New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

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. ViswanathanSeyhan 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, Yih Chung Tham, Tiger Zhou, Elisabeth M. van Leeuwen, Stefan Nickels, Paul 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, Paulus T.V.M. de Jong, Ben A. Oostra, André G. Uitterlinden, Qiao Fan, Albert Hofman, NEIGHBORHOOD Consortium

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)438-453
Number of pages16
JournalHuman Molecular Genetics
Issue number2
Publication statusPublished - 2017


We gratefully acknowledge the contributions of all participants who volunteered within each cohort and the personnel responsible for the recruitment and administration of each study. We also thank the various funding sources that made this work possible. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Complete funding information and acknowledgements can be found in the Supplementary Material.Terri L. Young, MD, MBA is supported by National Institutes of Health/National Eye Institute (NIH/NEI) 1R01EY018246-01, NIH/NEI R01 EY014685, Research to Prevent Blindness, Inc. and The University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund. Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NH&MRC), Canberra Australia (974159, 211069, 457349, 512423, 475604, 529912); the Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases, 519923); NH&MRC research fellowships (358702, 632909 to J.J.W); and the Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster) for genotyping costs of the entire BMES population (085475/B/08/Z, 085475/Z/08/Z, 076113). The Southampton acknowledges funding from the UK and Eire Glaucoma Society and the International Glaucoma Association (in association with the Royal College of Ophthalmologists). EY015473 (LRP) supported generation of the cohort at risk for POAG in Nurses Health Study (NHS, UM1 CA186107) and Health Professionals Followup Study (HPFS, UM1 CA167552). HG004728 (LRP) supported genotyping in a subset of the Neighborhood consortium, specifically NHS, HPFS and Massachusetts Eye and Ear Infirmary (MEEI) cases and controls. We acknowledge funding from National Institutes of Health NIH R01 EY022305 (JLW) and NEI grant K08EY022943 (RW). Genetic analyses for the Orkney Complex Disease Study (ORCADES) were supported by the MRC HGU "QTL in Health and Disease" core programme.

FundersFunder number
Canberra Australia457349, 529912, 475604, 512423, 211069, 974159
Centre for Clinical Research Excellence
Eire Glaucoma Society
Massachusetts Eye and Ear Infirmary
Royal College of OphthalmologistsUM1 CA167552, HG004728, EY015473, UM1 CA186107
Translational Clinical Research in Major Eye Diseases519923, 632909, 358702
University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund
Wellcome Trust Case Control Consortium 2085475/Z/08/Z, 076113, 085475/B/08/Z
National Institutes of HealthR01 EY022305
National Eye Institute1R01EY018246-01, K08EY022943, R01 EY014685, P30EY014104
Research to Prevent Blindness
Wellcome Trust
International Glaucoma Association
National Health and Medical Research Council


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