1. Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations.
- Author
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Huang LZ, Li YJ, Xie XF, Zhang JJ, Cheng CY, Yamashiro K, Chen LJ, Ma XY, Cheung CM, Wang YS, Zhang CF, Bai YJ, Hou J, Chen XL, Qi Y, Li SS, Sun YY, Mei JP, Cheng Y, Yu WZ, Hu XB, Zhuang FF, Fan L, Lu Y, Sun XH, Zhu XJ, Shen DF, Chan CC, Zhao MW, Yoshimura N, Pang CP, Wong TY, Khor CC, Zhang K, Zhou P, and Li XX
- Subjects
- Aged, Angiography, Animals, Case-Control Studies, China, Coloring Agents, Electroretinography, Exome genetics, Female, Genetic Predisposition to Disease, Hong Kong, Humans, Indocyanine Green, Japan, Macular Degeneration pathology, Male, Mice, Mice, Knockout, Middle Aged, Polymorphism, Single Nucleotide, Retinal Pigment Epithelium pathology, Sequence Analysis, DNA, Singapore, Tomography, Optical Coherence, Asian People genetics, Macular Degeneration genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous single-nucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. As a follow-up validation, we evaluate 3,772 neovascular AMD cases and 6,942 controls from five independent cohorts in the East Asian population. Here we show strong evidence of an association at a novel, missense SNV, rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene (Pmeta=1.46 × 10(-9), odds ratio (OR)=0.74, 95% confidence interval (CI): 0.63-0.88). Furthermore, ablation of the UBE3D protein lead to an abnormal amount of pigment granules deposited in retinal pigment epithelium microvilli area and an abnormal response on electroretinography (ERG) in UBE3D(+/-) heterozygous mice. Our findings indicate that the ubiquitin-proteasome system may play a role in the pathogenesis of neovascular AMD.
- Published
- 2015
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