Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

作者：Lvzhen Huang, Yingjie Li, Xuefeng Xie, Jingjing Zhang, Ching‐Yu Cheng, Kenji Yamashiro, Lijia Chen, Xiaoyun Ma, Chui Ming Gemmy Cheung, Yusheng Wang, Chunfang Zhang, Yujing Bai, Jing Hou, Xiaoli Chen, Yun Qi, Shanshan Li, Yaoyao Sun, Junpu Mei, Yong Cheng, Wenzhen Yu, Xiongbing Hu, Fengfeng Zhuang, Lei Fan, Yi Lü, Xinghuai Sun, Xiangjia Zhu, Defen Shen, Chi‐Chao Chan, Mingwei Zhao, Nagahisa Yoshimura, Chi Pui Pang, Tien Yin Wong, Chiea Chuen Khor, Kang Zhang, Peng Zhou, Xiaoxin Li · 发表于：Nature Communications · 年份：2015 · DOI：10.1038/ncomms7687 · 被引用次数：51 · 研究领域：Retinal Diseases and Treatments、Retinal Imaging and Analysis、Retinal Development and Disorders

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. Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.