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.

Identifying causal variants and genes is an essential step in interpreting GWAS loci. Here, the authors investigate a kidney disease GWAS locus with functional genomics data, CRISPR editing and mouse experiments to identify DPEP1 and CHMP1A as putative kidney disease genes via ferroptosis.

Details

Title
A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
Author
Guan Yuting 1   VIAFID ORCID Logo  ; Liang Xiujie 1 ; Ma Ziyuan 1   VIAFID ORCID Logo  ; Hu, Hailong 1 ; Liu, Hongbo 1   VIAFID ORCID Logo  ; Miao Zhen 2   VIAFID ORCID Logo  ; Linkermann Andreas 3   VIAFID ORCID Logo  ; Hellwege, Jacklyn N 4   VIAFID ORCID Logo  ; Voight, Benjamin F 5   VIAFID ORCID Logo  ; Susztak Katalin 1   VIAFID ORCID Logo 

1  Perelman School of Medicine, University of Pennsylvania, Department of Medicine, Renal Electrolyte and Hypertension Division, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Genetics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
2  Perelman School of Medicine, University of Pennsylvania, Department of Medicine, Renal Electrolyte and Hypertension Division, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Genetics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Perelman School of Medicine, University of Pennsylvania, Graduate group in Genomics and Computational Biology, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
3  University Hospital Carl Gustav Carus at the Technische Universität Dresden, Division of Nephrology, Department of Internal Medicine, Dresden, Germany (GRID:grid.412282.f) (ISNI:0000 0001 1091 2917); Biotechnology Center, Technische Universität Dresden, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257) 
4  Vanderbilt Genetics Institute, Division of Genetic Medicine, Department of Medicine, Nashville, USA (GRID:grid.4488.0) 
5  University of Pennsylvania, Department of Genetics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Perelman School of Medicine, University of Pennsylvania, Department of Systems Pharmacology and Translational Therapeutics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Perelman School of Medicine, University of Pennsylvania, Institute of Translational Medicine and Therapeutics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-25377-x
ProQuest document ID
2576118207
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.