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Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

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机构: [1]Centre for Quantitative Medicine, Duke-NUS Medial School, Singapore [2]Department of Statistical Science, Schoolof Mathematics & Computational Science, Sun Yat-Sen University, Guangzhou, China [3]State Key Laboratoryof Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China [4]Department ofEpidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [5]Department of Ophthalmology, ErasmusMedical Center, Rotterdam, The Netherlands [6]Department of Ophthalmology, King’s College London, St Thomas’Hospital campus, London, UK [7]Department of Twin Research and Genetic Epidemiology, King’s College LondonSchool of Medicine, London, UK [8]Centre for Ophthalmology and Visual Science, Lions Eye Institute, Universityof Western Australia, Perth, Australia [9]Genetics and Genome Biology Program, Hospital for Sick Children andUniversity of Toronto, Toronto, Ontario, Canada [10]MRC Integrative Epidemiology Unit (IEU) at the University ofBristol, Bristol, UK [11]School of Social and Community Medicine, University of Bristol, Bristol, UK [12]Max PlanckInstitute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands [13]University of QueenslandDiamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia [14]MRC Social, Genetic andDevelopmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London,London, UK [15]Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing,China [16]Beijing Ophthalmology and Visual Science Key Lab, Beijing, China [17]Department of Ophthalmology, MedicalFaculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany [18]Centre for Eye Research Australia(CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia [19]Centre forVision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney,Sydney, Australia [20]Department of Ophthalmology, National University Health Systems, National University ofSingapore, Singapore [21]Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore [22]Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore [23]SawSwee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore,Singapore [24]Computational and Statistical Genomics Branch, National Human Genome Research Institute, NationalInstitutes of Health, Baltimore, MD, USA [25]Department of Epidemiology, Johns Hopkins Bloomberg School ofPublic Health, Baltimore, Maryland, USA [26]Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore,MD [27]Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA [28]Duke-NationalUniversity of Singapore Graduate Medical School, Singapore, Singapore [29]Department of Health Sciences andGerontology Research Center, University of Jyväskylä, Jyväskylä, Finland [30]Department of Ophthalmology,Central Hospital of Central Finland, Jyväskylä, Finland [31]Institute of Human Genetics, Technical University Munich,Munich, Germany [32]Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany [33]School ofOptometry & Vision Sciences, Cardiff University, Cardiff, UK
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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).

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