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

Yuting Guan, Xiujie Liang, Ziyuan Ma, Hailong Hu, Hongbo Liu, Zhen Miao, Andreas Linkermann, Jacklyn N. Hellwege, Benjamin F. Voight and Katalin Susztak ()
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Yuting Guan: Perelman School of Medicine, University of Pennsylvania
Xiujie Liang: Perelman School of Medicine, University of Pennsylvania
Ziyuan Ma: Perelman School of Medicine, University of Pennsylvania
Hailong Hu: Perelman School of Medicine, University of Pennsylvania
Hongbo Liu: Perelman School of Medicine, University of Pennsylvania
Zhen Miao: Perelman School of Medicine, University of Pennsylvania
Andreas Linkermann: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Jacklyn N. Hellwege: Vanderbilt Genetics Institute
Benjamin F. Voight: University of Pennsylvania
Katalin Susztak: Perelman School of Medicine, University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25377-x

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