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
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.
Department of Ophthalmology, Columbia University, New York, New York, United States of America.
PLoS Genet. 2015 Aug 27;11(8):e1005432. doi: 10.1371/journal.pgen.1005432. eCollection 2015 Aug.
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.
近视是全球最常见的视力障碍和视力损害的主要原因。然而，迄今为止鉴定出的基因变异仅解释了不到10%的屈光不正变异，大部分遗传力仍无法解释（“遗传力缺失”）。此前，我们报道在灵长类动物模型中，APLP2的表达与近视密切相关。在此，我们发现APLP2 5'端附近的低频变异与英国一个前瞻性出生队列（n = 3819名儿童；顶级单核苷酸多态性rs188663068，p = 5.0×10-4）和CREAM联盟小组（n = 45756名成年人；顶级单核苷酸多态性rs7127037，p = 6.6×10-3）中的屈光不正有关。这些变异显示出根据阅读时间对儿童纵向屈光不正轨迹有不同影响的证据（基因×阅读时间×年龄相互作用，p = 4.0×10-3）。此外，与杂合子（-0.8±2.0 D，p < 1.0×10-4）和野生型（+0.3±2.2 D，p < 1.0×10-4）同窝小鼠相比，Aplp2基因敲除小鼠出现了高度远视（+11.5±2.2 D，p < 1.0×10-4），并且对环境诱导近视的易感性呈剂量依赖性降低（F(2, 33) = 191.0，p < 1.0×10-4）。这种表型与对比敏感度降低（F(12, 120) = 3.6，p = 1.5×10-4）以及表达Aplp2的视网膜无长突细胞电生理特性的变化有关。这项研究确定APLP2为“缺失”的近视基因之一，证明了低频基因变异在人类近视发展中的重要性。它还证明了Aplp2在小鼠和人类屈光发育中的重要作用，表明屈光性眼发育潜在信号通路具有高度的进化保守性。
