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

• Published in: Nature communications Vol. 12; no. 1; pp. 5078 - 17
• Main Authors: Guan, Yuting, Liang, Xiujie, Ma, Ziyuan, Hu, Hailong, Liu, Hongbo, Miao, Zhen, Linkermann, Andreas, Hellwege, Jacklyn N., Voight, Benjamin F., Susztak, Katalin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/1; 38/88; 38/91; 631/208; 631/208/191; 64/60; 692/4022/1585; 82/29; 82/51; 96/106; 96/109; Animal models; Animals; Blood Urea Nitrogen; Chromatin; Chromatin - metabolism; Cisplatin; CRISPR; Dipeptidase; Dipeptidases - deficiency; Dipeptidases - genetics; Dipeptidases - metabolism; DNA methylation; DNA Methylation - genetics; Editing; Ferroptosis; Ferroptosis - genetics; Folic Acid; Gene Editing; Gene expression; Gene Expression Regulation; Gene mapping; Genes; Genetic Loci; Genetic Predisposition to Disease; Genome editing; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Haploinsufficiency - genetics; Humanities and Social Sciences; Humans; Iron - metabolism; Kidney - pathology; Kidney diseases; Kidney Diseases - chemically induced; Kidney Diseases - genetics; Kidneys; Mice; multidisciplinary; Necroptosis - genetics; Organ Specificity; Physical Chromosome Mapping; Pyroptosis - genetics; Quantitative Trait Loci; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Triangulation; Vesicular Transport Proteins - deficiency; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25377-x

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.