Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease.
Chengxiang QiuShizheng HuangJiwhan ParkYoSon ParkYi-An KoMatthew J SeasockJoshua S BryerXiang-Xi XuWen-Chao SongMatthew PalmerJon HillPaolo GuarnieriJulie HawkinsCarine M Boustany-KariSteven S PullenChristopher D BrownKatalin SusztákPublished in: Nature medicine (2018)
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.
Keyphrases
- chronic kidney disease
- end stage renal disease
- single cell
- genome wide
- poor prognosis
- genome wide association
- bioinformatics analysis
- rna seq
- binding protein
- endothelial cells
- genome wide identification
- long non coding rna
- dna methylation
- high throughput
- transforming growth factor
- copy number
- heavy metals
- type diabetes
- adipose tissue
- amino acid
- gene expression
- small molecule
- insulin resistance
- mass spectrometry
- case control