Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population

Jianzhong Su; Jian Yuan; Liangde Xu; Shilai Xing; Mengru Sun; Yinghao Yao; Yunlong Ma; Fukun Chen; Longda Jiang; Kai Li; Xiangyi Yu; Zhengbo Xue; Yaru Zhang; Dandan Fan; Ji Zhang; Hui Liu; Xinting Liu; Guosi Zhang; Hong Wang; Meng Zhou; Fan Lyu; Gang An; Xiaoguang Yu; Yuanchao Xue; Jian Yang; Jia Qu

doi:10.1016/j.celrep.2023.112510

Genetic & Genomic MedicineCell ReportsMay 1, 2023

Peer-reviewed journal article

Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population

Jianzhong Su iD, Jian Yuan iD, Liangde Xu iD, Shilai Xing iD, Mengru Sun iD, Yinghao Yao iD, Yunlong Ma iD, Fukun Chen iD, Longda Jiang iD, Kai Li iD, Xiangyi Yu, Zhengbo Xue iD, Yaru Zhang iD, Dandan Fan iD, Ji Zhang iD, Hui Liu iD, Xinting Liu iD, Guosi Zhang, Hong Wang iD, Meng Zhou iD, Fan Lyu iD, Gang An iD, Xiaoguang Yu iD, Yuanchao Xue iD, Jian Yang iD, Jia Qu iD

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Abstract

High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. Here, we report a whole-exome sequencing (WES) study in 9,613 HM cases and 9,606 controls of Han Chinese ancestry to pinpoint HM-associated risk variants. Single-variant association analysis identified three novel genetic loci associated with HM, including an East Asian ancestry-specific low-frequency variant (rs533280354) in FKBP5. Multi-ancestry meta-analysis with WES data of 2,696 HM cases and 7,186 controls of European ancestry from the UK Biobank discerned a novel European ancestry-specific rare variant in FOLH1. Functional experiments revealed a mechanism whereby a single G to A transition at rs533280354 disrupted the binding of transcription activator KLF15 to the promoter of FKBP5, resulting in decreased transcription of FKBP5. Furthermore, burden tests showed a significant excess of rare protein-truncating variants among HM cases involved in retinal blood vessel morphogenesis and neurotransmitter transport.