Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 28, Issue 3, Pages 981-994Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2016020131
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Funding
- Medical Research Council [MC_PC_U127561128] Funding Source: Medline
- NCI NIH HHS [UM1 CA182913] Funding Source: Medline
- NHLBI NIH HHS [R01 HL119443, R01 HL105756, R01 HL087660, U01 HL130114, R01 HL120393, R21 HL123677, R01 HL112064] Funding Source: Medline
- NIA NIH HHS [U01 AG009740] Funding Source: Medline
- NIDDK NIH HHS [R21 DK112087, R01 DK093757, R01 DK107904, R01 DK072193] Funding Source: Medline
- NIEHS NIH HHS [P30 ES010126] Funding Source: Medline
- NIGMS NIH HHS [R25 GM062459] Funding Source: Medline
- NIH HHS [S10 OD018522, S10 OD020069] Funding Source: Medline
- Chief Scientist Office [CZD/16/6/4] Funding Source: Medline
- Chief Scientist Office [CZD/16/6/4] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561128] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10219, NF-SI-0616-10080] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0011049, NNF15OC0016320, NNF16OC0021370] Funding Source: researchfish
- Steno Diabetes Center Copenhagen (SDCC) [SDCC 3.A Complications] Funding Source: researchfish
- Wellcome Trust [098395/Z/12/Z] Funding Source: researchfish
- MRC [MC_PC_U127561128] Funding Source: UKRI
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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 (n(stage1);111,666;n(stage2): 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; P-stage1<3.7 x10(-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=5.4x 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.
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