Kidney disease genetic risk variants alter lysosomal beta-mannosidase () expression and disease severity.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney-specific expression quantitative trait analysis and identified that the expression of beta-mannosidase () was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in using phenome-wide association analysis of 40,963 subjects with exome sequencing data. is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. loss altered multiple pathways, including endocytosis and autophagy. In the absence of toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.