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Genome-Wide Analysis Points to Roles for Extracellular Matrix Remodeling, the Visual Cycle, and Neuronal Development in Myopia

Author

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  • Amy K Kiefer
  • Joyce Y Tung
  • Chuong B Do
  • David A Hinds
  • Joanna L Mountain
  • Uta Francke
  • Nicholas Eriksson

Abstract

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (45,771 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 22 significant associations (), two of which are replications of earlier associations with refractive error. Ten of the 20 novel associations identified replicate in a separate cohort of 8,323 participants who reported if they had developed myopia before age 10. These 22 associations in total explain 2.9% of the variance in myopia age of onset and point toward a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point toward multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans. Author Summary: The genetic basis of myopia, or nearsightedness, is believed to be complex and affected by multiple genes. Two genetic association studies have each identified a single genetic region associated with myopia in European populations. Here we report the results of the largest ever genetic association study on myopia in over 45,000 people of European ancestry. We identified 22 genetic regions significantly associated with myopia age of onset. Two are replications of the previously identified associations, and 20 are novel. Ten of the novel associations replicate in a small separate cohort. Sixteen of the novel associations are in or near genes implicated in eye development, neuronal development and signaling, the visual cycle of the retina, and general morphology: BMP3, BMP4, DLG2, DLX1, KCNMA1, KCNQ5, LAMA2, LRRC4C, PRSS56, RBFOX1, RDH5, RGR, SFRP1, TJP2, ZBTB38, and ZIC2. These findings point to numerous biological pathways involved in the development of myopia and, in particular, suggest that early eye and neuronal development may lead to the eventual development of myopia in humans.

Suggested Citation

  • Amy K Kiefer & Joyce Y Tung & Chuong B Do & David A Hinds & Joanna L Mountain & Uta Francke & Nicholas Eriksson, 2013. "Genome-Wide Analysis Points to Roles for Extracellular Matrix Remodeling, the Visual Cycle, and Neuronal Development in Myopia," PLOS Genetics, Public Library of Science, vol. 9(2), pages 1-8, February.
  • Handle: RePEc:plo:pgen00:1003299
    DOI: 10.1371/journal.pgen.1003299
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    References listed on IDEAS

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    1. Qiao Fan & Veluchamy A Barathi & Ching-Yu Cheng & Xin Zhou & Akira Meguro & Isao Nakata & Chiea-Chuen Khor & Liang-Kee Goh & Yi-Ju Li & Wan'e Lim & Candice E H Ho & Felicia Hawthorne & Yingfeng Zheng , 2012. "Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia," PLOS Genetics, Public Library of Science, vol. 8(6), pages 1-14, June.
    2. Joyce Y Tung & Chuong B Do & David A Hinds & Amy K Kiefer & J Michael Macpherson & Arnab B Chowdry & Uta Francke & Brian T Naughton & Joanna L Mountain & Anne Wojcicki & Nicholas Eriksson, 2011. "Efficient Replication of over 180 Genetic Associations with Self-Reported Medical Data," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-9, August.
    3. Nicholas Eriksson & J Michael Macpherson & Joyce Y Tung & Lawrence S Hon & Brian Naughton & Serge Saxonov & Linda Avey & Anne Wojcicki & Itsik Pe'er & Joanna Mountain, 2010. "Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits," PLOS Genetics, Public Library of Science, vol. 6(6), pages 1-20, June.
    4. Hideo Nakanishi & Ryo Yamada & Norimoto Gotoh & Hisako Hayashi & Kenji Yamashiro & Noriaki Shimada & Kyoko Ohno-Matsui & Manabu Mochizuki & Masaaki Saito & Tomohiro Iida & Keitaro Matsuo & Kazuo Tajim, 2009. "A Genome-Wide Association Analysis Identified a Novel Susceptible Locus for Pathological Myopia at 11q24.1," PLOS Genetics, Public Library of Science, vol. 5(9), pages 1-7, September.
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