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

Autor: YoSon Park, Christopher D. Brown, Matthew Palmer, Steven S. Pullen, Matthew J. Seasock, Paolo Guarnieri, Wen-Chao Song, Chengxiang Qiu, Shizheng Huang, Carine M. Boustany-Kari, Katalin Susztak, Yi-An Ko, Julie Hawkins, Xiang Xi Xu, Jon Hill, Jihwan Park, Joshua S. Bryer
Rok vydání: 2018
Předmět:
0301 basic medicine
Kidney Glomerulus
Quantitative Trait Loci
030232 urology & nephrology
Genome-wide association study
Computational biology
Biology
eQTL
Kidney
urologic and male genital diseases
Polymorphism
Single Nucleotide
Article
General Biochemistry
Genetics and Molecular Biology
Kidney Tubules
Proximal
Mice
03 medical and health sciences
0302 clinical medicine
renal disease
Transforming Growth Factor beta
Genetic variation
medicine
Animals
Humans
Genetic Predisposition to Disease
compartment-specific
Renal Insufficiency
Chronic
Gene
Adaptor Proteins
Signal Transducing
Genetic association
Tumor Suppressor Proteins
Genetic Variation
Signal transducing adaptor protein
Kidney metabolism
Genomics
General Medicine
medicine.disease
female genital diseases and pregnancy complications
Cell Compartmentation
3. Good health
Disease Models
Animal
030104 developmental biology
Gene Expression Regulation
Expression quantitative trait loci
Apoptosis Regulatory Proteins
Genome-Wide Association Study
Signal Transduction
Kidney disease
Zdroj: Nature medicine
ISSN: 1546-170X
1078-8956
DOI: 10.1038/s41591-018-0194-4
Popis: 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.
Databáze: OpenAIRE
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