title: Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.
abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).
authors.affiliation: Centre for Quantitative Medicine, Duke-NUS Medial School, Singapore.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Statistical Science, School of Mathematics &Computational Science, Sun Yat-Sen University, Guangzhou, China.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: J Willem L
authors.initials: JW
authors.lastname: Tideman
authors.affiliation: Department of Ophthalmology, King's College London, St Thomas' Hospital campus, London, UK.|Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Williams
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: Genetics and Genome Biology Program, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Howe
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands.
authors.forename: Beaté St
authors.initials: BS
authors.lastname: Pourcain
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Krapohl
authors.affiliation: Beijing Institute of Ophthalmology, 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: Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.|Beijing Ophthalmology and Visual Science Key Lab, Beijing, China.|Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany.
authors.forename: Jost B
authors.initials: JB
authors.lastname: Jonas
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Paul Nigel
authors.initials: PN
authors.lastname: Baird
authors.affiliation: Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.|Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore.|Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.|Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore, Singapore.
authors.forename: Yik-Ying
authors.initials: YY
authors.lastname: Teo
authors.affiliation: Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore.|Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
authors.forename: Tien-Yin
authors.initials: TY
authors.lastname: Wong
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ding
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.|Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Robert
authors.initials: R
authors.lastname: Wojciechowski
authors.affiliation: Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA.|Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
authors.affiliation: Department of Health Sciences and Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland.|Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland.
authors.forename: Olavi
authors.initials: O
authors.lastname: Pärssinen
authors.affiliation: Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.affiliation: Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Pfeiffer
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: Genetics and Genome Biology Program, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
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: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Plomin
authors.affiliation: Department of Ophthalmology, King's College London, St Thomas' Hospital campus, London, UK.|Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
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: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.|Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Mingguang
authors.initials: M
authors.lastname: He
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.|Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore, Singapore.
authors.forename: Seang-Mei
authors.initials: SM
authors.lastname: Saw
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Williams
authors.affiliation: School of Optometry &Vision Sciences, Cardiff University, Cardiff, UK.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Guggenheim
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D044466:Asian People / Q000235:genetics*; D002648:Child; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009216:Myopia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012030:Refractive Errors / Q000235:genetics*; D044465:White People / Q000235:genetics*