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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    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.