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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Compartmentation / genetics
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Mice
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / physiopathology
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / genetics
  • Tumor Suppressor Proteins / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • DAB2 protein, human
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins