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

Huang, Lvzhen; Li, Yingjie; Xie, Xuefeng; Zhang, Jingjing; Cheng, Ching‐Yu; Yamashiro, Kenji; Chen, Lijia; Ma, Xiaoli; Cheung, Chui Ming Gemmy; Wang, Yusheng; Zhang, Chunfang; Bai, Yujing; Hou, Jing; Chen, Xiaoli; Qi, Yun; Li, Shanshan; Sun, Yaoyao; Mei, Junpu; Cheng, Yong; Yu, Wenzhen; Hu, Xiongbing; Zhuang, Fang‐Dong; Fan, Lei; Lü, Yi; Sun, Xuwu; Zhu, Xiangjia; Shen, Defen; Chan, Chi‐Chao; Zhao, Mingwei; Yoshimura, Nagahisa; Pang, Chi Pui; Wong, Tien Yin; Khor, Chiea‐Chuen; Zhang, Kang; Zhou, Peng; Li, Xiaoxin

doi:10.1038/ncomms7687

Cited by 44 publications

(37 citation statements)

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“…Recently, in a whole exome sequencing study, by using a genebased mutational load analysis, we and coworkers found that ANGPT2 was nominally associated with AMD (P ¼ 9.85 3 10 À3 ) in the East Asian populations. 33 Our current finding that the ANGPT2 gene is associated with nAMD and PCV provides further evidence to support the pathogenic role of Ang2.…”

Section: Discussionsupporting

confidence: 50%

Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations

Brelén

Tsujikawa

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Ma L, Brelen ME, Tsujikawa M, et al. Identification of ANGPT2 as a new gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in the Chinese and Japanese populations. Invest Ophthalmol Vis Sci. 2017;58:107658: -108358: . DOI:10.1167 PURPOSE. We determine the angiopoietin 2 (ANGPT2) gene as a new susceptibility gene for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS.A total of 34 haplotype-tagging single-nucleotide polymorphisms (SNPs) were first genotyped in an exploratory Hong Kong Chinese cohort. Suggestive SNPs were replicated in a Shantou Chinese cohort and an Osaka Japanese cohort, with a total of 2343 subjects. The SNP rs800292 in the complement factor H (CFH) gene was genotyped in all the subjects. Genetic association and gene-gene interaction were analyzed.RESULTS. In the Hong Kong cohort, four SNPs in ANGPT2 (rs13255574, rs4455855, rs13269021, and rs11775442) were nominally associated with nAMD and PCV. The four ANGPT2 SNPs showed the same trends of association in the Shantou and Osaka cohorts. Combining the data from the 3 study cohorts revealed that SNPs rs4455855 and rs13269021 achieved study-wise significance (P < 0.0016), conferring an approximately 1.3-fold of increased risk for nAMD and PCV. Interaction analysis revealed the CFH SNP rs800292 has a highly significant interaction with the ANGPT2 SNP rs13269021 in nAMD and PCV in the combined analysis. Subsequent stratification analysis confirmed the interaction.CONCLUSIONS. This study reveals ANGPT2 as a new susceptibility gene for nAMD and PCV, and it may affect disease susceptibility in association with CFH. Thus, this report provides new insights into the genetic architecture of nAMD and PCV.Keywords: ANGPT2, gene association, age-related macular degeneration, polypoidal choroidal vasculopathy, gene-gene interaction A ge-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly, especially in developed countries. Neovascular AMD (nAMD), a major form of advanced AMD characterized by choroidal neovascularization (CNV), accounts for the majority of severe visual loss in AMD patients. Polypoidal choroidal vasculopathy (PCV) is a macular disease characterized by polyp-like lesions in the choroidal vessels, which are best seen in indocyanine green angiography (ICGA).1 Polypoidal choroidal vasculopathy and nAMD have similarities in clinical manifestations. For example, they can cause submacular hemorrhage, exudation, and scarring, leading to central vision loss. Interestingly, CNV and PCV can present concurrently in approximately 3.23% of patients, 2 suggesting that they may have a shared mechanism. However, while the prevalence of nAMD (approximately 0.46%) is similar between Caucasian and Asian populations, 3 the prevalence of PCV is approximately 3-fold higher in Asians than in Caucasians, 4 suggesting an ethnic background is related to the occurrence of PCV. Moreover, nAMD and PCV respond differentl...

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Section: Discussionsupporting

confidence: 50%

Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations

Brelén

Tsujikawa

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…22 Additionally, two relatively small case-control WES studies have been reported for AMD. 23,24 Examining the biological pathways in which the associated genes function suggests the complement cascade, lipid metabolism, and extracellular matrix (ECM) remodeling to be the major pathways implicated in AMD pathogenesis (Supplementary Table S1). Although these genomics studies improved the biological insights into AMD, still many questions remain unsolved.…”

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%

Omics Biomarkers in Ophthalmology

Jong

Lefeber

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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''Omics'' refers to high-throughput analyses of genes, proteins, or metabolites in a biological system, and is increasingly used for ophthalmic research. These system-based approaches can unravel disease-related processes and are valuable for biomarker discovery. Furthermore, potential therapeutic targets can be identified based on omics results, and targeted follow-up experiments can be designed to gain molecular understanding of the disease and to test new therapies. Here, we review the application of omics techniques in eye diseases, focusing on age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal detachment (RD), myopia, glaucoma, Fuchs' corneal dystrophy (FCD), cataract, keratoconus, and dry eyes. We observe that genomic analyses were mainly successful in AMD research (almost half of the genomic heritability has been explained), whereas large parts of disease variability or risk remain unsolved in most of the other diseases. Other omics studies like transcriptomics, proteomics, and metabolomics provided additional candidate proteins and pathways for several eye diseases, although sample sizes in these studies were often very small and replication is lacking. In order to translate omics results into clinical biomarkers, larger sample sizes and validation across different cohorts would be essential. In conclusion, omicsbased studies are increasing in ophthalmology, and further application to the clinic might develop in the years to come. Integration of genomics with other type of omics data has the potential to improve the accuracy of predictive tests. Moreover, in the future, omics may lead to stratification of patients into subgroups based on molecular profiles, enabling the development of personalized treatments.

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“…Although the etiology and pathogenesis of AMD remain elusive, several genome‐wide association studies (GWAS) have identified numerous susceptibility loci for AMD in European‐ancestry and Asian populations . However, in those studies, PCV is not identified and investigated separately and such GWAS studies in Chinese are scarce . PCV is more prevalent in Chinese populations (22–33% of all nAMD cases) than in European populations (10–13% of all nAMD cases) .…”

Section: Introductionmentioning

confidence: 99%