IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50580-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50580-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-50580-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Zi-Bing Jin & Xiu-Feng Huang & Ji-Neng Lv & Lue Xiang & Dong-Qing Li & Jiangfei Chen & Changjiang Huang & Jinyu Wu & Fan Lu & Jia Qu, 2014. "SLC7A14 linked to autosomal recessive retinitis pigmentosa," Nature Communications, Nature, vol. 5(1), pages 1-9, May.
    2. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    3. Pradeep Gautam & Kiyofumi Hamashima & Ying Chen & Yingying Zeng & Bar Makovoz & Bhav Harshad Parikh & Hsin Yee Lee & Katherine Anne Lau & Xinyi Su & Raymond C. B. Wong & Woon-Khiong Chan & Hu Li & Tim, 2021. "Multi-species single-cell transcriptomic analysis of ocular compartment regulons," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. B. Devlin & Kathryn Roeder, 1999. "Genomic Control for Association Studies," Biometrics, The International Biometric Society, vol. 55(4), pages 997-1004, December.
    5. Shin-ichi Ikeda & Toshihide Kurihara & Xiaoyan Jiang & Yukihiro Miwa & Deokho Lee & Naho Serizawa & Heonuk Jeong & Kiwako Mori & Yusaku Katada & Hiromitsu Kunimi & Nobuhiro Ozawa & Chiho Shoda & Mari , 2022. "Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    2. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Paul W. Chrystal & Nils J. Lambacher & Lance P. Doucette & James Bellingham & Elena R. Schiff & Nicole C. L. Noel & Chunmei Li & Sofia Tsiropoulou & Geoffrey A. Casey & Yi Zhai & Nathan J. Nadolski & , 2022. "The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Mingsen Li & Huizhen Guo & Bofeng Wang & Zhuo Han & Siqi Wu & Jiafeng Liu & Huaxing Huang & Jin Zhu & Fengjiao An & Zesong Lin & Kunlun Mo & Jieying Tan & Chunqiao Liu & Li Wang & Xin Deng & Guigang L, 2024. "The single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. David J. Green & Vincent Michaud & Eulalie Lasseaux & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Graeme C. Black & Benoît Arveiler & Panagiotis I. Sergouniotis, 2024. "The co-occurrence of genetic variants in the TYR and OCA2 genes confers susceptibility to albinism," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    6. Lei Zhang & Yu-Fang Pei & Jian Li & Christopher J Papasian & Hong-Wen Deng, 2009. "Univariate/Multivariate Genome-Wide Association Scans Using Data from Families and Unrelated Samples," PLOS ONE, Public Library of Science, vol. 4(8), pages 1-12, August.
    7. Dominic Holland & Oleksandr Frei & Rahul Desikan & Chun-Chieh Fan & Alexey A Shadrin & Olav B Smeland & V S Sundar & Paul Thompson & Ole A Andreassen & Anders M Dale, 2020. "Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model," PLOS Genetics, Public Library of Science, vol. 16(5), pages 1-30, May.
    8. Asmundur Oddsson & Patrick Sulem & Gardar Sveinbjornsson & Gudny A. Arnadottir & Valgerdur Steinthorsdottir & Gisli H. Halldorsson & Bjarni A. Atlason & Gudjon R. Oskarsson & Hannes Helgason & Henriet, 2023. "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Xiangwei Li & Thomas Delerue & Ben Schöttker & Bernd Holleczek & Eva Grill & Annette Peters & Melanie Waldenberger & Barbara Thorand & Hermann Brenner, 2022. "Derivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Parsa Akbari & Dragana Vuckovic & Luca Stefanucci & Tao Jiang & Kousik Kundu & Roman Kreuzhuber & Erik L. Bao & Janine H. Collins & Kate Downes & Luigi Grassi & Jose A. Guerrero & Stephen Kaptoge & Ju, 2023. "A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    11. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Yasuhiko Haga & Yoshitaka Sakamoto & Keiko Kajiya & Hitomi Kawai & Miho Oka & Noriko Motoi & Masayuki Shirasawa & Masaya Yotsukura & Shun-Ichi Watanabe & Miyuki Arai & Junko Zenkoh & Kouya Shiraishi &, 2023. "Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    13. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    14. Laura M. Mueller & Abigail Isaacson & Heather Wilson & Anna Salowka & Isabel Tay & Maolian Gong & Nancy Samir Elbarbary & Klemens Raile & Francesca M. Spagnoli, 2024. "Heterozygous missense variant in GLI2 impairs human endocrine pancreas development," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    15. Gang Zheng & Zhaohai Li & Mitchell H. Gail & Joseph L. Gastwirth, 2010. "Impact of Population Substructure on Trend Tests for Genetic Case–Control Association Studies," Biometrics, The International Biometric Society, vol. 66(1), pages 196-204, March.
    16. Sandosh Padmanabhan & Olle Melander & Toby Johnson & Anna Maria Di Blasio & Wai K Lee & Davide Gentilini & Claire E Hastie & Cristina Menni & Maria Cristina Monti & Christian Delles & Stewart Laing & , 2010. "Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension," PLOS Genetics, Public Library of Science, vol. 6(10), pages 1-11, October.
    17. Ryan J. Geusz & Allen Wang & Dieter K. Lam & Nicholas K. Vinckier & Konstantinos-Dionysios Alysandratos & David A. Roberts & Jinzhao Wang & Samy Kefalopoulou & Araceli Ramirez & Yunjiang Qiu & Joshua , 2021. "Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    18. Jakris Eu-ahsunthornwattana & E Nancy Miller & Michaela Fakiola & Wellcome Trust Case Control Consortium 2 & Selma M B Jeronimo & Jenefer M Blackwell & Heather J Cordell, 2014. "Comparison of Methods to Account for Relatedness in Genome-Wide Association Studies with Family-Based Data," PLOS Genetics, Public Library of Science, vol. 10(7), pages 1-20, July.
    19. Alexendar R. Perez & Laura Sala & Richard K. Perez & Joana A. Vidigal, 2021. "CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    20. Andreas Herchenröther & Stefanie Gossen & Tobias Friedrich & Alexander Reim & Nadine Daus & Felix Diegmüller & Jörg Leers & Hakimeh Moghaddas Sani & Sarah Gerstner & Leah Schwarz & Inga Stellmacher & , 2023. "The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50580-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.