SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

CHARGE Glycemic-T2D Working Group,, CHARGE Blood Pressure Working Group

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology
Vol/bind28
Udgave nummer3
Sider (fra-til)981-994
ISSN1046-6673
DOI
StatusUdgivet - 2017

Fingeraftryk

Exome
Kidney
ras Guanine Nucleotide Exchange Factors
Rho Guanine Nucleotide Exchange Factors
Cytochrome P-450 CYP1A1
Genome-Wide Association Study
Zebrafish
Single Nucleotide Polymorphism
Meta-Analysis
Creatinine
Embryonic Structures
Serum

Citer dette

CHARGE Glycemic-T2D Working Group, ; CHARGE Blood Pressure Working Group. / SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. I: Journal of the American Society of Nephrology. 2017 ; Bind 28, Nr. 3. s. 981-994.
@article{26f1b12aac7c4d9fa08df7a104b09477,
title = "SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function",
abstract = "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.",
author = "Man Li and Yong Li and Olivia Weeks and Vladan Mijatovic and Alexander Teumer and Huffman, {Jennifer E} and Gerard Tromp and Christian Fuchsberger and Mathias Gorski and Leo-Pekka Lyytik{\"a}inen and Teresa Nutile and Sanaz Sedaghat and Rossella Sorice and Adrienne Tin and Qiong Yang and Ahluwalia, {Tarunveer S} and Arking, {Dan E} and Bihlmeyer, {Nathan A} and B{\"o}ger, {Carsten A} and Carroll, {Robert J} and Chasman, {Daniel I} and Cornelis, {Marilyn C} and Abbas Dehghan and Faul, {Jessica D} and Feitosa, {Mary F} and Giovanni Gambaro and Paolo Gasparini and Franco Giulianini and Iris Heid and Jinyan Huang and Medea Imboden and Jackson, {Anne U} and Janina Jeff and Jhun, {Min A} and Ronit Katz and Annette Kifley and Kilpel{\"a}inen, {Tuomas O} and Ashish Kumar and Markku Laakso and Ruifang Li-Gao and Kurt Lohman and Yingchang Lu and Reedik M{\"a}gi and Giovanni Malerba and Evelin Mihailov and Mohlke, {Karen L} and Mook-Kanamori, {Dennis O} and Ivan Brandslund and Cramer Christensen and J{\o}rgensen, {Marit E} and {CHARGE Glycemic-T2D Working Group,} and {CHARGE Blood Pressure Working Group}",
note = "Copyright {\circledC} 2016 by the American Society of Nephrology.",
year = "2017",
doi = "10.1681/ASN.2016020131",
language = "English",
volume = "28",
pages = "981--994",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "The American Society of Nephrology",
number = "3",

}

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. / CHARGE Glycemic-T2D Working Group,; CHARGE Blood Pressure Working Group.

I: Journal of the American Society of Nephrology, Bind 28, Nr. 3, 2017, s. 981-994.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - Malerba, Giovanni

AU - Mihailov, Evelin

AU - Mohlke, Karen L

AU - Mook-Kanamori, Dennis O

AU - Brandslund, Ivan

AU - Christensen, Cramer

AU - Jørgensen, Marit E

AU - CHARGE Glycemic-T2D Working Group,

AU - CHARGE Blood Pressure 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

VL - 28

SP - 981

EP - 994

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 3

ER -