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 | |
| State | Published - Mar 2017 |
| Externally published | Yes |
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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; Malerba, Giovanni; Mihailov, Evelin; Mohlke, Karen L.; Mook-Kanamori, Dennis O.; Robino, Antonietta; Ruderfer, Douglas; Salvi, Erika; Schick, Ursula M.; Schulz, Christina Alexandra; Smith, Albert V.; Smith, Jennifer A.; Traglia, Michela; Yerges-Armstrong, Laura M.; Zhao, Wei; Goodarzi, Mark O.; Kraja, Aldi T.; Liu, Chunyu; Wessel, Jennifer; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bottinger, Erwin P.; Braga, Daniele; Brandslund, Ivan; Brody, Jennifer A.; Campbell, Archie; Carey, David J.; Christensen, Cramer; Coresh, Josef; Crook, Errol; Curhan, Gary C.; Cusi, Daniele; De Boer, Ian H.; De Vries, Aiko P.J.; Denny, Joshua C.; Devuyst, Olivier; Dreisbach, Albert W.; Endlich, Karlhans; Esko, Tõnu; Franco, Oscar H.; Fulop, Tibor; Gerhard, Glenn S.; Glümer, Charlotte; Gottesman, Omri; Grarup, Niels; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B.; Hayward, Caroline; Hocking, Lynne; Hofman, Albert; Hu, Frank B.; Husemoen, Lise Lotte N.; Jackson, Rebecca D.; Jørgensen, Torben; Jørgensen, Marit E.; Kähönen, Mika; Kardia, Sharon L.R.; König, Wolfgang; Kooperberg, Charles; Kriebel, Jennifer; Launer, Lenore J.; Lauritzen, Torsten; Lehtimäki, Terho; Levy, Daniel; Linksted, Pamela; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J.F.; Lupo, Antonio; Meisinger, Christine; Melander, Olle; Metspalu, Andres; Mitchell, Paul; Nauck, Matthias; Nürnberg, Peter; Orho-Melander, Marju; Parsa, Afshin; Pedersen, Oluf; Peters, Annette; Peters, Ulrike; Polasek, Ozren; Porteous, David; Probst-Hensch, Nicole M.; Psaty, Bruce M.; Qi, Lu; Raitakari, Olli T.; Reiner, Alex P.; Rettig, Rainer; Ridker, Paul M.; Rivadeneira, Fernando; Rossouw, Jacques E.; Schmidt, Frank; Siscovick, David; Soranzo, Nicole; Strauch, Konstantin; Toniolo, Daniela; Turner, Stephen T.; Uitterlinden, André G.; Ulivi, Sheila; Velayutham, Dinesh; Völker, Uwe; Völzke, Henry; Waldenberger, Melanie; Wang, Jie Jin; Weir, David R.; Witte, Daniel; Kuivaniemi, Helena; Fox, Caroline S.; Franceschini, Nora; Goessling, Wolfram; Köttgen, Anna; Chu, Audrey Y.
In: Journal of the American Society of Nephrology, Vol. 28, No. 3, 03.2017, p. 981-994.Research output: Contribution to journal › Article › peer-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 - 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.
N1 - Publisher Copyright: © 2017 by the American Society of Nephrology. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
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 -