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J Am Soc Nephrol. 2017 Mar;28(3):981-994. doi: 10.1681/ASN.2016020131. Epub 2016 Dec 5.

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

Li M1,2, Li Y3, Weeks O4, Mijatovic V5, Teumer A6, Huffman JE7,8, Tromp G9,10, Fuchsberger C11,12, Gorski M13,14, Lyytikäinen LP15, Nutile T16, Sedaghat S17, Sorice R16, Tin A1, Yang Q18, Ahluwalia TS19,20, Arking DE21, Bihlmeyer NA21, Böger CA14, Carroll RJ22, Chasman DI4,22,23, Cornelis MC24, Dehghan A17, Faul JD25, Feitosa MF26, Gambaro G27, Gasparini P28, Giulianini F29, Heid I13,30, Huang J31,32, Imboden M33, Jackson AU12, Jeff J34, Jhun MA35, Katz R36, Kifley A37, Kilpeläinen TO19, Kumar A33, Laakso M38, Li-Gao R17, Lohman K39, Lu Y34, Mägi R40, Malerba G41, Mihailov E40, Mohlke KL42, Mook-Kanamori DO43,44, Robino A45, Ruderfer D46, Salvi E47, Schick UM48, Schulz CA49, Smith AV50,51, Smith JA35, Traglia M52, Yerges-Armstrong LM53, Zhao W35, Goodarzi MO54,55, Kraja AT56, Liu C7, Wessel J57,58; CHARGE Glycemic-T2D Working Group,; CHARGE Blood Pressure Working Group,, Boerwinkle E59, Borecki IB26, Bork-Jensen J19, Bottinger EP34, Braga D47, Brandslund I60, Brody JA61, Campbell A8, Carey DJ9, Christensen C62, Coresh J1, Crook E63, Curhan GC64, Cusi D47,65, de Boer IH36, de Vries AP66, Denny JC22, Devuyst O67, Dreisbach AW68, Endlich K69, Esko T21,40,70,71, Franco OH17, Fulop T68, Gerhard GS72, Glümer C73, Gottesman O34, Grarup N19, Gudnason V50, Hansen T19,74, Harris TB75, Hayward C8,76, Hocking L77, Hofman A17, Hu FB78, Husemoen LL73, Jackson RD79, Jørgensen T73, Jørgensen ME20, Kähönen M14, Kardia SL35, König W80,81,82, Kooperberg C48, Kriebel J83,83, Launer LJ75, Lauritzen T84, Lehtimäki T15, Levy D7, Linksted P8, Linneberg A73,85,74, Liu Y86, Loos RJ34, Lupo A87, Meisinger C83, Melander O49, Metspalu A40, Mitchell P37, Nauck M88,89, Nürnberg P90, Orho-Melander M49, Parsa A91, Pedersen O19, Peters A83,83,92, Peters U48, Polasek O93, Porteous D8, Probst-Hensch NM33, Psaty BM61,94,95, Qi L78, Raitakari OT96, Reiner AP48, Rettig R97, Ridker PM29,98, Rivadeneira F99, Rossouw JE100, Schmidt F101, Siscovick D61, Soranzo N41, Strauch K83,102, Toniolo D52, Turner ST103, Uitterlinden AG99, Ulivi S45, Velayutham D47, Völker U89,101, Völzke H6,89,104, Waldenberger M83,83, Wang JJ37, Weir DR25, Witte D105, Kuivaniemi H9,10, Fox CS7, Franceschini N106, Goessling W4,20,107,108,109, Köttgen A110,3, Chu AY111,29.

Collaborators (300)

Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, Dauriz M, Hivert MF, Raghavan S, Lipovich L, Hidalgo B, Fox K, Huffman JE, An P, Lu Y, Rasmussen-Torvik LJ, Grarup N, Ehm MG, Baldridge AS, Stančáková A, Abrol R, Besse CL, Boland A, Bork-Jensen J, Fornage M, Freitag DF, Garcia ME, Guo X, Hara K, Isaacs A, Jakobsdottir J, Lange LA, Layton JC, Li M, Zhao JH, Meidtner K, Morrison AC, Nalls MA, Peters MJ, Sabater-Lleal M, Schurmann C, Silveira A, Smith AV, Southam L, Stoiber MH, Strawbridge RJ, Taylor KD, Varga TV, Allin KH, Amin N, Aponte JL, Aung T, Barbieri C, Bihlmeyer NA, Boehnke M, Bombieri C, Bowden DW, Burns SM, Chen Y, Chen YD, Cheng CY, Correa A, Czajkowski J, Dehghan A, Ehret GB, Eiriksdottir G, Escher SA, Farmaki AE, Frånberg M, Gambaro G, Giulianini F, Goddard WA 3rd, Goel A, Gottesman O, Grove ML, Gustafsson S, Hai Y, Hallmans GR, Heo J, Hoffmann P, Ikram MK, Jensen RA, Jørgensen ME, Jørgensen T, Karaleftheri M, Khor CC, Kirkpatrick A, Kraja AT, Kuusisto J, Lange EM 1st, Lee T, Lee WJ, Leong A, Liao J, Liu C, Liu Y, Lindgren CM, Linneberg A, Malerba G, Mamakou V, Marouli E, Maruthur NM, Matchan A, McKean-Cowdin R, McLeod O, Metcalf GA, Mohlke KL, Muzny DM, Ntalla I, Palmer ND, Pasko D, Peter A, Rayner NW, Renstro M F, Rice K, Sala CF, Sennblad B, Serafetinidis I, Smith JA, Soranzo N, Speliotes EK, Stahl EA, Stirrups K, Tentolouris N, Thanopoulou A, Torres M, Traglia M, Tsafantakis E, Javad S, Yanek LR, Zengini E, Becker DM, Bis JC, Brown JB, Cupples LA, Hansen T, Ingelsson E, Karter AJ, Lorenzo C, Mathias RA, Norris JM, Peloso GM, Sheu WH, Toniolo D, Vaidya D, Varma R, Wagenknecht LE, Boeing H, Bottinger EP, Dedoussis G, Deloukas P, Ferrannini E, Franco OH, Franks PW, Gibbs RA, Gudnason V, Hamsten A, Harris TB, Hattersley AT, Hayward C, Hofman A, Jansson JH, Langenberg C, Launer LJ, Levy D, Oostra BA, O'Donnell CJ, O'Rahilly S, Padmanabhan S, Pankow JS, Polasek O, Province MA, Rich SS, Ridker PM, Rudan I, Schulze MB, Smith BH, Uitterlinden AG, Walker M, Watkins H, Wong TY, Zeggini E, Consortiumy TE, Laakso M, Borecki IB, Chasman DI, Pedersen O, Psaty BM, Tai ES, van Duijn CM, Wareham NJ, Waterworth DM, Boerwinkle E, Kao WH, Florez JC, Loos RJ, Wilson JG, Frayling TM, Siscovick DS, Dupuis JE, Rotter JI, Meigs JB, Scott RA, Goodarzi MO, Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, Rice K, Morrison AC, Lu Y, Weiss S, Guo X, Palmas W, Martin LW, Chen YI, Surendran P, Drenos F, Cook JP, Auer PL, Chu AY, Giri A, Zhao W, Jakobsdottir J, Lin LA, Stafford JM, Amin N, Mei H, Yao J, Voorman A, Larson MG, Grove ML, Smith AV, Hwang SJ, Chen H, Huan T, Kosova G, Stitziel NO, Kathiresan S, Samani N, Schunkert H, Deloukas P, Genetics MI, Li M, Fuchsberger C, Pattaro C, Gorski M, Kooperberg C, Papanicolaou GJ, Rossouw JE, Faul JD, Kardia SL, Bouchard C, Raffel LJ, Uitterlinden AG, Franco OH, Vasan RS, O'Donnell CJ, Taylor KD, Liu K, Bottinger EP, Gottesman O, Daw EW, Giulianini F, Ganesh S, Salfati E, Harris TB, Launer LJ, Dörr M, Felix SB, Rettig R, Völzke H, Kim E, Lee WJ 1st, Lee T, Sheu WH, Tsosie KS, Edwards DR, Liu Y, Correa A, Weir DR, Völker U, Ridker PM, Boerwinkle E, Gudnason V, Reiner AP, van Duijn CM, Borecki IB, Edwards TL, Chakravarti A, Rotter JI, Psaty BM, Loos RJ, Fornage M, Ehret G, Newton-Cheh C, Levy D, Chasman DI.

