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New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
journal contributionposted on 2023-05-19, 05:22 authored by Springelkamp, H, Iglesias, AI, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Cooke Bailey, JN, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, WD, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, N, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, J, van der Linde, H, Zhao, W, van Koolwijk, LME, Zheng, L, Rivadeneira, F, Baskaran, M, van der Lee, SJ, Perera, S, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Fan, Q, Hofman, A, Tai, E-S, Vingerling, JR, Sim, X, Wolfs, RCW, Teo, YY, Lemij, HG, Khor, CC, Willemsen, R, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Kathryn BurdonKathryn Burdon, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, CCW, Alexander HewittAlexander Hewitt, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, David MackeyDavid Mackey, Hammond, CJ, Wiggs, JL, Cheng, C-Y, van Duijn, CM, MacGregor, S
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.
Publication titleHuman Molecular Genetics
Department/SchoolMenzies Institute for Medical Research
PublisherOxford Univ Press
Place of publicationGreat Clarendon St, Oxford, England, Ox2 6Dp
Rights statementCopyright The Author 2017. Published by Oxford University Press. All rights reserved.