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

Author(s): Springelkamp H (1,2), Iglesias AI, Mishra A (3,4), Höhn R (5,6), Wojciechowski R, Khawaja AP (7), Nag A (8), Wang YX (9,10), Wang JJ (11), Cuellar (-)Partida G (3), Gibson J (12), Cooke Bailey JN (13), Vithana EN, Gharahkhani P (3), Boutin T (14), Ramdas WD (2), Zeller T (15), Luben RN (16), Yonova (-)Doing E (8), Viswanathan AC (7), Yazar S (17), Cree AJ (18), Haines JL (13), Koh JY (19), Souzeau E (20), Wilson JF (14,21), Amin N (1), Müller C (15), Venturini C (8), Kearns LS (22), Hee Kang J (23), Consortium N, Tham YC (19,24), Zhou T (20), van Leeuwen EM (1), Nickels S (6), Sanfilippo P (17,22), Liao J (19,24), Linde HV (25), Zhao W (19), van Koolwijk LM (1), Zheng L (19,26), Rivadeneira F (1,27,28), Baskaran M, van der Lee SJ (1), Perera S (19,29), de Jong PT, Oostra BA (25), Uitterlinden AG (1,27,28), Fan Q (19), Hofman A (1,28), Shyong Tai E (29,30,31), Vingerling JR (2), Sim X (31), Wolfs RC (2), Teo YY (31,32), Lemij HG (33), Khor CC (19,26), Willemsen R (25), Lackner KJ (5), Aung T (19,24), Jansonius NM (34), Montgomery G (35), Wild PS, Young TL (36), Burdon KP (37), Hysi PG (8), Pasquale LR (23,38), Wong TY, Klaver CC (1,2), Hewitt AW (22,37), Jonas JB (39), Mitchell P (11), Lotery AJ (18), Foster PJ (7), Vitart V (14), Pfeiffer N (6), Craig JE (20), Mackey DA (17,37), Hammond CJ (8), Wiggs JL (38), Cheng CY, van Duijn CM (1), MacGregor S (40)

1 1 Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
2 2 Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
3 4 Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
4 5 Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
5 6 Department of Ophthalmology, Inselspital, Bern, Switzerland.
6 7 Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
7 11 NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
8 12 Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
9 13 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
10 14 Beijing Ophthalmology and Visual Science Key Lab, Beijing, China.
11 15 Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
12 16 Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
13 17 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
14 21 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
15 22 Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
16 23 Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
17 24 Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
18 25 Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
19 18 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
20 26 Department of Ophthalmology, Flinders University, Adelaide, Australia.
21 27 Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Scotland, UK.
22 28Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
23 29 Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
24 20 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
25 3 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
26 30 Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
27 31 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
28 32 Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands.
29 19 Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
30 36 Department of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
31 37 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
32 38 Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
33 39 Glaucoma Service, The Rotterdam Eye Hospital, Rotterdam, the Netherlands.
34 40 Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
35 41 Department of Molecular Epidemiology, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia.
36 45 Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
37 46 School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
38 47 Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
39 48 Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
40 4 Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia. Stuart.MacGregor@qimrberghofer.edu.au.

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.

© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Hum Mol Genet. 2017 Jan 10. pii: ddw399. doi: 10.1093/hmg/ddw399

PMID: 28073927

http://www.ncbi.nlm.nih.gov/pubmed/28073927

Experimental Paper of the Month manager: Andreas Boehm