June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Novel Myopia Genes and Pathways identified from Syndromic Forms of Myopia
Author Affiliations & Notes
  • Daniel Ian Flitcroft
    Ophthalmology, Childrens University Hospital, Dublin, Ireland
    College of Sciences and Health , Dublin Institute of Technology, Dublin, Dublin, Ireland
  • James Loughman
    College of Sciences and Health , Dublin Institute of Technology, Dublin, Dublin, Ireland
  • Christine Frances Wildsoet
    School of Optometry, University College Berkeley, Berkeley, CA, Ireland
  • Cathy Williams
    Bristol Eye Hospital, Bristol, United Kingdom
  • Jeremy A Guggenheim
    School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom
  • Footnotes
    Commercial Relationships   Daniel Flitcroft, None; James Loughman, None; Christine Wildsoet, None; Cathy Williams, None; Jeremy Guggenheim, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5480. doi:
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      Daniel Ian Flitcroft, James Loughman, Christine Frances Wildsoet, Cathy Williams, Jeremy A Guggenheim; Novel Myopia Genes and Pathways identified from Syndromic Forms of Myopia. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5480.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : This study tests the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to non-syndromic refractive error.

Methods : Clinical phenotypes and syndromes that have refractive error as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. Pathway analysis was undertaken to find biological processes over-represented for identified genes. Genetic variants located within 50 kb of the 119 myopia-related genes were evaluated for involvement in refractive error, by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM consortium and 23andMe, using both single-marker and gene-based tests.

Results : 154 unique causative genes were identified, with 119 specifically linked with myopia, and 114 representing syndromic myopia (i.e. myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia, the only refractive error for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis identified several biological processes already implicated in refractive error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis and Schwann cell differentiation. Hyperopia was linked to different biological processes, mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1, COL9A2, ERBB3, FBN1, GJA1, GNPTG, IFIH1, KIF11, LTBP2, OCA2, POLR3B, POMT1, PTPN11, TFAP2A, ZNF469).

Conclusions : Common genetic variants within or nearby genes that cause syndromic myopia are enriched for variants that cause non-syndromic (common) myopia. These variants account for some of the missing heritability for refractive error. Analysis of syndromic forms of refractive error can provide new insights into the etiology of myopia and identify potential targets for therapeutic interventions.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.


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