title: A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.
abstract: Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Institute of Chengdu Biology, Chinese Academy of Sciences, Chengdu, China.|Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Lulin
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authors.lastname: Huang
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Houbin
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authors.lastname: Zhang
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Pancy O S
authors.initials: PO
authors.lastname: Tam
authors.affiliation: Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Joint Shantou International Eye Center, Shantou University and Chinese University of Hong Kong, Shantou, China.
authors.forename: Haoyu
authors.identifier: 0000-0003-0676-4610
authors.initials: H
authors.lastname: Chen
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Department of Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Zheng
authors.identifier: 0000-0002-7060-2213
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Lijia
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Institute of Chengdu Biology, Chinese Academy of Sciences, Chengdu, China.|Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Tai
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenji
authors.identifier: 0000-0001-9354-8558
authors.initials: K
authors.lastname: Yamashiro
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Shaoping
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authors.lastname: Deng
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Xianjun
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authors.affiliation: Joint Shantou International Eye Center, Shantou University and Chinese University of Hong Kong, Shantou, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Chen
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Li
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.initials: F
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Yuanfeng
authors.initials: Y
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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authors.identifier: 0000-0003-3358-3516
authors.initials: CM
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Yi
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authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Yin
authors.initials: Y
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.|Department of Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Kar-Seng
authors.identifier: 0000-0002-3822-7759
authors.initials: KS
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Princess Alexandra Eye Pavilion, Edinburgh, UK.
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authors.affiliation: Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.
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authors.affiliation: Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Duke-National University of Singapore Graduate Medical School, Singapore.
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Department of Human Genetics, Genome Institute of Singapore, Singapore.
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authors.initials: CC
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authors.affiliation: Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
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authors.initials: CP
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authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.|Institute of Chengdu Biology, Chinese Academy of Sciences, Chengdu, China.|Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.|Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
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mesh_terms: D002478:Cells, Cultured; D002681:China; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005006:Ethnicity; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D013347:Subcellular Fractions / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000235:genetics*
chemical_list: C000620889:FGD6 protein, human; D020662:Guanine Nucleotide Exchange Factors