Centre for Eye Research Australia (CERA) - Research Publications

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    Seeing the impact of the Glaucoma Inheritance Study in Tasmania after 25 years
    Mackey, DA ; Craig, JE ; Hewitt, AW (WILEY, 2019-07-01)
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    Current state and future prospects of artificial intelligence in ophthalmology: a review
    Hogarty, DT ; Mackey, DA ; Hewitt, AW (WILEY, 2019-01-01)
    Artificial intelligence (AI) has emerged as a major frontier in computer science research. Although AI has broad application across many medical fields, it will have particular utility in ophthalmology and will dramatically change the diagnostic and treatment pathways for many eye conditions such as corneal ectasias, glaucoma, age-related macular degeneration and diabetic retinopathy. However, given that AI has primarily been driven as a computer science, its concepts and terminology are unfamiliar to many medical professionals. Important key terms such as machine learning and deep learning are often misunderstood and incorrectly used interchangeably. This article presents an overview of AI and new developments relevant to ophthalmology.
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    Plurality in multi-disciplinary research: multiple institutional affiliations are associated with increased citations
    Sanfilippo, P ; Hewitt, AW ; Mackey, DA (PEERJ INC, 2018-09-24)
    BACKGROUND: The institutional affiliations and associated collaborative networks that scientists foster during their research careers are salient in the production of high-quality science. The phenomenon of multiple institutional affiliations and its relationship to research output remains relatively unexplored in the literature. METHODS: We examined 27,612 scientific articles, modelling the normalized citation counts received against the number of authors and affiliations held. RESULTS: In agreement with previous research, we found that teamwork is an important factor in high impact papers, with average citations received increasing concordant with the number of co-authors listed. For articles with more than five co-authors, we noted an increase in average citations received when authors with more than one institutional affiliation contributed to the research. DISCUSSION: Multiple author affiliations may play a positive role in the production of high-impact science. This increased researcher mobility should be viewed by institutional boards as meritorious in the pursuit of scientific discovery.
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    Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus
    Fan, BJ ; Chen, X ; Sondhi, N ; Sharmila, PF ; Soumittra, N ; Sripriya, S ; Sacikala, S ; Asokan, R ; Friedman, DS ; Pasquale, LR ; Gao, XR ; Vijaya, L ; Bailey, JC ; Vitart, V ; MacGregor, S ; Hammond, CJ ; Khor, CC ; Haines, JL ; George, R ; Wiggs, JL (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-05-01)
    Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = -0.57, 95% confidence interval [CI]: -0.78 to -0.36; P = 1.7 × 10-7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = -3.94, 95% CI: -5.23 to -2.66; P = 1.7 × 10-9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.
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    Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect
    Shaaban, S ; MacKinnon, S ; Andrews, C ; Staffieri, SE ; Maconachie, GDE ; Chan, W-M ; Whitman, MC ; Morton, SU ; Yazar, S ; MacGregor, S ; Elder, JE ; Traboulsi, EI ; Gottlob, I ; Hewitt, AW ; Hunter, DG ; Mackey, DA ; Engle, EC (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-08-01)
    Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.
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    Longitudinal expression profiling of CD4+and CD8+cells in patients with active to quiescent giant cell arteritis
    De Smit, E ; Lukowski, SW ; Anderson, L ; Senabouth, A ; Dauyey, K ; Song, S ; Wyse, B ; Wheeler, L ; Chen, CY ; Cao, K ; Ten Yuen, AW ; Shuey, N ; Clarke, L ; Sanchez, IL ; Hung, SSC ; Pebay, A ; Mackey, DA ; Brown, MA ; Hewitt, AW ; Powell, JE (BMC, 2018-07-23)
    BACKGROUND: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. METHODS: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. RESULTS: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. CONCLUSIONS: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.
