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Exome-wide association study identifies KDELR3 mutations in extreme myopia

Author

Listed:
  • Jian Yuan

    (Wenzhou Medical University
    Vision and Brain Health)

  • You-Yuan Zhuang

    (Wenzhou Medical University)

  • Xiaoyu Liu

    (Wenzhou Medical University)

  • Yue Zhang

    (Wenzhou Medical University)

  • Kai Li

    (University of Chinese Academy of Sciences)

  • Zhen Ji Chen

    (Wenzhou Medical University)

  • Dandan Li

    (Wenzhou Medical University)

  • He Chen

    (Hainan University)

  • Jiacheng Liang

    (Wenzhou Medical University)

  • Yinghao Yao

    (Vision and Brain Health)

  • Xiangyi Yu

    (Institute of PSI Genomics)

  • Ran Zhuo

    (Wenzhou Medical University)

  • Fei Zhao

    (Wenzhou Medical University)

  • Xiangtian Zhou

    (Wenzhou Medical University
    Vision and Brain Health)

  • Xiaoguang Yu

    (Institute of PSI Genomics)

  • Jia Qu

    (Wenzhou Medical University
    Vision and Brain Health
    Hainan University)

  • Jianzhong Su

    (Wenzhou Medical University
    Vision and Brain Health
    University of Chinese Academy of Sciences)

Abstract

Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis.

Suggested Citation

  • Jian Yuan & You-Yuan Zhuang & Xiaoyu Liu & Yue Zhang & Kai Li & Zhen Ji Chen & Dandan Li & He Chen & Jiacheng Liang & Yinghao Yao & Xiangyi Yu & Ran Zhuo & Fei Zhao & Xiangtian Zhou & Xiaoguang Yu & J, 2024. "Exome-wide association study identifies KDELR3 mutations in extreme myopia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50580-x
    DOI: 10.1038/s41467-024-50580-x
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    References listed on IDEAS

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