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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

Publication year 2017
Published in Human Molecular Genetics
Authors E.M. van Leeuwen, P.T.V.M. de Jong, Henriët Springelkamp, Adriana I Iglesias, Aniket Mishra, René Höhn, Robert Wojciechowski, Anthony P Khawaja, Abhishek Nag, Ya Xing Wang, Jie Jin Wang, Gabriel Cuellar-Partida, Jane Gibson, Jessica N Cooke Bailey, Eranga N Vithana, Puya Gharahkhani, Thibaud Boutin, Wishal D Ramdas, Tanja Zeller, Robert N Luben, Ekaterina Yonova-Doing, Ananth C Viswanathan, Seyhan Yazar, Angela J Cree, Jonathan L Haines, Jia Yu Koh, Emmanuelle Souzeau, James F Wilson, Najaf Amin, Christian Müller, Cristina Venturini, Lisa S Kearns, Jae Hee Kang, Neighborhood Consortium, Yih Chung Tham, Tiger Zhou, Stefan Nickels, Paul G Sanfilippo, Jiemin Liao, Herma van der Linde, Wanting Zhao, Leonieke M E van Koolwijk, Li Zheng, Fernando Rivadeneira, Mani Baskaran, Sven J van der Lee, Shamira Perera, Ben A Oostra, André G Uitterlinden, Qiao Fan, Albert Hofman, E-Shyong Tai, Johannes R Vingerling, Xueling Sim, Roger C W Wolfs, Yik-Ying Teo, Hans G Lemij, Chiea-Chuen Khor, Rob Willemsen, Karl J Lackner, Tin Aung, Nomdo M Jansonius, Grant W Montgomery, Philipp S Wild, Terri L Young, Kathryn P Burdon, Pirro G Hysi, Louis R Pasquale, Tien-Yin Wong, Caroline C W Klaver, Alex W Hewitt, Jost B Jonas, Paul Mitchell, Andrew J Lotery, Paul J Foster, Veronique Vitart, Norbert Pfeiffer, Jamie E Craig, David A Mackey, Christopher J Hammond, Janey L Wiggs, Ching-Yu Cheng, Cornelia M van Duijn, Stuart Macgregor,
The order of authors may deviate from the original publication due to temporary technical issues.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase 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.

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