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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 (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), 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, SOS2 (P=5.4×10-8 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 acp1- and sos2-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.

Original publication

DOI

10.1681/ASN.2016020131

Type

Journal article

Journal

Journal of the american society of nephrology : jasn

Publication Date

03/2017

Volume

28

Pages

981 - 994

Addresses

Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.

Keywords

CHARGE Glycemic-T2D Working Group,, CHARGE Blood Pressure Working Group,, Kidney, Animals, Zebrafish, Humans, Son of Sevenless Proteins, Proto-Oncogene Proteins, Glomerular Filtration Rate, Protein Tyrosine Phosphatases, Genome-Wide Association Study, Genetic Loci, Exome