The estimated heritability of kidney disease is around 50%. Common variants, that are almost always non-coding, account for much of the predisposition to prevalent, later-onset kidney diseases such as diabetic and hypertensive kidney disease (DKD, HKD). Genome wide association studies (GWAS) have provided a comprehensive inventory of these variants, each variant with modest impact on disease risk, but in aggregate they can explain most of disease heritability. Despite the remarkable success of GWAS, it has not translated into improved disease diagnostics and therapeutics as we fail to understand how non-coding variants cause kidney disease. The generally agreed model is that disease causing variants are on gene regulatory (open chromatin) region, alter transcription factor binding strength and quantitatively change the expression of a target gene in a cell type specific manner. Causal variant identification is impeded as DNA sequences that are close to each other are inherited together making it difficult to pick from the many linked variants. Due to secondary chromatin structure the nearest coding gene is not always the causal gene. The genotype effect may be cell-type specific explaining organ specific disease development. During the last award cycle, we catalogued genotype-driven gene-expression variation (eQTL; expression quantitative trait loci) in the glomerular and tubule compartments of human kidneys. Integration of the kidney GWAS and eQTL catalogues has been successful in identifying putative disease-causing genes and in a follow-up mouse gene knock-out study we showed that Dab2 is such new disease-causing gene. Kidney single cell gene expression analysis pointed to enrichment of disease associated genes in proximal tubules.

One in ten Americans are affected by chronic kidney disease. Chronic kidney disease is a gene environmental disease. Critical cell type(s) and pathway(s) responsible for disease development remains unknown limiting kidney disease understanding and new therapeutics development.