APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans

Andrei V. Tkatchenko, Tatiana V. Tkatchenko, Jeremy A. Guggenheim, Virginie J M Verhoeven, Pirro G. Hysi, Robert Wojciechowski, Pawan Kumar Singh, Ashok Kumar, Gopal Thinakaran, Cathy Williams

Research output: Contribution to journalArticle

Abstract

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p <1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p <1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p <1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p <1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

Original languageEnglish (US)
Article numbere1005432
JournalPLoS Genetics
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Refractive Errors
Myopia
gene
Vision Disorders
mice
heritability
Single Nucleotide Polymorphism
Reading
Genes
Amacrine Cells
vision disorders
Contrast Sensitivity
Human Development
Gene Frequency
Knockout Mice
primate
genes
human development
Primates
phenotype

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Tkatchenko, A. V., Tkatchenko, T. V., Guggenheim, J. A., Verhoeven, V. J. M., Hysi, P. G., Wojciechowski, R., ... Williams, C. (2015). APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. PLoS Genetics, 11(8), [e1005432]. https://doi.org/10.1371/journal.pgen.1005432

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. / Tkatchenko, Andrei V.; Tkatchenko, Tatiana V.; Guggenheim, Jeremy A.; Verhoeven, Virginie J M; Hysi, Pirro G.; Wojciechowski, Robert; Singh, Pawan Kumar; Kumar, Ashok; Thinakaran, Gopal; Williams, Cathy.

In: PLoS Genetics, Vol. 11, No. 8, e1005432, 01.08.2015.

Research output: Contribution to journalArticle

Tkatchenko, AV, Tkatchenko, TV, Guggenheim, JA, Verhoeven, VJM, Hysi, PG, Wojciechowski, R, Singh, PK, Kumar, A, Thinakaran, G & Williams, C 2015, 'APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans', PLoS Genetics, vol. 11, no. 8, e1005432. https://doi.org/10.1371/journal.pgen.1005432
Tkatchenko AV, Tkatchenko TV, Guggenheim JA, Verhoeven VJM, Hysi PG, Wojciechowski R et al. APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. PLoS Genetics. 2015 Aug 1;11(8). e1005432. https://doi.org/10.1371/journal.pgen.1005432
Tkatchenko, Andrei V. ; Tkatchenko, Tatiana V. ; Guggenheim, Jeremy A. ; Verhoeven, Virginie J M ; Hysi, Pirro G. ; Wojciechowski, Robert ; Singh, Pawan Kumar ; Kumar, Ashok ; Thinakaran, Gopal ; Williams, Cathy. / APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. In: PLoS Genetics. 2015 ; Vol. 11, No. 8.
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