SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
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SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. / Li, Man; Li, Yong; Weeks, Olivia; Mijatovic, Vladan; Teumer, Alexander; Huffman, Jennifer E; Tromp, Gerard; Fuchsberger, Christian; Gorski, Mathias; Lyytikäinen, Leo-Pekka; Nutile, Teresa; Sedaghat, Sanaz; Sorice, Rossella; Tin, Adrienne; Yang, Qiong; Ahluwalia, Tarunveer S; Arking, Dan E; Bihlmeyer, Nathan A; Böger, Carsten A; Carroll, Robert J; Chasman, Daniel I; Cornelis, Marilyn C; Dehghan, Abbas; Faul, Jessica D; Feitosa, Mary F; Gambaro, Giovanni; Gasparini, Paolo; Giulianini, Franco; Heid, Iris; Huang, Jinyan; Imboden, Medea; Jackson, Anne U; Jeff, Janina; Jhun, Min A; Katz, Ronit; Kifley, Annette; Kilpeläinen, Tuomas O; Kumar, Ashish; Laakso, Markku; Li-Gao, Ruifang; Lohman, Kurt; Lu, Yingchang; Mägi, Reedik; Bork-Jensen, Jette; Glümer, Charlotte; Grarup, Niels; Husemoen, Lise Lotte N; Jørgensen, Torben; Linneberg, Allan; Pedersen, Oluf; CHARGE Glycemic-T2D Working Group,.
In: Journal of the American Society of Nephrology, Vol. 28, No. 3, 2017, p. 981-994.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
AU - Li, Man
AU - Li, Yong
AU - Weeks, Olivia
AU - Mijatovic, Vladan
AU - Teumer, Alexander
AU - Huffman, Jennifer E
AU - Tromp, Gerard
AU - Fuchsberger, Christian
AU - Gorski, Mathias
AU - Lyytikäinen, Leo-Pekka
AU - Nutile, Teresa
AU - Sedaghat, Sanaz
AU - Sorice, Rossella
AU - Tin, Adrienne
AU - Yang, Qiong
AU - Ahluwalia, Tarunveer S
AU - Arking, Dan E
AU - Bihlmeyer, Nathan A
AU - Böger, Carsten A
AU - Carroll, Robert J
AU - Chasman, Daniel I
AU - Cornelis, Marilyn C
AU - Dehghan, Abbas
AU - Faul, Jessica D
AU - Feitosa, Mary F
AU - Gambaro, Giovanni
AU - Gasparini, Paolo
AU - Giulianini, Franco
AU - Heid, Iris
AU - Huang, Jinyan
AU - Imboden, Medea
AU - Jackson, Anne U
AU - Jeff, Janina
AU - Jhun, Min A
AU - Katz, Ronit
AU - Kifley, Annette
AU - Kilpeläinen, Tuomas O
AU - Kumar, Ashish
AU - Laakso, Markku
AU - Li-Gao, Ruifang
AU - Lohman, Kurt
AU - Lu, Yingchang
AU - Mägi, Reedik
AU - Bork-Jensen, Jette
AU - Glümer, Charlotte
AU - Grarup, Niels
AU - Husemoen, Lise Lotte N
AU - Jørgensen, Torben
AU - Linneberg, Allan
AU - Pedersen, Oluf
AU - CHARGE Glycemic-T2D Working Group,
N1 - Copyright © 2016 by the American Society of Nephrology.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1681/ASN.2016020131
DO - 10.1681/ASN.2016020131
M3 - Journal article
C2 - 27920155
VL - 28
SP - 981
EP - 994
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 3
ER -
ID: 172433856