title: APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.
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.
authors: Department of Ophthalmology, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
authors: Andrei V
authors: AV
authors: Tkatchenko
authors: Department of Ophthalmology, Columbia University, New York, New York, United States of America.
authors: Tatiana V
authors: TV
authors: Tkatchenko
authors: School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom.
authors: Jeremy A
authors: JA
authors: Guggenheim
authors: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Virginie J M
authors: VJ
authors: Verhoeven
authors: Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, United Kingdom.
authors: Pirro G
authors: PG
authors: Hysi
authors: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America; Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute (NIH), Baltimore, Maryland, United States of America.
authors: Robert
authors: R
authors: Wojciechowski
authors: Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States of America.
authors: Pawan Kumar
authors: PK
authors: Singh
authors: Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States of America; Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States of America.
authors: Ashok
authors: A
authors: Kumar
authors: Departments of Neurobiology, Neurology, and Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors: Gopal
authors: G
authors: Thinakaran
authors: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors: Cathy
authors: C
authors: Williams
mesh_terms: D000293:Adolescent; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002648:Child; D002522:Chlorocebus aethiops; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D006956:Hyperopia / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008992:Monkey Diseases / Q000235:genetics; D009216:Myopia / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000502:physiology; D014792:Visual Acuity / Q000235:genetics* / Q000502:physiology
chemical_list: C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D009419:Nerve Tissue Proteins