SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
Authors: 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 ,   CHARGE Glycemic-T2D Working Group,,   CHARGE Blood Pressure Working Group,, 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. 
Published: December 2016

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 (n
Stage1: 111,666; n
Stage2: 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; P
Stage1<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.