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    Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium
    Verhoeven, VJM ; Hysi, PG ; Saw, S-M ; Vitart, V ; Mirshahi, A ; Guggenheim, JA ; Cotch, MF ; Yamashiro, K ; Baird, PN ; Mackey, DA ; Wojciechowski, R ; Ikram, MK ; Hewitt, AW ; Duggal, P ; Janmahasatian, S ; Khor, C-C ; Fan, Q ; Zhou, X ; Young, TL ; Tai, E-S ; Goh, L-K ; Li, Y-J ; Aung, T ; Vithana, E ; Teo, Y-Y ; Tay, W ; Sim, X ; Rudan, I ; Hayward, C ; Wright, AF ; Polasek, O ; Campbell, H ; Wilson, JF ; Fleck, BW ; Nakata, I ; Yoshimura, N ; Yamada, R ; Matsuda, F ; Ohno-Matsui, K ; Nag, A ; McMahon, G ; St Pourcain, B ; Lu, Y ; Rahi, JS ; Cumberland, PM ; Bhattacharya, S ; Simpson, CL ; Atwood, LD ; Li, X ; Raffel, LJ ; Murgia, F ; Portas, L ; Despriet, DDG ; van Koolwijk, LME ; Wolfram, C ; Lackner, KJ ; Toenjes, A ; Maegi, R ; Lehtimaki, T ; Kahonen, M ; Esko, T ; Metspalu, A ; Rantanen, T ; Parssinen, O ; Klein, BE ; Meitinger, T ; Spector, TD ; Oostra, BA ; Smith, AV ; de Jong, PTVM ; Hofman, A ; Amin, N ; Karssen, LC ; Rivadeneira, F ; Vingerling, JR ; Eiriksdottir, G ; Gudnason, V ; Doering, A ; Bettecken, T ; Uitterlinden, AG ; Williams, C ; Zeller, T ; Castagne, R ; Oexle, K ; van Duijn, CM ; Iyengar, SK ; Mitchell, P ; Wang, JJ ; Hoehn, R ; Pfeiffer, N ; Bailey-Wilson, JE ; Stambolian, D ; Wong, T-Y ; Hammond, CJ ; Klaver, CCW (SPRINGER, 2012-09-01)
    Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
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    Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability
    Hysi, PG ; Valdes, AM ; Liu, F ; Furlotte, NA ; Evans, DM ; Bataille, V ; Visconti, A ; Hemani, G ; McMahon, G ; Ring, SM ; Smith, GD ; Duffy, DL ; Zhu, G ; Gordon, SD ; Medland, SE ; Lin, BD ; Willemsen, G ; Hottenga, JJ ; Vuckovic, D ; Girotto, G ; Gandin, I ; Sala, C ; Concas, MP ; Brumat, M ; Gasparini, P ; Toniolo, D ; Cocca, M ; Robino, A ; Yazar, S ; Hewitt, AW ; Chen, Y ; Zeng, C ; Uitterlinden, AG ; Ikram, MA ; Hamer, MA ; van Duijn, CM ; Nijsten, T ; Mackey, DA ; Falchi, M ; Boomsma, DI ; Martin, NG ; Hinds, DA ; Kayser, M ; Spector, TD (NATURE PUBLISHING GROUP, 2018-05-01)
    Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
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    Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
    Bailey, JNC ; Loomis, SJ ; Kang, JH ; Allingham, RR ; Gharahkhani, P ; Khor, CC ; Burdon, KP ; Aschard, H ; Chasman, DI ; Igo, RP ; Hysi, PG ; Glastonbury, CA ; Ashley-Koch, A ; Brilliant, M ; Brown, AA ; Budenz, DL ; Buil, A ; Cheng, C-Y ; Choi, H ; Christen, WG ; Curhan, G ; De Vivo, I ; Fingert, JH ; Foster, PJ ; Fuchs, C ; Gaasterland, D ; Gaasterland, T ; Hewitt, AW ; Hu, F ; Hunter, DJ ; Khawaja, AP ; Lee, RK ; Li, Z ; Lichter, PR ; Mackey, DA ; McGuffin, P ; Mitchell, P ; Moroi, SE ; Perera, SA ; Pepper, KW ; Qi, Q ; Realini, T ; Richards, JE ; Ridker, PM ; Rimm, E ; Ritch, R ; Ritchie, M ; Schuman, JS ; Scott, WK ; Singh, K ; Sit, AJ ; Song, YE ; Tamimi, RM ; Topouzis, F ; Viswanathan, AC ; Verma, SS ; Vollrath, D ; Wang, JJ ; Weisschuh, N ; Wissinger, B ; Wollstein, G ; Wong, TY ; Yaspan, BL ; Zack, DJ ; Zhang, K ; Weinreb, RN ; Pericak-Vance, MA ; Small, K ; Hammond, CJ ; Aung, T ; Liu, Y ; Vithana, EN ; MacGregor, S ; Craig, JE ; Kraftl, P ; Howell, G ; Hauser, MA ; Pasguale, LR ; Haines, JL ; Wiggs, JL (NATURE PUBLISHING GROUP, 2016-02-01)
    Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
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    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
    Fritsche, LG ; Igl, W ; Bailey, JNC ; Grassmann, F ; Sengupta, S ; Bragg-Gresham, JL ; Burdon, KP ; Hebbring, SJ ; Wen, C ; Gorski, M ; Kim, IK ; Cho, D ; Zack, D ; Souied, E ; Scholl, HPN ; Bala, E ; Lee, KE ; Hunter, DJ ; Sardell, RJ ; Mitchell, P ; Merriam, JE ; Cipriani, V ; Hoffman, JD ; Schick, T ; Lechanteur, YTE ; Guymer, RH ; Johnson, MP ; Jiang, Y ; Stanton, CM ; Buitendijk, GHS ; Zhan, X ; Kwong, AM ; Boleda, A ; Brooks, M ; Gieser, L ; Ratnapriya, R ; Branham, KE ; Foerster, JR ; Heckenlively, JR ; Othman, MI ; Vote, BJ ; Liang, HH ; Souzeau, E ; McAllister, IL ; Isaacs, T ; Hall, J ; Lake, S ; Mackey, DA ; Constable, IJ ; Craig, JE ; Kitchner, TE ; Yang, Z ; Su, Z ; Luo, H ; Chen, D ; Hong, O ; Flagg, K ; Lin, D ; Mao, G ; Ferreyra, H ; Starke, K ; von Strachwitz, CN ; Wolf, A ; Brandl, C ; Rudolph, G ; Olden, M ; Morrison, MA ; Morgan, DJ ; Schu, M ; Ahn, J ; Silvestri, G ; Tsironi, EE ; Park, KH ; Farrer, LA ; Orlin, A ; Brucker, A ; Li, M ; Curcio, CA ; Mohand-Said, S ; Sahel, J-M ; Audo, I ; Benchaboune, M ; Cree, AJ ; Rennie, CA ; Goverdhan, SV ; Grunin, M ; Hagbi-Levi, S ; Campochiaro, P ; Katsanis, N ; Holz, FG ; Blond, F ; Blanche, H ; Deleuze, J-F ; Igo, RP ; Truitt, B ; Peachey, NS ; Meuer, SM ; Myers, CE ; Moore, EL ; Klein, R ; Hauser, MA ; Postel, EA ; Courtenay, MD ; Schwartz, SG ; Kovach, JL ; Scott, WK ; Liew, G ; Tan, AG ; Gopinath, B ; Merriam, JC ; Smith, RT ; Khan, JC ; Shahid, H ; Moore, AT ; McGrath, JA ; Laux, R ; Brantley, MA ; Agarwal, A ; Ersoy, L ; Caramoy, A ; Langmann, T ; Saksens, NTM ; de Jong, EK ; Hoyng, CB ; Cain, MS ; Richardson, AJ ; Martin, TM ; Blangero, J ; Weeks, DE ; Dhillon, B ; van Duijn, CM ; Doheny, KF ; Romm, J ; Klaver, CCW ; Hayward, C ; Gorin, MB ; Klein, ML ; Baird, PN ; den Hollander, AI ; Fauser, S ; Yates, JRW ; Allikmets, R ; Wang, JJ ; Schaumberg, DA ; Klein, BEK ; Hagstrom, SA ; Chowers, I ; Lotery, AJ ; Leveillard, T ; Zhang, K ; Brilliant, MH ; Hewitt, AW ; Swaroop, A ; Chew, EY ; Pericak-Vance, MA ; DeAngelis, M ; Stambolian, D ; Haines, JL ; Iyengar, SK ; Weber, BHF ; Abecasis, GR ; Heid, IM (NATURE PUBLISHING GROUP, 2016-02-01)
    Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.