and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

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J Am Soc Nephrol. 2017 28 (3): 981-994

PMID: 27920155 · PMCID: PMC5328154 · DOI:10.1681/ASN.2016020131

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Copyright © 2017 by the American Society of Nephrology.

MeSH Terms (11)

Animals Exome Genetic Loci Genome-Wide Association Study Glomerular Filtration Rate Humans Kidney Protein Tyrosine Phosphatases Proto-Oncogene Proteins Son of Sevenless Proteins Zebrafish

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