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Sci Rep. 2016 May 13;6:25853. doi: 10.1038/srep25853.

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

Author information

1
Centre for Quantitative Medicine, Duke-NUS Medial School, Singapore.
2
Department of Statistical Science, School of Mathematics &Computational Science, Sun Yat-Sen University, Guangzhou, China.
3
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
4
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
5
Department of Ophthalmology, Erasmus Medical 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 London School of Medicine, London, UK.
8
Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
9
Genetics and Genome Biology Program, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
10
MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.
11
School of Social and Community Medicine, University of Bristol, Bristol, UK.
12
Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands.
13
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
14
MRC Social, Genetic and Developmental 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, Medical Faculty 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 for Vision 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 of Singapore, 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
Saw Swee 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, National Institutes of Health, Baltimore, MD, USA.
25
Department of Epidemiology, Johns Hopkins Bloomberg School of Public 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-National University of Singapore Graduate Medical School, Singapore, Singapore.
29
Department of Health Sciences and Gerontology 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 of Optometry &Vision Sciences, Cardiff University, Cardiff, UK.

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).

PMID:
27174397
PMCID:
PMC4865831
DOI:
10.1038/srep25853
[Indexed for MEDLINE]
Free PMC Article

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