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.
Highlights
Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide
Our findings indicate that the ubiquitin proteasome system (UPS) may play a role in the pathogenesis of neovascular AMD
We performed Whole-exome sequencing (WES) of 216 neovascular AMD cases and 1,553 controls (Table 1, Supplementary Fig. 1 and Supplementary Table 1) with sequence coverage of B31X, and we identified 62,870 single-nucleotide polymorphisms (SNPs)
Summary
Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous singlenucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. Genome-wide association studies focus on common variants (minor allele frequency (MAF) 45%), which are usually located in the intronic regions of the chromosome and do not encode specific functional proteins[11,12]. Whole-exome sequencing (WES)-based studies are emerging as a popular approach to test for the association of coding variants with complex traits and diseases[13,14,15]. There is strong interest in exome sequencing because of its potential to identify genes underlying complex traits and enable straightforward functional annotation of coding variation[15]. We validate the contribution of functional coding variants to genetic susceptibility for AMD in six independent samples. Our findings indicate that the ubiquitin proteasome system (UPS) may play a role in the pathogenesis of neovascular AMD
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