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 Carroll; Daniel I Chasman; Marilyn C Cornelis; Abbas Dehghan; Jessica D Faul; Mary F Feitosa; Giovanni Gambaro; Paolo Gasparini; Franco Giulianini; Iris Heid; Jinyan Huang; Medea Imboden; Anne U Jackson; Janina Jeff; Min A Jhun; Ronit Katz; Annette Kifley; Tuomas O Kilpeläinen; Ashish Kumar; Markku Laakso; Ruifang Li-Gao; Kurt Lohman; Yingchang Lu; Reedik Mägi; Jette Bork-Jensen; Charlotte Glümer; Niels Grarup; Lise Lotte N Husemoen; Torben Jørgensen; Allan Linneberg; Oluf Pedersen; CHARGE Glycemic-T2D Working Group,

doi:10.1681/asn.2016020131

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 Heid, Jinyan Huang, Medea Imboden, Anne U Jackson, Janina Jeff, Min A Jhun, Ronit Katz, Annette Kifley, Tuomas O Kilpeläinen, Ashish Kumar, Markku Laakso, Ruifang Li-Gao, Kurt Lohman, Yingchang Lu, Reedik Mägi, Jette Bork-Jensen, Charlotte Glümer, Niels Grarup, Lise Lotte N Husemoen, Torben Jørgensen, Allan Linneberg, Oluf Pedersen, CHARGE Glycemic-T2D Working Group,

26 Citations (Scopus)

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 fromthe 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, andATXN2L; PStage1,3.731027), 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=5.431028 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 language	English
Journal	Journal of the American Society of Nephrology
Volume	28
Issue number	3
Pages (from-to)	981-994
Number of pages	14
ISSN	1046-6673
DOIs	https://doi.org/10.1681/asn.2016020131
Publication status	Published - Mar 2017

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Li, M., Li, Y., Weeks, O., Mijatovic, V., Teumer, A., Huffman, J. E., Tromp, G., Fuchsberger, C., Gorski, M., Lyytikäinen, L-P., Nutile, T., Sedaghat, S., Sorice, R., Tin, A., Yang, Q., Ahluwalia, T. S., Arking, D. E., Bihlmeyer, N. A., Böger, C. A., ... 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, 28(3), 981-994. https://doi.org/10.1681/asn.2016020131

Li, M, Li, Y, Weeks, O, Mijatovic, V, Teumer, A, Huffman, JE, Tromp, G, Fuchsberger, C, Gorski, M, Lyytikäinen, L-P, 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, I, Huang, J, Imboden, M, Jackson, AU, Jeff, J, Jhun, MA, Katz, R, Kifley, A, Kilpeläinen, TO, Kumar, A, Laakso, M, Li-Gao, R, Lohman, K, Lu, Y, Mägi, R, Bork-Jensen, J, Glümer, C, Grarup, N, Husemoen, LLN, Jørgensen, T, Linneberg, A , Pedersen, O & 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, vol. 28, no. 3, pp. 981-994. https://doi.org/10.1681/asn.2016020131

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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 fromthe 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, andATXN2L; PStage1,3.731027), 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=5.431028 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 Jette Bork-Jensen and Charlotte Gl{\"u}mer and Niels Grarup and Husemoen, {Lise Lotte N} and Torben J{\o}rgensen and Allan Linneberg and Oluf Pedersen and {CHARGE Glycemic-T2D Working Group,}",

note = "Copyright {\textcopyright} 2016 by the American Society of Nephrology.",

year = "2017",

month = mar,

doi = "10.1681/asn.2016020131",

language = "English",

volume = "28",

pages = "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

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,

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 fromthe 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, andATXN2L; PStage1,3.731027), 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=5.431028 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 fromthe 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, andATXN2L; PStage1,3.731027), 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=5.431028 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

SN - 1046-6673

VL - 28

SP - 981

EP - 994

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

IS - 3

ER -

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

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