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Population genetics
Whole-exome sequencing reveals sex difference in the genetic architecture of high myopia
  1. Xingchen Liu1,2,
  2. Jiacheng Liang1,2,
  3. Shasha Li1,2,3,
  4. Yuhe Yang1,2,
  5. Qinghao Zhu1,2,
  6. Ruowen Qiu1,2,
  7. Zheng Ji Chen1,2,
  8. Yinghao Yao1,2,3,
  9. Qing Ren1,2,
  10. Xiaoguang Yu4,
  11. Jia Qu1,2,3,
  12. Jianzhong Su1,2,3,
  13. Jian Yuan1,2
  14. Myopia Associated Genetics and Intervention Consortium
    1. 1 National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
    2. 2 State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
    3. 3 Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
    4. 4 Institute of PSI Genomics, Wenzhou, China
    1. Correspondence to Dr Jian Yuan; danielwyuan{at}gmail.com

    Abstract

    Background High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. To understand the sex difference in the genetic architecture of HM, which may contribute to understanding HM aetiology and help further the realisation of precision medicine for HM.

    Methods We performed sex-stratified exome-wide association studies (ExWAS) with n (males)=7492 and n (females)=8090, along with gene- and pathway-based tests and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to HM in a sex-specific manner.

    Results In our ExWAS, we identified that a male-specific gene, CHRNB1 (Zfemales=1.382, Pfemales=0.083; Zmales=4.029, Pmales=2.80×10−05; Pdifference=0.003), was associated with higher risk scores of HM in males than in females. Rare variant burden tests showed a significant excess of rare protein-truncating variants among HM males in CHRNB1-related pathways, including cell-cell signalling and muscle structure development. Sex-based differences in gene expression within CHRNB1-enriched ciliary body cells were observed; specifically, increased expression of mitochondrial metabolism-related genes in males and antioxidant genes in females. Functional differences in mitochondrial metabolism were confirmed in male-derived H1 and female-derived H9 human embryonic stem cell lines, with H1 cells specifically exhibiting significant dysregulation of mitochondrial organisation and mitochondrial respiratory chain complex assembly after CHRNB1 knockdown.

    Conclusion Together, our study provides insight into the sex differences in the genetic architecture of HM and highlights CHRNB1’s role in HM pathogenesis in males.

    • Genetic Association Studies
    • Eye Diseases

    Data availability statement

    The raw genetic sequencing data for EM patients and control individuals generated in this study have been deposited in the Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/gsa-human/) under accession numbers HRA007816 in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences. Raw RNA-seq data generated in this study have been deposited in the GSA under the accession number HRA008597. All raw sequencing data deposited in GSA are under restricted access, and only academic use will be approved via email to Jianzhong Su (sujz@wmu.edu.cn). A response would be expected within a week. Single-cell RNA-seq (scRNA-seq) expression matrix of human iris from GSE147979 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE147979). Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

    https://doi.org/10.1136/jmg-2024-110467

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      Data availability statement

      The raw genetic sequencing data for EM patients and control individuals generated in this study have been deposited in the Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/gsa-human/) under accession numbers HRA007816 in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences. Raw RNA-seq data generated in this study have been deposited in the GSA under the accession number HRA008597. All raw sequencing data deposited in GSA are under restricted access, and only academic use will be approved via email to Jianzhong Su (sujz@wmu.edu.cn). A response would be expected within a week. Single-cell RNA-seq (scRNA-seq) expression matrix of human iris from GSE147979 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE147979). Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

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      Footnotes

      • XL, JL and SL contributed equally.

      • Collaborators Myopia Associated Genetics and Intervention Consortium (MAGIC): Jianzhong Su, Liangde Xu, Jia Qu, Fan Lyu, Hong Wang, Xiaoguang Yu, Jian Yuan, Yinghao Yao, Zhen Ji Chen, Yunlong Ma, Zhengbo Xue, Zhenguang Zheng, Hui Liu, Wei Dai, Riyan Zhang and Ran Zhuo.

      • Contributors The study was conceived, designed and supervised by JQ, JS and JY. Analysis of data was performed by XL, JL, QZ, RQ, ZJC, YinghaoY and XY. The experiments were conducted by SL, YuheY and QR. Patient sample recruitment was conducted by JS, LX, JQ, FL, HW, XY, JY, YinghaoY, ZC, YM, ZX, ZZ, HL, WD, RiyanZ and RanZ, the members of the Myopia Associated Genetics and Intervention Consortium. DNA extraction and sequencing were carried out by XY. The manuscript was written by JY and JS with contributions from all other authors. JY acts as the guarantor.

      • Funding This work was supported by the National Natural Science Foundation of China (81830027, U20A20364) and the Zhejiang Provincial Key Research and Development Program Grant (2021C03102) to JQ; the National Natural Science Foundation of China (82172882) to JS; the National Natural Science Foundation of China (32400549) to JY.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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