title: Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.
abstract: Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Simpson
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Wojciechowski
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Murgia
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Portas
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Virginie J M
authors.initials: VJ
authors.lastname: Verhoeven
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Schache
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, and DCCT/EDIC Research Group, The Diabetes Control and Complications Trial and Follow-up Study, The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America.
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Raffel
authors.affiliation: Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: Cotch
authors.affiliation: Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Chew
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Barbara E K
authors.initials: BE
authors.lastname: Klein
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Seang Mei
authors.initials: SM
authors.lastname: Saw
authors.affiliation: Dipartimento di Scienze Chirurgiche, Clinica Oculistica Universita' degli studi di Cagliari, Cagliari, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fossarello
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
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: 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: 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.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Karssen
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.affiliation: Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.affiliation: Department of Ophthalmology, Hospital "Sestre Milosrdnice", Zagreb, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Bencic
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Venturini
authors.affiliation: Princess Alexandra Eye Pavilion, Edinburgh, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Fleck
authors.affiliation: MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Phillippa M
authors.initials: PM
authors.lastname: Cumberland
authors.affiliation: MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom; Ulverscroft Vision Research Group, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Jugnoo S
authors.initials: JS
authors.lastname: Rahi
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Hammond
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, and DCCT/EDIC Research Group, The Diabetes Control and Complications Trial and Follow-up Study, The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dwight
authors.initials: D
authors.lastname: Stambolian
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D005123:Eye / Q000503:physiopathology*; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D006956:Hyperopia / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009216:Myopia / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers