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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    A saturated map of common genetic variants associated with human height
    Yengo, L ; Vedantam, S ; Marouli, E ; Sidorenko, J ; Bartell, E ; Sakaue, S ; Graff, M ; Eliasen, AU ; Jiang, Y ; Raghavan, S ; Miao, J ; Arias, JD ; Graham, SE ; Mukamel, RE ; Spracklen, CN ; Yin, X ; Chen, S-H ; Ferreira, T ; Highland, HH ; Ji, Y ; Karaderi, T ; Lin, K ; Lull, K ; Malden, DE ; Medina-Gomez, C ; Machado, M ; Moore, A ; Rueger, S ; Sim, X ; Vrieze, S ; Ahluwalia, TS ; Akiyama, M ; Allison, MA ; Alvarez, M ; Andersen, MK ; Ani, A ; Appadurai, V ; Arbeeva, L ; Bhaskar, S ; Bielak, LF ; Bollepalli, S ; Bonnycastle, LL ; Bork-Jensen, J ; Bradfield, JP ; Bradford, Y ; Braund, PS ; Brody, JA ; Burgdorf, KS ; Cade, BE ; Cai, H ; Cai, Q ; Campbell, A ; Canadas-Garre, M ; Catamo, E ; Chai, J-F ; Chai, X ; Chang, L-C ; Chang, Y-C ; Chen, C-H ; Chesi, A ; Choi, SH ; Chung, R-H ; Cocca, M ; Concas, MP ; Couture, C ; Cuellar-Partida, G ; Danning, R ; Daw, EW ; Degenhard, F ; Delgado, GE ; Delitala, A ; Demirkan, A ; Deng, X ; Devineni, P ; Dietl, A ; Dimitriou, M ; Dimitrov, L ; Dorajoo, R ; Ekici, AB ; Engmann, JE ; Fairhurst-Hunter, Z ; Farmaki, A-E ; Faul, JD ; Fernandez-Lopez, J-C ; Forer, L ; Francescatto, M ; Freitag-Wolf, S ; Fuchsberger, C ; Galesloot, TE ; Gao, Y ; Gao, Z ; Geller, F ; Giannakopoulou, O ; Giulianini, F ; Gjesing, AP ; Goel, A ; Gordon, SD ; Gorski, M ; Grove, J ; Guo, X ; Gustafsson, S ; Haessler, J ; Hansen, TF ; Havulinna, AS ; Haworth, SJ ; He, J ; Heard-Costa, N ; Hebbar, P ; Hindy, G ; Ho, Y-LA ; Hofer, E ; Holliday, E ; Horn, K ; Hornsby, WE ; Hottenga, J-J ; Huang, H ; Huang, J ; Huerta-Chagoya, A ; Huffman, JE ; Hung, Y-J ; Huo, S ; Hwang, MY ; Iha, H ; Ikeda, DD ; Isono, M ; Jackson, AU ; Jager, S ; Jansen, IE ; Johansson, I ; Jonas, JB ; Jonsson, A ; Jorgensen, T ; Kalafati, I-P ; Kanai, M ; Kanoni, S ; Karhus, LL ; Kasturiratne, A ; Katsuya, T ; Kawaguchi, T ; Kember, RL ; Kentistou, KA ; Kim, H-N ; Kim, YJ ; Kleber, ME ; Knol, MJ ; Kurbasic, A ; Lauzon, M ; Le, P ; Lea, R ; Lee, J-Y ; Leonard, HL ; Li, SA ; Li, X ; Li, X ; Liang, J ; Lin, H ; Lin, S-Y ; Liu, J ; Liu, X ; Lo, KS ; Long, J ; Lores-Motta, L ; Luan, J ; Lyssenko, V ; Lyytikainen, L-P ; Mahajan, A ; Mamakou, V ; Mangino, M ; Manichaikul, A ; Marten, J ; Mattheisen, M ; Mavarani, L ; McDaid, AF ; Meidtner, K ; Melendez, TL ; Mercader, JM ; Milaneschi, Y ; Miller, JE ; Millwood, IY ; Mishra, PP ; Mitchell, RE ; Mollehave, LT ; Morgan, A ; Mucha, S ; Munz, M ; Nakatochi, M ; Nelson, CP ; Nethander, M ; Nho, CW ; Nielsen, AA ; Nolte, IM ; Nongmaithem, SS ; Noordam, R ; Ntalla, I ; Nutile, T ; Pandit, A ; Christofidou, P ; Parna, K ; Pauper, M ; Petersen, ERB ; Petersen, L ; Pitkanen, N ; Polasek, O ; Poveda, A ; Preuss, MH ; Pyarajan, S ; Raffield, LM ; Rakugi, H ; Ramirez, J ; Rasheed, A ; Raven, D ; Rayner, NW ; Riveros, C ; Rohde, R ; Ruggiero, D ; Ruotsalainen, SE ; Ryan, KA ; Sabater-Lleal, M ; Saxena, R ; Scholz, M ; Sendamarai, A ; Shen, B ; Shi, J ; Shin, JH ; Sidore, C ; Sitlani, CM ; Slieker, RKC ; Smit, RAJ ; Smith, A ; Smith, JA ; Smyth, LJ ; Southam, LE ; Steinthorsdottir, V ; Sun, L ; Takeuchi, F ; Tallapragada, D ; Taylor, KD ; Tayo, BO ; Tcheandjieu, C ; Terzikhan, N ; Tesolin, P ; Teumer, A ; Theusch, E ; Thompson, DJ ; Thorleifsson, G ; Timmers, PRHJ ; Trompet, S ; Turman, C ; Vaccargiu, S ; van der Laan, SW ; van der Most, PJ ; van Klinken, JB ; van Setten, J ; Verma, SS ; Verweij, N ; Veturi, Y ; Wang, CA ; Wang, C ; Wang, L ; Wang, Z ; Warren, HR ; Wei, WB ; Wickremasinghe, AR ; Wielscher, M ; Wiggins, KL ; Winsvold, BS ; Wong, A ; Wu, Y ; Wuttke, M ; Xia, R ; Xie, T ; Yamamoto, K ; Yang, J ; Yao, J ; Young, H ; Yousri, NA ; Yu, L ; Zeng, L ; Zhang, W ; Zhang, X ; Zhao, J-H ; Zhao, W ; Zhou, W ; Zimmermann, ME ; Zoledziewska, M ; Adair, LS ; Adams, HHH ; Aguilar-Salinas, CA ; Al-Mulla, F ; Arnett, DK ; Asselbergs, FW ; Asvold, BO ; Attia, J ; Banas, B ; Bandinelli, S ; Bennett, DA ; Bergler, T ; Bharadwaj, D ; Biino, G ; Bisgaard, H ; Boerwinkle, E ; Boger, CA ; Bonnelykke, K ; Boomsma, D ; Borglum, AD ; Borja, JB ; Bouchard, C ; Bowden, DW ; Brandslund, I ; Brumpton, B ; Buring, JE ; Caulfield, MJ ; Chambers, JC ; Chandak, GR ; Chanock, SJ ; Chaturvedi, N ; Chen, Y-DI ; Chen, Z ; Cheng, C-Y ; Christophersen, IE ; Ciullo, M ; Cole, JW ; Collins, FS ; Cooper, RS ; Cruz, M ; Cucca, F ; Cupples, LA ; Cutler, MJ ; Damrauer, SM ; Dantoft, TM ; de Borst, GJ ; de Groot, LCPGM ; De Jager, PL ; de Kleijn, DP ; de Silva, HJ ; Dedoussis, G ; den Hollander, A ; Du, S ; Easton, DF ; Elders, PJM ; Eliassen, AH ; Ellinor, PT ; Elmstahl, S ; Erdmann, J ; Evans, MK ; Fatkin, D ; Feenstra, B ; Feitosa, MF ; Ferrucci, L ; Ford, I ; Fornage, M ; Franke, A ; Franks, PW ; Freedman, B ; Gasparini, P ; Gieger, C ; Girotto, G ; Goddard, ME ; Golightly, YM ; Gonzalez-Villalpando, C ; Gordon-Larsen, P ; Grallert, H ; Grant, SFA ; Grarup, N ; Griffiths, L ; Gudnason, V ; Haiman, C ; Hakonarson, H ; Hansen, T ; Hartman, CA ; Hattersley, AT ; Hayward, C ; Heckbert, SR ; Heng, C-K ; Hengstenberg, C ; Hewitt, AW ; Hishigaki, H ; Hoyng, CB ; Huang, PL ; Huang, W ; Hunt, SC ; Hveem, K ; Hypponen, E ; Iacono, WG ; Ichihara, S ; Ikram, MA ; Isasi, CR ; Jackson, RD ; Jarvelin, M-R ; Jin, Z-B ; Jockel, K-H ; Joshi, PK ; Jousilahti, P ; Jukema, JW ; Kahonen, M ; Kamatani, Y ; Kang, KD ; Kaprio, J ; Kardia, SLR ; Karpe, F ; Kato, N ; Kee, F ; Kessler, T ; Khera, A ; Khor, CC ; Kiemeney, LALM ; Kim, B-J ; Kim, EK ; Kim, H-L ; Kirchhof, P ; Kivimaki, M ; Koh, W-P ; Koistinen, HA ; Kolovou, GD ; Kooner, JS ; Kooperberg, C ; Kottgen, A ; Kovacs, P ; Kraaijeveld, A ; Kraft, P ; Krauss, RM ; Kumari, M ; Kutalik, Z ; Laakso, M ; Lange, LA ; Langenberg, C ; Launer, LJ ; Le Marchand, L ; Lee, H ; Lee, NR ; Lehtimaki, T ; Li, H ; Li, L ; Lieb, W ; Lin, X ; Lind, L ; Linneberg, A ; Liu, C-T ; Liu, J ; Loeffler, M ; London, B ; Lubitz, SA ; Lye, SJ ; Mackey, DA ; Magi, R ; Magnusson, PKE ; Marcus, GM ; Vidal, PM ; Martin, NG ; Marz, W ; Matsuda, F ; McGarrah, RW ; McGue, M ; McKnight, AJ ; Medland, SE ; Mellstrom, D ; Metspalu, A ; Mitchell, BD ; Mitchell, P ; Mook-Kanamori, DO ; Morris, AD ; Mucci, LA ; Munroe, PB ; Nalls, MA ; Nazarian, S ; Nelson, AE ; Neville, MJ ; Newton-Cheh, C ; Nielsen, CS ; Nothen, MM ; Ohlsson, C ; Oldehinkel, AJ ; Orozco, L ; Pahkala, K ; Pajukanta, P ; Palmer, CNA ; Parra, EJ ; Pattaro, C ; Pedersen, O ; Pennell, CE ; Penninx, BWJH ; Perusse, L ; Peters, A ; Peyser, PA ; Porteous, DJ ; Posthuma, D ; Power, C ; Pramstaller, PP ; Province, MA ; Qi, Q ; Qu, J ; Rader, DJ ; Raitakari, OT ; Ralhan, S ; Rallidis, LS ; Rao, DC ; Redline, S ; Reilly, DF ; Reiner, AP ; Rhee, SY ; Ridker, PM ; Rienstra, M ; Ripatti, S ; Ritchie, MD ; Roden, DM ; Rosendaal, FR ; Rotter, J ; Rudan, I ; Rutters, F ; Sabanayagam, C ; Saleheen, D ; Salomaa, V ; Samani, NJ ; Sanghera, DK ; Sattar, N ; Schmidt, B ; Schmidt, H ; Schmidt, R ; Schulze, MB ; Schunkert, H ; Scott, LJ ; Scott, RJ ; Sever, P ; Shiroma, EJ ; Shoemaker, MB ; Shu, X-O ; Simonsick, EM ; Sims, M ; Singh, JR ; Singleton, AB ; Sinner, MF ; Smith, JG ; Snieder, H ; Spector, TD ; Stampfer, MJ ; Stark, KJ ; Strachan, DP ; t' Hart, LM ; Tabara, Y ; Tang, H ; Tardif, J-C ; Thanaraj, TA ; Timpson, NJ ; Tonjes, A ; Tremblay, A ; Tuomi, T ; Tuomilehto, J ; Tusie-Luna, M-T ; Uitterlinden, AG ; van Dam, RM ; van der Harst, P ; Van der Velde, N ; van Duijn, CM ; van Schoor, NM ; Vitart, V ; Volker, U ; Vollenweider, P ; Volzke, H ; Wacher-Rodarte, NH ; Walker, M ; Wang, YX ; Wareham, NJ ; Watanabe, RM ; Watkins, H ; Weir, DR ; Werge, TM ; Widen, E ; Wilkens, LR ; Willemsen, G ; Willett, WC ; Wilson, JF ; Wong, T-Y ; Woo, J-T ; Wright, AF ; Wu, J-Y ; Xu, H ; Yajnik, CS ; Yokota, M ; Yuan, J-M ; Zeggini, E ; Zemel, BS ; Zheng, W ; Zhu, X ; Zmuda, JM ; Zonderman, AB ; Zwart, J-A ; Chasman, D ; Cho, YS ; Heid, IM ; McCarthy, M ; Ng, MCY ; O'Donnell, CJ ; Rivadeneira, F ; Thorsteinsdottir, U ; Sun, Y ; Tai, ES ; Boehnke, M ; Deloukas, P ; Justice, AE ; Lindgren, CM ; Loos, RJF ; Mohlke, KL ; North, KE ; Stefansson, K ; Walters, RG ; Winkler, TW ; Young, KL ; Loh, P-R ; Yang, J ; Esko, T ; Assimes, TL ; Auton, A ; Abecasis, GR ; Willer, CJ ; Locke, AE ; Berndt, S ; Lettre, G ; Frayling, TM ; Okada, Y ; Wood, AR ; Visscher, PM ; Hirschhorn, JN (NATURE PORTFOLIO, 2022-10-27)
    Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
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    Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
    Senabouth, A ; Daniszewski, M ; Lidgerwood, GE ; Liang, HH ; Hernandez, D ; Mirzaei, M ; Keenan, SN ; Zhang, R ; Han, X ; Neavin, D ; Rooney, L ; Sanchez, MIGL ; Gulluyan, L ; Paulo, JA ; Clarke, L ; Kearns, LS ; Gnanasambandapillai, V ; Chan, C-L ; Nguyen, U ; Steinmann, AM ; McCloy, RA ; Farbehi, N ; Gupta, VK ; Mackey, DA ; Bylsma, G ; Verma, N ; MacGregor, S ; Watt, MJ ; Guymer, RH ; Powell, JE ; Hewitt, AW ; Pebay, A (NATURE PORTFOLIO, 2022-07-26)
    There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.
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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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    Current state and future prospects of artificial intelligence in ophthalmology: a review
    Hogarty, DT ; Mackey, DA ; Hewitt, AW (WILEY, 2019-01)
    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)
    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)
    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.