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; Giovanni Malerba; Evelin Mihailov; Karen L. Mohlke; Dennis O. Mook-Kanamori; Antonietta Robino; Douglas Ruderfer; Erika Salvi; Ursula M. Schick; Christina Alexandra Schulz; Albert V. Smith; Jennifer A. Smith; Michela Traglia; Laura M. Yerges-Armstrong; Wei Zhao; Mark O. Goodarzi; Aldi T. Kraja; Chunyu Liu; Jennifer Wessel; Eric Boerwinkle; Ingrid B. Borecki; Jette Bork-Jensen; Erwin P. Bottinger; Daniele Braga; Ivan Brandslund; Jennifer A. Brody; Archie Campbell; David J. Carey; Cramer Christensen; Josef Coresh; Errol Crook; Gary C. Curhan; Daniele Cusi; Ian H. De Boer; Aiko P.J. De Vries; Joshua C. Denny; Olivier Devuyst; Albert W. Dreisbach; Karlhans Endlich; Tõnu Esko; Oscar H. Franco; Tibor Fulop; Glenn S. Gerhard; Charlotte Glümer; Omri Gottesman; Niels Grarup; Vilmundur Gudnason; Torben Hansen; Tamara B. Harris; Caroline Hayward; Lynne Hocking; Albert Hofman; Frank B. Hu; Lise Lotte N. Husemoen; Rebecca D. Jackson; Torben Jørgensen; Marit E. Jørgensen; Mika Kähönen; Sharon L.R. Kardia; Wolfgang König; Charles Kooperberg; Jennifer Kriebel; Lenore J. Launer; Torsten Lauritzen; Terho Lehtimäki; Daniel Levy; Pamela Linksted; Allan Linneberg; Yongmei Liu; Ruth J.F. Loos; Antonio Lupo; Christine Meisinger; Olle Melander; Andres Metspalu; Paul Mitchell; Matthias Nauck; Peter Nürnberg; Marju Orho-Melander; Afshin Parsa; Oluf Pedersen; Annette Peters; Ulrike Peters; Ozren Polasek; David Porteous; Nicole M. Probst-Hensch; Bruce M. Psaty; Lu Qi; Olli T. Raitakari; Alex P. Reiner; Rainer Rettig; Paul M. Ridker; Fernando Rivadeneira; Jacques E. Rossouw; Frank Schmidt; David Siscovick; Nicole Soranzo; Konstantin Strauch; Daniela Toniolo; Stephen T. Turner; André G. Uitterlinden; Sheila Ulivi; Dinesh Velayutham; Uwe Völker; Henry Völzke; Melanie Waldenberger; Jie Jin Wang; David R. Weir; Daniel Witte; Helena Kuivaniemi; Caroline S. Fox; Nora Franceschini; Wolfram Goessling; Anna Köttgen; Audrey Y. Chu

