title: SOS2andACP1Loci 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 from the 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<3.7×10-7), 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=5.4×10-8by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney ofacp1-andsos2-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.
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authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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authors.affiliation: Kidney Research Institute.
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authors.affiliation: Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Ulm, Germany.|The German Heart Center Munich, Technical University of Munich, Munich, Germany.|German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: Research Center for Prevention and Health, The Capital Region of Denmark, Glostrup University Hospital, Glostrup, Denmark.|Department of Clinical Experimental Research, Rigshospitalet, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
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authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, and.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Cardiovascular Disease Research, Munich, Germany.
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authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, and.|Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
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authors.initials: OT
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authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
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authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
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authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, and.
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authors.affiliation: Section of Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Daniela
authors.initials: D
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authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
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authors.initials: ST
authors.lastname: Turner
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulivi
authors.affiliation: Department of Health Science, University of Milano, Milano, Italy.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Velayutham
authors.affiliation: German Center for Cardiovascular Research, partner site Greifswald, Greifswald, Germany.|Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Institute for Community Medicine.|German Center for Cardiovascular Research, partner site Greifswald, Greifswald, Germany.|German Center for Diabetes Research, partner site Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Center for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Westmead, Sydney, New South Wales, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Survey Research Center, Institute for Social Research, and.
authors.forename: David R
authors.initials: DR
authors.lastname: Weir
authors.affiliation: Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Witte
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania.|Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, Massachusetts.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Genetics Division.|Steno Diabetes Center, Gentofte, Denmark.|Harvard Stem Cell Institute, Cambridge, Massachusetts; and.|Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland; audrey.chu@nih.gov anna.koettgen@uniklinik-freiburg.de.|Division of Genetic Epidemiology, Medical Center - University of Freiburg, Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, Massachusetts; audrey.chu@nih.gov anna.koettgen@uniklinik-freiburg.de.|Division of Preventive Medicine.
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
mesh_terms: D000818:Animals; D059472:Exome / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000196:embryology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020664:Son of Sevenless Proteins / Q000235:genetics*; D015027:Zebrafish
chemical_list: D011518:Proto-Oncogene Proteins; C485509:SOS2 protein, human; D020664:Son of Sevenless Proteins; C490429:ACP1 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: human genetics; kidney development; renal function