A Genome-Wide Association Study for Susceptibility to Visual Experience-Induced Myopia

, Yu Huang, Chea-Su Kee, Paul M. Hocking, Cathy Williams, Shea Ping Yip, Jeremy A. Guggenheim

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Abstract

PURPOSE. The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G X E) interactions in myopia susceptibility. Few such G X E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G X E interaction loci. METHODS. Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989). RESULTS. A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G X E interaction with time spent reading (effect size -0.23 D, P = 0.022). CONCLUSIONS. This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.

Original languageEnglish
Pages (from-to)559-569
Number of pages11
JournalInvestigative Ophthalmology & Visual Science
Volume60
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint

Genome-Wide Association Study
Myopia
Refractive Errors
Genetic Predisposition to Disease
Genetic Markers
Genes
Longitudinal Studies
Meta-Analysis
Reading
Ultrasonography
Animal Models
Parents
Genome

Keywords

  • Alspac
  • Genome-wide association study
  • Myopia
  • Refractive error
  • Uk biobank

Cite this

Huang, Yu ; Kee, Chea-Su ; Hocking, Paul M. ; Williams, Cathy ; Yip, Shea Ping ; Guggenheim, Jeremy A. / A Genome-Wide Association Study for Susceptibility to Visual Experience-Induced Myopia. In: Investigative Ophthalmology & Visual Science. 2019 ; Vol. 60, No. 2. pp. 559-569.
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abstract = "PURPOSE. The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G X E) interactions in myopia susceptibility. Few such G X E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G X E interaction loci. METHODS. Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20{\%} of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989). RESULTS. A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G X E interaction with time spent reading (effect size -0.23 D, P = 0.022). CONCLUSIONS. This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.",
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A Genome-Wide Association Study for Susceptibility to Visual Experience-Induced Myopia. / ; Huang, Yu; Kee, Chea-Su; Hocking, Paul M.; Williams, Cathy; Yip, Shea Ping; Guggenheim, Jeremy A.

In: Investigative Ophthalmology & Visual Science, Vol. 60, No. 2, 01.02.2019, p. 559-569.

Research output: Contribution to journalArticle

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AU - Kee, Chea-Su

AU - Hocking, Paul M.

AU - Williams, Cathy

AU - Yip, Shea Ping

AU - Guggenheim, Jeremy A.

N1 - This research has been conducted using the UK Biobank Resource (application #17351). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Supported by General Research Fund Grant PolyU 5610/13M from the Hong Kong University Grants Council (Hong Kong, China). CW is funded by NIHR Career Development Fellowship CDF-2009-02-35 (London, UK). The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2; London, UK) and the University of Bristol (Bristol, UK) provide core support for ALSPAC. Collection of eye and vision data was supported by The Department for Health through an award made by the NIH(London, UK) to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, UK (Grant no. BRC2_009).

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Y1 - 2019/2/1

N2 - PURPOSE. The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G X E) interactions in myopia susceptibility. Few such G X E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G X E interaction loci. METHODS. Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989). RESULTS. A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G X E interaction with time spent reading (effect size -0.23 D, P = 0.022). CONCLUSIONS. This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.

AB - PURPOSE. The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G X E) interactions in myopia susceptibility. Few such G X E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G X E interaction loci. METHODS. Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989). RESULTS. A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G X E interaction with time spent reading (effect size -0.23 D, P = 0.022). CONCLUSIONS. This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.

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