title: Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma.
abstract: Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Puya
authors.initials: P
authors.lastname: Gharahkhani
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.|Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, 7000, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Rhys
authors.initials: R
authors.lastname: Fogarty
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Law
authors.affiliation: University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia.
authors.forename: Katie
authors.initials: K
authors.lastname: Cremin
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jessica N Cooke
authors.initials: JNC
authors.lastname: Bailey
authors.affiliation: Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Loomis
authors.affiliation: Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
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: MRC Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, De Crespigny Park, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
authors.forename: Fotis
authors.initials: F
authors.lastname: Topouzis
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: Ophthalmology and Vision Science, Macquarie University, Sydney, New South Wales, Australia.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Graham
authors.affiliation: South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Casson
authors.affiliation: South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Chehade
authors.affiliation: Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Tiger
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Landers
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Jude T
authors.initials: JT
authors.lastname: Fitzgerald
authors.affiliation: Department of Anatomical Pathology, Flinders University, Flinders Medical Centre, South Australia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.affiliation: Department of Ophthalmology, University of Sydney, Sydney Eye Hospital, Sydney, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mills
authors.affiliation: Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.|School of Medicine, University of Queensland, Herston Campus, Brisbane, QLD, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: RadfordSmith
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, 7000, Australia.|Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D015151:Immunoblotting; D008297:Male; D015201:Meta-Analysis as Topic; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014481:United States
chemical_list: C577836:ABCA1 protein, human; C497360:AFAP1 protein, human; D064286:ATP Binding Cassette Transporter 1; D008840:Microfilament Proteins; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase