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Original Investigation | Ophthalmic Molecular Genetics

Common Mechanisms Underlying Refractive Error Identified in Functional Analysis of Gene Lists From Genome-Wide Association Study Results in 2 European British Cohorts

Pirro G. Hysi, PhD1; Omar A. Mahroo, PhD2,3; Phillippa Cumberland, MS4; Robert Wojciechowski, MPH5; Katie M. Williams, MD2; Terri L. Young, MD6; David A. Mackey, MD, FRANZCO7; Jugnoo S. Rahi, MD4; Christopher J. Hammond, MD1,2
[+] Author Affiliations
1Department of Twin Research and Genetic Epidemiology, King’s College London, London, England
2Department of Ophthalmology, King's College London, London, England
3Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, England
4Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, London, England
5Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
6Center for Human Genetics, Duke University Medical Center, Durham, North Carolina
7Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Australia
JAMA Ophthalmol. 2014;132(1):50-56. doi:10.1001/jamaophthalmol.2013.6022.
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Importance  To date, relatively few genes responsible for a fraction of heritability have been identified by means of large genetic association studies of refractive error.

Objective  To explore the genetic mechanisms that lead to refractive error in the general population.

Design, Setting, and Participants  Genome-wide association studies were carried out in 2 British population-based independent cohorts (N = 5928 participants) to identify genes moderately associated with refractive error.

Main Outcomes and Measures  Enrichment analyses were used to identify sets of genes overrepresented in both cohorts. Enriched groups of genes were compared between both participating cohorts as a further measure against random noise.

Results  Groups of genes enriched at highly significant statistical levels were remarkably consistent in both cohorts. In particular, these results indicated that plasma membrane (P = 7.64 × 10−30), cell-cell adhesion (P = 2.42 × 10−18), synaptic transmission (P = 2.70 × 10−14), calcium ion binding (P = 3.55 × 10−15), and cation channel activity (P = 2.77 × 10−14) were significantly overrepresented in relation to refractive error.

Conclusions and Relevance  These findings provide evidence that development of refractive error in the general population is related to the intensity of photosignal transduced from the retina, which may have implications for future interventions to minimize this disorder. Pathways connected to the procession of the nerve impulse are major mechanisms involved in the development of refractive error in populations of European origin.

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Scheme of the Main Gene Ontology Entries Significantly Enriched in TwinsUK and 1958 British Birth Cohort Data sets

The 3 schemes correspond to the 3 Gene Ontology categories, A, Biological processes. B, Molecular function. C, Cellular component.

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