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, Giovanni Malerba, Evelin Mihailov, Karen L. Mohlke, Dennis O. Mook-Kanamori, Antonietta Robino, Douglas Ruderfer, Erika Salvi, Ursula M. Schick, Christina Alexandra Schulz, Albert V. Smith, Jennifer A. Smith, Michela Traglia, Laura M. Yerges-Armstrong, Wei Zhao, Mark O. Goodarzi, Aldi T. Kraja, Chunyu Liu, Jennifer Wessel, Eric Boerwinkle, Ingrid B. Borecki, Jette Bork-Jensen, Erwin P. Bottinger, Daniele Braga, Ivan Brandslund, Jennifer A. Brody, Archie Campbell, David J. Carey, Cramer Christensen, Josef Coresh, Errol Crook, Gary C. Curhan, Daniele Cusi, Ian H. De Boer, Aiko P.J. De Vries, Joshua C. Denny, Olivier Devuyst, Albert W. Dreisbach, Karlhans Endlich, Tõnu Esko, Oscar H. Franco, Tibor Fulop, Glenn S. Gerhard, Charlotte Glümer, Omri Gottesman, Niels Grarup, Vilmundur Gudnason, Torben Hansen, Tamara B. Harris, Caroline Hayward, Lynne Hocking, Albert Hofman, Frank B. Hu, Lise Lotte N. Husemoen, Rebecca D. Jackson, Torben Jørgensen, Marit E. Jørgensen, Mika Kähönen, Sharon L.R. Kardia, Wolfgang König, Charles Kooperberg, Jennifer Kriebel, Lenore J. Launer, Torsten Lauritzen, Terho Lehtimäki, Daniel Levy, Pamela Linksted, Allan Linneberg, Yongmei Liu, Ruth J.F. Loos, Antonio Lupo, Christine Meisinger, Olle Melander, Andres Metspalu, Paul Mitchell, Matthias Nauck, Peter Nürnberg, Marju Orho-Melander, Afshin Parsa, Oluf Pedersen, Annette Peters, Ulrike Peters, Ozren Polasek, David Porteous, Nicole M. Probst-Hensch, Bruce M. Psaty, Lu Qi, Olli T. Raitakari, Alex P. Reiner, Rainer Rettig, Paul M. Ridker, Fernando Rivadeneira, Jacques E. Rossouw, Frank Schmidt, David Siscovick, Nicole Soranzo, Konstantin Strauch, Daniela Toniolo, Stephen T. Turner, André G. Uitterlinden, Sheila Ulivi, Dinesh Velayutham, Uwe Völker, Henry Völzke, Melanie Waldenberger, Jie Jin Wang, David R. Weir, Daniel Witte, Helena Kuivaniemi, Caroline S. Fox, Nora Franceschini, Wolfram Goessling, Anna Köttgen, Audrey Y. Chu

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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 (US)
Pages (from-to)	981-994
Number of pages	14
Journal	Journal of the American Society of Nephrology
Volume	28
Issue number	3
DOIs	https://doi.org/10.1681/ASN.2016020131
State	Published - Mar 2017
Externally published	Yes

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Publisher Copyright:
© 2017 by the American Society of Nephrology.

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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., ... Chu, A. Y. (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, 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, 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, Malerba, G, Mihailov, E, Mohlke, KL, Mook-Kanamori, DO, Robino, A, Ruderfer, D, Salvi, E, Schick, UM, Schulz, CA, Smith, AV, Smith, JA, Traglia, M, Yerges-Armstrong, LM, Zhao, W, Goodarzi, MO, Kraja, AT, Liu, C, Wessel, J, Boerwinkle, E, Borecki, IB, Bork-Jensen, J, Bottinger, EP, Braga, D, Brandslund, I, Brody, JA, Campbell, A, Carey, DJ, Christensen, C, Coresh, J, Crook, E, Curhan, GC, Cusi, D, De Boer, IH, De Vries, APJ, Denny, JC, Devuyst, O, Dreisbach, AW, Endlich, K, Esko, T, Franco, OH, Fulop, T, Gerhard, GS, Glümer, C, Gottesman, O, Grarup, N, Gudnason, V, Hansen, T, Harris, TB, Hayward, C, Hocking, L, Hofman, A, Hu, FB, Husemoen, LLN, Jackson, RD, Jørgensen, T, Jørgensen, ME, Kähönen, M, Kardia, SLR, König, W, Kooperberg, C, Kriebel, J, Launer, LJ, Lauritzen, T, Lehtimäki, T, Levy, D, Linksted, P, Linneberg, A, Liu, Y, Loos, RJF, Lupo, A, Meisinger, C, Melander, O, Metspalu, A, Mitchell, P, Nauck, M, Nürnberg, P, Orho-Melander, M, Parsa, A, Pedersen, O, Peters, A, Peters, U, Polasek, O, Porteous, D, Probst-Hensch, NM, Psaty, BM, Qi, L, Raitakari, OT, Reiner, AP, Rettig, R, Ridker, PM, Rivadeneira, F, Rossouw, JE, Schmidt, F, Siscovick, D, Soranzo, N, Strauch, K, Toniolo, D, Turner, ST, Uitterlinden, AG, Ulivi, S, Velayutham, D, Völker, U, Völzke, H, Waldenberger, M, Wang, JJ, Weir, DR, Witte, D, Kuivaniemi, H, Fox, CS, Franceschini, N, Goessling, W, Köttgen, A & Chu, AY 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

