Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations.
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.
Huang, L-Z; Li, Y-J; Xie, X-F; Zhang, J-J; Cheng, C-Y; Yamashiro, K; Chen, L-J; Ma, X-Y; Cheung, CMG; Wang, Y-S; Zhang, C-F; Bai, Y-J; Hou, J; Chen, X-L; Qi, Y; Li, S-S; Sun, Y-Y; Mei, J-P; Cheng, Y; Yu, W-Z; Hu, X-B; Zhuang, F-F; Fan, L; Lu, Y; Sun, X-H; Zhu, X-J; Shen, D-F; Chan, C-C; Zhao, M-W; Yoshimura, N; Pang, CP; Wong, TY; Khor, CC; Zhang, K; Zhou, P; Li, X-X
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