title: New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.
abstract: 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.
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Henriët
authors.initials: H
authors.lastname: Springelkamp
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Adriana I
authors.initials: AI
authors.lastname: Iglesias
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.|Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
authors.forename: Aniket
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Ophthalmology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.|Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Höhn
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute (NIH), Baltimore, MD, USA.|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.|Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wojciechowski
authors.affiliation: NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Khawaja
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Nag
authors.affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.|Beijing Ophthalmology and Visual Science Key Lab, Beijing, China.
authors.forename: Ya Xing
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cuellar-Partida
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jessica N Cooke
authors.initials: JN
authors.lastname: Bailey
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Puya
authors.initials: P
authors.lastname: Gharahkhani
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Boutin
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Wishal D
authors.initials: WD
authors.lastname: Ramdas
authors.affiliation: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg/Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Yonova-Doing
authors.affiliation: NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Ananth C
authors.initials: AC
authors.lastname: Viswanathan
authors.affiliation: Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
authors.forename: Seyhan
authors.initials: S
authors.lastname: Yazar
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Cree
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
authors.forename: Jia Yu
authors.initials: JY
authors.lastname: Koh
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Scotland, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg/Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Venturini
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Kearns
authors.affiliation: Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yih Chung
authors.initials: YC
authors.lastname: Tham
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, Australia.
authors.forename: Tiger
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nickels
authors.affiliation: Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.|Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Sanfilippo
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Herma
authors.initials: H
authors.lastname: van der Linde
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Wanting
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Leonieke M E
authors.initials: LM
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Mani
authors.initials: M
authors.lastname: Baskaran
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Shamira
authors.initials: S
authors.lastname: Perera
authors.affiliation: Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.|Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.|The Netherlands Institute of Neuroscience KNAW, Amsterdam, the Netherlands.
authors.forename: Paulus T V M
authors.initials: PT
authors.lastname: de Jong
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.|Department of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
authors.forename: E-Shyong
authors.initials: ES
authors.lastname: Tai
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
authors.forename: Xueling
authors.initials: X
authors.lastname: Sim
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Roger C W
authors.initials: RC
authors.lastname: Wolfs
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.|Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
authors.forename: Yik Ying
authors.initials: YY
authors.lastname: Teo
authors.affiliation: Glaucoma Service, The Rotterdam Eye Hospital, Rotterdam, the Netherlands.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Lemij
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.affiliation: Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Nomdo M
authors.initials: NM
authors.lastname: Jansonius
authors.affiliation: Department of Molecular Epidemiology, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Montgomery
authors.affiliation: Preventive Cardiology and Preventive Medicine/Center for Cardiology, University Medical Center Mainz, Mainz, Germany.|Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.|German Center for Cardiovascular Research (DZHK), partner site RhineMain, Mainz, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
authors.affiliation: School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA and.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.|School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
authors.forename: Jost B
authors.initials: JB
authors.lastname: Jonas
authors.affiliation: Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.affiliation: NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Foster
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Pfeiffer
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.affiliation: Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.|School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
authors.affiliation: Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA and.
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
mesh_terms: D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009898:Optic Disk / Q000473:pathology; D009901:Optic Nerve Diseases / Q000235:genetics* / Q000473:pathology; D014065:Tonometry, Ocular; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; C114547:Six7 protein, zebrafish; D029961:Zebrafish Proteins