@article{e982d4f1b3d841448e44c3822138b56d,

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 Lyytik{\"a}inen, {Leo Pekka} 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 Antonietta Robino and Douglas Ruderfer and Erika Salvi and Schick, {Ursula M.} and Schulz, {Christina Alexandra} and Smith, {Albert V.} and Smith, {Jennifer A.} and Michela Traglia and Yerges-Armstrong, {Laura M.} and Wei Zhao and Goodarzi, {Mark O.} and Kraja, {Aldi T.} and Chunyu Liu and Jennifer Wessel and Eric Boerwinkle and Borecki, {Ingrid B.} and Jette Bork-Jensen and Bottinger, {Erwin P.} and Daniele Braga and Ivan Brandslund and Brody, {Jennifer A.} and Archie Campbell and Carey, {David J.} and Cramer Christensen and Josef Coresh and Errol Crook and Curhan, {Gary C.} and Daniele Cusi and {De Boer}, {Ian H.} and {De Vries}, {Aiko P.J.} and Denny, {Joshua C.} and Olivier Devuyst and Dreisbach, {Albert W.} and Karlhans Endlich and T{\~o}nu Esko and Franco, {Oscar H.} and Tibor Fulop and Gerhard, {Glenn S.} and Charlotte Gl{\"u}mer and Omri Gottesman and Niels Grarup and Vilmundur Gudnason and Torben Hansen and Harris, {Tamara B.} and Caroline Hayward and Lynne Hocking and Albert Hofman and Hu, {Frank B.} and Husemoen, {Lise Lotte N.} and Jackson, {Rebecca D.} and Torben J{\o}rgensen and J{\o}rgensen, {Marit E.} and Mika K{\"a}h{\"o}nen and Kardia, {Sharon L.R.} and Wolfgang K{\"o}nig and Charles Kooperberg and Jennifer Kriebel and Launer, {Lenore J.} and Torsten Lauritzen and Terho Lehtim{\"a}ki and Daniel Levy and Pamela Linksted and Allan Linneberg and Yongmei Liu and Loos, {Ruth J.F.} and Antonio Lupo and Christine Meisinger and Olle Melander and Andres Metspalu and Paul Mitchell and Matthias Nauck and Peter N{\"u}rnberg and Marju Orho-Melander and Afshin Parsa and Oluf Pedersen and Annette Peters and Ulrike Peters and Ozren Polasek and David Porteous and Probst-Hensch, {Nicole M.} and Psaty, {Bruce M.} and Lu Qi and Raitakari, {Olli T.} and Reiner, {Alex P.} and Rainer Rettig and Ridker, {Paul M.} and Fernando Rivadeneira and Rossouw, {Jacques E.} and Frank Schmidt and David Siscovick and Nicole Soranzo and Konstantin Strauch and Daniela Toniolo and Turner, {Stephen T.} and Uitterlinden, {Andr{\'e} G.} and Sheila Ulivi and Dinesh Velayutham and Uwe V{\"o}lker and Henry V{\"o}lzke and Melanie Waldenberger and Wang, {Jie Jin} and Weir, {David R.} and Daniel Witte and Helena Kuivaniemi and Fox, {Caroline S.} and Nora Franceschini and Wolfram Goessling and Anna K{\"o}ttgen and Chu, {Audrey Y.}",

note = "Publisher Copyright: {\textcopyright} 2017 by the American Society of Nephrology.",

year = "2017",

month = mar,

doi = "10.1681/ASN.2016020131",

language = "English (US)",

volume = "28",

pages = "981--994",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "American Society of Nephrology",

number = "3",

}

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 - Robino, Antonietta

AU - Ruderfer, Douglas

AU - Salvi, Erika

AU - Schick, Ursula M.

