Kidney disease genetic risk variants alter lysosomal beta-mannosidase (

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 studies and human kidney-specific expression quantitative trait analysis (eQTL) and identified that the expression of beta mannosidase (MANBA) 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 MANBA using phenome-wide association analysis (PheWAS) of 40,963 subjects with exome sequencing data. MANBA 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 Manba. Manba heterozygous and knock-out mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Taken together, these results illustrate the convergence of common non-coding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.