereby provides a rapid and simplified production of RPE cells for downstream applications such as disease modelling and drug screening.
    Stem Cell Reviews and Reports 11/2015; DOI:10.1007/s12015-015-9636-2 · 2.77 Impact Factor
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    ABSTRACT: Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.
    PLoS ONE 10/2015; 10(10):e0140919. DOI:10.1371/journal.pone.0140919 · 3.23 Impact Factor
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    ABSTRACT: Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.
    Genetic Epidemiology 10/2015; DOI:10.1002/gepi.21936 · 2.60 Impact Factor
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    ABSTRACT: Purpose: Elevated intraocular pressure (IOP) is the only known modifiable risk factor for primary open angle glaucoma (POAG), and it can be caused by reduced aqueous humor outflow from the anterior chamber. Outflow is predominantly regulated by the trabecular meshwork, consisting of specialized cells within a complex extracellular matrix (ECM). An imbalance between ECM-degrading matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) within the trabecular meshwork is thought to contribute to POAG. This study aimed to quantify levels of TIMPs and MMPs in aqueous humor samples from glaucomatous and non-glaucomatous eyes, analyze MMP/TIMP ratios, and correlate results with age, IOP, and Humphrey’s visual field pattern standard deviation (PSD). Methods: Aqueous humor samples were collected from 26 non-glaucomatous control subjects before cataract surgery and 23 POAG patients undergoing trabeculectomy or cataract surgery. Analyte concentrations were measured using multiplexed immunoassays. Statistical significance was assessed with Mann-Whitney U tests, and Spearman’s method was used to assess correlations with age, IOP, and PSD. Results: Concentrations of TIMP1 (p = 0.0008), TIMP2 (p = 0.002), TIMP4 (p = 0.002), and MMP2 (p = 0.020) were significantly increased in aqueous humor samples from POAG versus cataract samples. For the majority of MMP/TIMP molar ratios calculated for the cataract group, TIMPs outweighed MMPs. In POAG, molar ratios of MMP2/TIMP1 (p = 0.007) and MMP9/TIMP1 (p = 0.005) showed a significant decrease, corresponding to an elevated excess of TIMPs over MMPs in POAG compared to cataract samples. Conversely, MMP2/TIMP3 (p = 0.045) and MMP3/TIMP3 (p = 0.032) molar ratios increased. Several MMP/TIMP molar ratios correlated with IOP (r = 0.476-0.609, p = 0.007-0.034) and PSD (r =-0.482 to −0.655, p = 0.005-0.046) in POAG samples and with age in cataract control samples. Conclusions: An imbalance among MMPs and TIMPs was found in glaucomatous aqueous humor samples, with a shift toward raised TIMP levels. This may result in the inhibition of MMP activity, leading to an altered ECM composition in the TM and thereby contributing to increased outflow resistance.
    Molecular vision 10/2015; 21:1162-1172. · 1.99 Impact Factor

  • Mitochondrion 09/2015; 24:S21. DOI:10.1016/j.mito.2015.07.063 · 3.25 Impact Factor
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    ABSTRACT: Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 × 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays.
    Investigative ophthalmology & visual science 08/2015; 56(9):5087-5093. DOI:10.1167/iovs.15-17305 · 3.40 Impact Factor
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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; 58(10). DOI:10.1007/s00125-015-3697-2 · 6.67 Impact Factor
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    ABSTRACT: Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2(+) CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2(+) CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2(+) CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRα, ISL1 or WT1. W8B2(+) CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodelling, cell growth and survival. In vitro, conditioned medium collected from W8B2(+) CRSCs displayed pro-survival, pro-angiogenic and pro-migratory effects on endothelial cells, superior to that of other stem cells, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2(+) CRSCs into immunocompromised rats one week after myocardial infarction markedly improved cardiac function (∼40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2(+) CRSCs showed less adverse remodelling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67(+) cTnT(+) cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163(+) cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2(+) CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 07/2015; 33(10). DOI:10.1002/stem.2101 · 6.52 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 · 2.35 Impact Factor

  • International Society for Stem Cell Research annual meeting, Stockholm, Sweden; 06/2015
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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; 122(9). DOI:10.1016/j.ophtha.2015.05.004 · 6.14 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; 24(17). DOI:10.1093/hmg/ddv211 · 6.39 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; 133(7). DOI:10.1001/jamaophthalmol.2015.0980 · 3.32 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; 43(7). DOI:10.1111/ceo.12541 · 2.35 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 · 6.39 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 03/2015; 6:6689. DOI:10.1038/ncomms7689 · 11.47 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 · 29.35 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 · 3.92 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; 43(6). DOI:10.1111/ceo.12508 · 2.35 Impact Factor

Publication Stats

3k Citations
1,022.97 Total Impact Points


  • 2006-2015
    • University of Melbourne
      • • Centre for Eye Research Australia
      • • Department of Ophthalmology
      Melbourne, Victoria, Australia
  • 2005-2015
    • Royal Victorian Eye and Ear Hospital
      Melbourne, Victoria, Australia
    • 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
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 2005-2012
    • Flinders University
      • Department of Ophthalmology
      Tarndarnya, 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