AU - Schulz, Christina Alexandra

AU - Smith, Albert V.

AU - Smith, Jennifer A.

AU - Traglia, Michela

AU - Yerges-Armstrong, Laura M.

AU - Zhao, Wei

AU - Goodarzi, Mark O.

AU - Kraja, Aldi T.

AU - Liu, Chunyu

AU - Wessel, Jennifer

AU - Boerwinkle, Eric

AU - Borecki, Ingrid B.

AU - Bork-Jensen, Jette

AU - Bottinger, Erwin P.

AU - Braga, Daniele

AU - Brandslund, Ivan

AU - Brody, Jennifer A.

AU - Campbell, Archie

AU - Carey, David J.

AU - Christensen, Cramer

AU - Coresh, Josef

AU - Crook, Errol

AU - Curhan, Gary C.

AU - Cusi, Daniele

AU - De Boer, Ian H.

AU - De Vries, Aiko P.J.

AU - Denny, Joshua C.

AU - Devuyst, Olivier

AU - Dreisbach, Albert W.

AU - Endlich, Karlhans

AU - Esko, Tõnu

AU - Franco, Oscar H.

AU - Fulop, Tibor

AU - Gerhard, Glenn S.

AU - Glümer, Charlotte

AU - Gottesman, Omri

AU - Grarup, Niels

AU - Gudnason, Vilmundur

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Hocking, Lynne

AU - Hofman, Albert

AU - Hu, Frank B.

AU - Husemoen, Lise Lotte N.

AU - Jackson, Rebecca D.

AU - Jørgensen, Torben

AU - Jørgensen, Marit E.

AU - Kähönen, Mika

AU - Kardia, Sharon L.R.

AU - König, Wolfgang

AU - Kooperberg, Charles

AU - Kriebel, Jennifer

AU - Launer, Lenore J.

AU - Lauritzen, Torsten

AU - Lehtimäki, Terho

AU - Levy, Daniel

AU - Linksted, Pamela

AU - Linneberg, Allan

AU - Liu, Yongmei

AU - Loos, Ruth J.F.

AU - Lupo, Antonio

AU - Meisinger, Christine

AU - Melander, Olle

AU - Metspalu, Andres

AU - Mitchell, Paul

AU - Nauck, Matthias

AU - Nürnberg, Peter

AU - Orho-Melander, Marju

AU - Parsa, Afshin

AU - Pedersen, Oluf

AU - Peters, Annette

AU - Peters, Ulrike

AU - Polasek, Ozren

AU - Porteous, David

AU - Probst-Hensch, Nicole M.

AU - Psaty, Bruce M.

AU - Qi, Lu

AU - Raitakari, Olli T.

AU - Reiner, Alex P.

AU - Rettig, Rainer

AU - Ridker, Paul M.

AU - Rivadeneira, Fernando

AU - Rossouw, Jacques E.

AU - Schmidt, Frank

AU - Siscovick, David

AU - Soranzo, Nicole

AU - Strauch, Konstantin

AU - Toniolo, Daniela

AU - Turner, Stephen T.

AU - Uitterlinden, André G.

AU - Ulivi, Sheila

AU - Velayutham, Dinesh

AU - Völker, Uwe

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Wang, Jie Jin

AU - Weir, David R.

AU - Witte, Daniel

AU - Kuivaniemi, Helena

AU - Fox, Caroline S.

AU - Franceschini, Nora

AU - Goessling, Wolfram

AU - Köttgen, Anna

AU - Chu, Audrey Y.

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.

UR - http://www.scopus.com/inward/record.url?scp=85021851118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021851118&partnerID=8YFLogxK

U2 - 10.1681/ASN.2016020131

DO - 10.1681/ASN.2016020131

M3 - Article

C2 - 27920155

AN - SCOPUS:85021851118

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 -

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

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