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

Man Li, Yong Li, Olivia Weeks, Vladan Mijatovic, Alexander Teumer, Jennifer E. Huffman, Gerard Tromp, Christian Fuchsberger, Mathias Gorski, Leo Pekka Lyytikäinen, Teresa Nutile, Sanaz Sedaghat, Rossella Sorice, Adrienne Tin, Qiong Yang, Tarunveer S. Ahluwalia, Dan E. Arking, Nathan A. Bihlmeyer, Carsten A. Böger, Robert J. CarrollDaniel I. Chasman, Marilyn C. Cornelis, Abbas Dehghan, Jessica D. Faul, Mary F. Feitosa, Giovanni Gambaro, Paolo Gasparini, Franco Giulianini, Iris M. Heid, Jinyan Huang, Medea Imboden, Anne U. Jackson, Janina M. Jeff, Min A. Jhun, Ronit Katz, Annette Kifley, Tuomas O. Kilpeläinen, Ashish Kumar, Markku Laakso, Ruifang Li-Gao, Kurt Lohman, Yingchang Lu, Reedik Mägi, Giovanni Malerba, Evelin Mihailov, Karen L. Mohlke, Dennis O Mook-Kanamori, Antonietta Robino, Daniela Toniolo, Sheila Ulivi, CHARGE Glycemic-T2D Working Group,

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)981-994
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume28
Issue number3
DOIs
Publication statusPublished - Mar 2017

Fingerprint

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

Keywords

  • Journal Article

Cite this

Li, M., Li, Y., Weeks, O., Mijatovic, V., Teumer, A., Huffman, J. E., ... CHARGE Glycemic-T2D Working Group, (2017). SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. Journal of the American Society of Nephrology : JASN, 28(3), 981-994. https://doi.org/10.1681/ASN.2016020131

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 M.; Huang, Jinyan; Imboden, Medea; Jackson, Anne U.; Jeff, Janina M.; Jhun, Min A.; Katz, Ronit; Kifley, Annette; Kilpeläinen, Tuomas O.; Kumar, Ashish; Laakso, Markku; Li-Gao, Ruifang; Lohman, Kurt; Lu, Yingchang; Mägi, Reedik; Malerba, Giovanni; Mihailov, Evelin; Mohlke, Karen L.; Mook-Kanamori, Dennis O; Robino, Antonietta; Toniolo, Daniela; Ulivi, Sheila; CHARGE Glycemic-T2D Working Group,.

In: Journal of the American Society of Nephrology : JASN, Vol. 28, No. 3, 03.2017, p. 981-994.

Research output: Contribution to journalArticle

Li, M, Li, Y, Weeks, O, Mijatovic, V, Teumer, A, Huffman, JE, Tromp, G, Fuchsberger, C, Gorski, M, Lyytikäinen, LP, Nutile, T, Sedaghat, S, Sorice, R, Tin, A, Yang, Q, Ahluwalia, TS, Arking, DE, Bihlmeyer, NA, Böger, CA, Carroll, RJ, Chasman, DI, Cornelis, MC, Dehghan, A, Faul, JD, Feitosa, MF, Gambaro, G, Gasparini, P, Giulianini, F, Heid, IM, Huang, J, Imboden, M, Jackson, AU, Jeff, JM, Jhun, MA, Katz, R, Kifley, A, Kilpeläinen, TO, Kumar, A, Laakso, M, Li-Gao, R, Lohman, K, Lu, Y, Mägi, R, Malerba, G, Mihailov, E, Mohlke, KL, Mook-Kanamori, DO, Robino, A, Toniolo, D, Ulivi, S & CHARGE Glycemic-T2D Working Group, 2017, 'SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function', Journal of the American Society of Nephrology : JASN, vol. 28, no. 3, pp. 981-994. https://doi.org/10.1681/ASN.2016020131
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 M. ; Huang, Jinyan ; Imboden, Medea ; Jackson, Anne U. ; Jeff, Janina M. ; Jhun, Min A. ; Katz, Ronit ; Kifley, Annette ; Kilpeläinen, Tuomas O. ; Kumar, Ashish ; Laakso, Markku ; Li-Gao, Ruifang ; Lohman, Kurt ; Lu, Yingchang ; Mägi, Reedik ; Malerba, Giovanni ; Mihailov, Evelin ; Mohlke, Karen L. ; Mook-Kanamori, Dennis O ; Robino, Antonietta ; Toniolo, Daniela ; Ulivi, Sheila ; CHARGE Glycemic-T2D Working Group,. / SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. In: Journal of the American Society of Nephrology : JASN. 2017 ; Vol. 28, No. 3. pp. 981-994.
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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 M.

AU - Huang, Jinyan

AU - Imboden, Medea

AU - Jackson, Anne U.

AU - Jeff, Janina M.

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 - Robino, Antonietta

AU - Toniolo, Daniela

AU - Ulivi, Sheila

AU - CHARGE Glycemic-T2D Working Group,

N1 - Copyright © 2017 by the American Society of Nephrology.

PY - 2017/3

Y1 - 2017/3

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.

KW - Journal Article

U2 - 10.1681/ASN.2016020131

DO - 10.1681/ASN.2016020131

M3 - Article

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EP - 994

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

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