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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 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 languageEnglish (US)
Pages (from-to)981-994
Number of pages14
JournalJournal of the American Society of Nephrology
Volume28
Issue number3
DOIs
StatePublished - Mar 2017

ASJC Scopus subject areas

  • Nephrology

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