Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Kidney failure, the decrease of kidney function below a threshold necessary to support life, is a major cause of morbidity and mortality in humans. Kidney function is highly heritable; yet, the cellular and molecular mechanisms which contribute to differences in human kidney function remain obscure. We performed a genome wide association study (GWAS), identifying 430 loci affecting kidney function in middle-aged adults. To investigate which cell types are affected by these loci, we integrated the GWAS with human kidney candidate cis-regulatory elements (cCREs), identified using scATAC-seq. 56% of kidney function heritability localized to kidney tubule epithelial cCREs and an additional 7% to kidney podocyte cCREs. Thus, most of the heritable differences in adult kidney function is due to altered gene expression in these two cell types. Using enhancer assays, allele-specific scATAC-seq and machine learning, we found that many kidney function variants alter cCRE chromatin accessibility and function. Using CRISPRi, we determined which genes some of these cCREs regulate, implicating NDRG1, CCNB1 and STC1 in human kidney function. This work provides an experimental approach to identify the variants, regulatory elements and genes involved in human traits and disease.