Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease

More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. Here we comprehensively characterize genetic associations for kidney function (n = 1,508,659 individuals), DNA methylation (n = 443 individuals) and gene expression (n = 686 individuals). We identify 878 (126 novel) kidney function associated GWAS loci and prioritize target genes for 87% of these loci using a multi-stage prioritization strategy. Heritability analysis reveal that methylation variation explains a larger fraction of GWAS heritability than gene expression. Integration of GWAS and single cell open chromatin (n = 57,229 cells) highlights the key role of proximal tubules and metabolism in kidney function regulation. Further, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits. 10x snATAC-seq for 4 human kidney samples. The processed data was based on six samples (including two samples from our previous dataset: GSE172008).