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, Katalin Suszták
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.