Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

The functional interpretation of GWAS remains challenging due to cell-type dependent influences of genetic variants.Here, we generated comprehensive maps of expression quantitative trait loci (eQTL) for 659 microdissected human kidney samples and identified cell-type eQTLs by mapping interactions between cell type abundance and genotype. Separately, we generated single cell open chromatin maps (by snATAC-seq) for human kidney samples. We highlight critical enrichment of proximal tubules in kidney function and endothelial cells and distal tubule segments in blood pressure by partitioning heritability using stratified LD-score regression to integrate GWAS with scRNA-seq and snATAC-seq data. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of the most commonly used antihypertensive and renal protective drugs and identifies drug repurposing opportunities for kidney disease.One Sentence SummaryWe define causal cell types, genes and mechanism for kidney dysfunction.