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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ChiCTR2000041373 ### Funding Statement This work was supported by the National Natural Science Foundation of China (61871294, 82172882), Zhejiang Provincial Natural Science Foundation of China (LR19C060001), and the Scientific Research Foundation for Talents of Wenzhou Medical University (QTJ18023) to J. Su. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Research performed on samples and data of human origin was conducted according to protocols approved by the institutional review boards of the Eye Hospital of Wenzhou Medical University, and informed consent was obtained from all subjects. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual-level data are not publicly available due to ethical and legal restrictions related to the Wenzhou Medical University. Supporting data are available from the corresponding author upon reasonable request but access to data must be granted by the MAGIC committees. VCF files will be uploaded to Genome Variation Map (GVM) in BIG Data Center (http://bigd.big.ac.cn/gsa), Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, with an accession number GVM000296. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.