TY - JOUR
T1 - New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
AU - NEIGHBORHOOD Consortium
AU - Springelkamp, Henriët
AU - Iglesias, Adriana I.
AU - Mishra, Aniket
AU - Höhn, René
AU - Wojciechowski, Robert
AU - Khawaja, Anthony P.
AU - Nag, Abhishek
AU - Wang, Ya Xing
AU - Wang, Jie Jin
AU - Cuellar-Partida, Gabriel
AU - Gibson, Jane
AU - Cooke Bailey, Jessica N.
AU - Vithana, Eranga N.
AU - Gharahkhani, Puya
AU - Boutin, Thibaud
AU - Ramdas, Wishal D.
AU - Zeller, Tanja
AU - Luben, Robert N.
AU - Yonova-Doing, Ekaterina
AU - Viswanathan, Ananth C.
AU - Yazar, Seyhan
AU - Cree, Angela J.
AU - Haines, Jonathan L.
AU - Koh, Jia Yu
AU - Souzeau, Emmanuelle
AU - Wilson, James F.
AU - Amin, Najaf
AU - Müller, Christian
AU - Venturini, Cristina
AU - Kearns, Lisa S.
AU - Kang, Jae Hee
AU - Tham, Yih Chung
AU - Zhou, Tiger
AU - van Leeuwen, Elisabeth M.
AU - Nickels, Stefan
AU - Sanfilippo, Paul
AU - Liao, Jiemin
AU - van der Linde, Herma
AU - Zhao, Wanting
AU - van Koolwijk, Leonieke M.E.
AU - Zheng, Li
AU - Rivadeneira, Fernando
AU - Baskaran, Mani
AU - van der Lee, Sven J.
AU - Perera, Shamira
AU - de Jong, Paulus T.V.M.
AU - Oostra, Ben A.
AU - Uitterlinden, André G.
AU - Fan, Qiao
AU - Hofman, Albert
N1 - Funding Information:
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.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddw399
DO - 10.1093/hmg/ddw399
M3 - Article
C2 - 28073927
AN - SCOPUS:85018321245
VL - 26
SP - 438
EP - 453
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 2
ER -