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Nat Med. 2018 Nov;24(11):1721-1731. doi: 10.1038/s41591-018-0194-4. Epub 2018 Oct 1.

Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease.

Author information

1
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
2
Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
3
Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
4
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at University of Pennsylvania, Pennsylvania, PA, USA.
5
Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
6
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
7
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA. ksusztak@pennmedicine.upenn.edu.
8
Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. ksusztak@pennmedicine.upenn.edu.

Abstract

Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-β pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.

PMID:
30275566
PMCID:
PMC6301011
DOI:
10.1038/s41591-018-0194-4
[Indexed for MEDLINE]
Free PMC Article

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