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A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Author

Listed:
  • Yuting Guan

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Xiujie Liang

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Ziyuan Ma

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Hailong Hu

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Hongbo Liu

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Zhen Miao

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Andreas Linkermann

    (University Hospital Carl Gustav Carus at the Technische Universität Dresden
    Biotechnology Center, Technische Universität Dresden)

  • Jacklyn N. Hellwege

    (Vanderbilt Genetics Institute)

  • Benjamin F. Voight

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Katalin Susztak

    (Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

Abstract

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.

Suggested Citation

  • Yuting Guan & Xiujie Liang & Ziyuan Ma & Hailong Hu & Hongbo Liu & Zhen Miao & Andreas Linkermann & Jacklyn N. Hellwege & Benjamin F. Voight & Katalin Susztak, 2021. "A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25377-x
    DOI: 10.1038/s41467-021-25377-x
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    Cited by:

    1. Carlos Company & Matthias Jürgen Schmitt & Yuliia Dramaretska & Michela Serresi & Sonia Kertalli & Ben Jiang & Jiang-An Yin & Adriano Aguzzi & Iros Barozzi & Gaetano Gargiulo, 2024. "Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Lulu Shang & Wei Zhao & Yi Zhe Wang & Zheng Li & Jerome J. Choi & Minjung Kho & Thomas H. Mosley & Sharon L. R. Kardia & Jennifer A. Smith & Xiang Zhou, 2023. "meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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