Centre for Eye Research Australia (CERA) - Research Publications

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    Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort
    Souzeau, E ; Siggs, OM ; Mullany, S ; Schmidt, JM ; Hassall, MM ; Dubowsky, A ; Chappell, A ; Breen, J ; Bae, H ; Nicholl, J ; Hadler, J ; Kearns, LS ; Staffieri, SE ; Hewitt, AW ; Mackey, DA ; Gupta, A ; Burdon, KP ; Klebe, S ; Craig, JE ; Mills, RA (WILEY, 2022-10)
    Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well-characterised cohort of 58 individuals from 44 families with different types of corneal dystrophy. Individuals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.
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    Attitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals
    Hollitt, GL ; Siggs, OM ; Ridge, B ; Keane, MC ; Mackey, DA ; MacGregor, S ; Hewitt, AW ; Craig, JE ; Souzeau, E (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-10)
    PURPOSE: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an individual's risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected individuals toward PRS testing for glaucoma, and sought to identify factors associated with interest in testing. METHODS: We surveyed 418 unaffected individuals including 193 with a first-degree relative with glaucoma, 117 who had a recent eye examination, and 108 general members of the community. RESULTS: Overall, 71.3% of the individuals indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (odds ratio [OR] = 14.58, 95% confidence interval [CI] = 1.15-185.50, P = 0.039), those concerned about developing glaucoma (OR = 4.37, 95% CI = 2.32-8.25, P < 0.001), those with an intention to take appropriate measures regarding eye health (OR = 2.39, 95% CI = 1.16-4.95, P = 0.019), and those preferring to know if considered to be at-risk or not (OR = 4.52, 95% CI = 2.32-8.83, P < 0.001). CONCLUSIONS: Our results show strong interest in genetic risk assessment for glaucoma among unaffected individuals in Australia. TRANSLATIONAL RELEVANCE: These findings represent a valuable assessment of interest in glaucoma polygenic risk testing among potential target populations, which will be integral to the implementation and uptake of novel PRS-based tests into clinical practice.
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    Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma
    Daniszewski, M ; Senabouth, A ; Liang, HH ; Han, X ; Lidgerwood, GE ; Hernandez, D ; Sivakumaran, P ; Clarke, JE ; Lim, SY ; Lees, JG ; Rooney, L ; Gulluyan, L ; Souzeau, E ; Graham, SL ; Chan, C-L ; Nguyen, U ; Farbehi, N ; Gnanasambandapillai, V ; Mccloy, RA ; Clarke, L ; Kearns, LS ; Mackey, DA ; Craig, JE ; Macgregor, S ; Powell, JE ; Pebay, A ; Hewitt, AW (ELSEVIER, 2022-06-08)
    To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
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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)
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    The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort
    Siggs, OM ; Awadalla, MS ; Souzeau, E ; Staffieri, SE ; Kearns, LS ; Laurie, K ; Kuot, A ; Qassim, A ; Edwards, TL ; Coote, MA ; Mancel, E ; Walland, MJ ; Dondey, J ; Galanopoulous, A ; Casson, RJ ; Mills, RA ; MacArthur, DG ; Ruddle, JB ; Burdon, KP ; Craig, JE (WILEY, 2020-05)
    Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
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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)
    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 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)
    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)
    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.
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    Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium
    Li, Q ; Wojciechowski, R ; Simpson, CL ; Hysi, PG ; Verhoeven, VJM ; Ikram, MK ; Hoehn, R ; Vitart, V ; Hewitt, AW ; Oexle, K ; Makela, K-M ; MacGregor, S ; Pirastu, M ; Fan, Q ; Cheng, C-Y ; St Pourcain, B ; McMahon, G ; Kemp, JP ; Northstone, K ; Rahi, JS ; Cumberland, PM ; Martin, NG ; Sanfilippo, PG ; Lu, Y ; Wang, YX ; Hayward, C ; Polasek, O ; Campbell, H ; Bencic, G ; Wright, AF ; Wedenoja, J ; Zeller, T ; Schillert, A ; Mirshahi, A ; Lackner, K ; Yip, SP ; Yap, MKH ; Ried, JS ; Gieger, C ; Murgia, F ; Wilson, JF ; Fleck, B ; Yazar, S ; Vingerling, JR ; Hofman, A ; Uitterlinden, A ; Rivadeneira, F ; Amin, N ; Karssen, L ; Oostra, BA ; Zhou, X ; Teo, Y-Y ; Tai, ES ; Vithana, E ; Barathi, V ; Zheng, Y ; Siantar, RG ; Neelam, K ; Shin, Y ; Lam, J ; Yonova-Doing, E ; Venturini, C ; Hosseini, SM ; Wong, H-S ; Lehtimaki, T ; Kahonen, M ; Raitakari, O ; Timpson, NJ ; Evans, DM ; Khor, C-C ; Aung, T ; Young, TL ; Mitchell, P ; Klein, B ; van Duijn, CM ; Meitinger, T ; Jonas, JB ; Baird, PN ; Mackey, DA ; Wong, TY ; Saw, S-M ; Parssinen, O ; Stambolian, D ; Hammond, CJ ; Klaver, CCW ; Williams, C ; Paterson, AD ; Bailey-Wilson, JE ; Guggenheim, JA (SPRINGER, 2015-02)
    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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    Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process
    Springelkamp, H ; Hoehn, R ; Mishra, A ; Hysi, PG ; Khor, C-C ; Loomis, SJ ; Bailey, JNC ; Gibson, J ; Thorleifsson, G ; Janssen, SF ; Luo, X ; Ramdas, WD ; Vithana, E ; Nongpiur, ME ; Montgomery, G ; Xu, L ; Mountain, JE ; Gharahkhani, P ; Lu, Y ; Amin, N ; Karssen, LC ; Sim, K-S ; van Leeuwen, EM ; Iglesias, AI ; Verhoeven, VJM ; Hauser, MA ; Loon, S-C ; Despriet, DDG ; Nag, A ; Venturini, C ; Sanfilippo, PG ; Schillert, A ; Kang, JH ; Landers, J ; Jonasson, F ; Cree, AJ ; van Koolwijk, LME ; Rivadeneira, F ; Souzeau, E ; Jonsson, V ; Menon, G ; Weinreb, RN ; de Jong, PTVM ; Oostra, BA ; Uitterlinden, AG ; Hofman, A ; Ennis, S ; Thorsteinsdottir, U ; Burdon, KP ; Spector, TD ; Mirshahi, A ; Saw, S-M ; Vingerling, JR ; Teo, Y-Y ; Haines, JL ; Wolfs, RCW ; Lemij, HG ; Tai, E-S ; Jansonius, NM ; Jonas, JB ; Cheng, C-Y ; Aung, T ; Viswanathan, AC ; Klaver, CCW ; Craig, JE ; Macgregor, S ; Mackey, DA ; Lotery, AJ ; Stefansson, K ; Bergen, AAB ; Young, TL ; Wiggs, JL ; Pfeiffer, N ; Wong, T-Y ; Pasquale, LR ; Hewitt, AW ; van Duijn, CM ; Hammond, CJ (NATURE PORTFOLIO, 2014-09)
    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.