Cell reports · 2023
Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population.
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Su Jianzhong, Yuan Jian, Xu Liangde, Xing Shilai, Sun Mengru, Yao Yinghao, Ma Yunlong, Chen Fukun, Jiang Longda, Li Kai, Yu Xiangyi, Xue Zhengbo, Zhang Yaru, Fan Dandan, Zhang Ji, Liu Hui, Liu Xinting, Zhang Guosi, Wang Hong, Zhou Meng, Lyu Fan, An Gang, Yu Xiaoguang, Myopia Associated Genetics and Intervention Consortium, Xue Yuanchao, Yang Jian, Qu Jia
Аннотация
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 newly identified -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 newly identified 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.