Author information

1
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
2
Division of Nephrology and Department of Human Genetics, University of Utah, Salt Lake City, Utah.
3
Division of Genetic Epidemiology, Medical Center - University of Freiburg, Freiburg, Germany.
4
Genetics Division.
5
Department of Life and Reproduction Sciences, and.
6
Institute for Community Medicine.
7
National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, Massachusetts.
8
Center for Genomic & Experimental Medicine, Institute of Genetics and Molecular Medicine.
9
The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania.
10
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
11
Center for Biomedicine, European Academy of Bolzano/Bozen, affiliated to the University of Lübeck, Bolzano/Bozen, Italy.
12
Department of Biostatistics, Center for Statistical Genetics.
13
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
14
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
15
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
16
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Napoli, Italy.
17
Department of Epidemiology, and.
18
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
19
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, and.
20
Steno Diabetes Center, Gentofte, Denmark.
21
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
22
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
23
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
24
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
25
Survey Research Center, Institute for Social Research, and.
26
Department of Genetics, School of Medicine, Washington University School of Medicine, St. Louis, Missouri.
27
Division of Nephrology, Gemelli Foundation University Hospital, Catholic University, Rome, Italy.
28
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, Trieste, Italy.
29
Division of Preventive Medicine.
30
Institute of Genetic Epidemiology and.
31
Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
32
State Key Laboratory of Medical Genomics, Shanghai, China.
33
Swiss Tropical and Public Health Institute, Basel, Switzerland.
34
The Charles Bronfman Institute for Personalized Medicine, and.
35
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan.
36
Kidney Research Institute.
37
Center for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Westmead, Sydney, New South Wales, Australia.
38
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
39
Division of Public Health Sciences, Biostatistical Sciences, and.
40
Estonian Genome Center of University of Tartu, Tartu, Estonia.
41
Section of Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
42
Department of Genetics, and.
43
Department of Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
44
Epidemiology Section, Department of Biostatistics Epidemiology & Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
45
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
46
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
47
Department of Health Science, University of Milano, Milano, Italy.
48
Fred Hutchinson Cancer Research Center, Seattle, Washington.
49
Department of Clinical Science, Lund University, Malmö, Sweden.
50
Icelandic Heart Association, Kopavogur, Iceland.
51
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
52
San Raffaele Scientific Institute, Milano, Italy.
53
Program in Personalized and Genomic Medicine and Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland.
54
Department of Medicine and Department of Biomedical Sciences, and.
55
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California.
56
Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University, St. Louis, Missouri.
57
Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana.
58
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
59
The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas.
60
Department of Clinical Biochemistry, and.
61
Cardiovascular Health Research Unit, Department of Medicine, and.
62
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
63
Department of Medicine, University of South Alabama College of Medicine, Mobile, Alabama.
64
Renal Division and Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts.
65
Division of Nephrology, San Paolo Hospital, Milan, Italy.
66
Division of Nephrology, Department of Medicine, Leiden University Medical Center and Leiden University, The Netherlands.
67
University of Zurich, Institute of Physiology, Zurich Center for Integrative Human Physiology, Mechanisms of Inherited Kidney Disorders Group, Zürich, Switzerland.
68
Department of Medicine, University of Mississippi, Jackson, Mississippi.
69
Department of Anatomy and Cell Biology.
70
Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts.
71
Department of Genetics, Harvard Medical School, Boston, Massachusetts.
72
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania.
73
Research Center for Prevention and Health, The Capital Region of Denmark, Glostrup University Hospital, Glostrup, Denmark.
74
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
75
National Institutes on Aging, Bethesda, Maryland.
76
Medical Research Council Human Genetics, Institute of Genetics and Molecular Medicine, and.
77
Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, United Kindom.
78
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
79
Department of Internal Medicine, The Ohio State University, Columbia, Ohio.
80
Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Ulm, Germany.
81
The German Heart Center Munich, Technical University of Munich, Munich, Germany.
82
German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany.
83
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
84
Department of General Practice, Aarhus University, Aarhus, Denmark.
85
Department of Clinical Experimental Research, Rigshospitalet, Denmark.
86
Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
87
Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy.
88
Institute of Clinical Chemistry and Laboratory Medicine.
89
German Center for Cardiovascular Research, partner site Greifswald, Greifswald, Germany.
90
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
91
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
92
German Center for Cardiovascular Disease Research, Munich, Germany.
93
Center for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
94
Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington.
95
Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
96
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
97
Institute of Physiology, and.
98
Cardiovascular Medicine Division, and.
99
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
100
National Heart, Lung, and Blood Institute, Bethesda, Maryland.
101
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
102
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
103
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
104
German Center for Diabetes Research, partner site Greifswald, Greifswald, Germany.
105
Department of Public Health, Aarhus University, Aarhus, Denmark.
106
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
107
Harvard Stem Cell Institute, Cambridge, Massachusetts; and.
108
Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
109
Dana-Farber Cancer Institute, Boston, Massachusetts.
110
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland; audrey.chu@nih.gov anna.koettgen@uniklinik-freiburg.de.
111
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.

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, and ATXN2L; 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=5.4×10-8 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.

KEYWORDS:

human genetics; kidney development; renal function

PMID:
27920155
PMCID:
PMC5328154
DOI:
10.1681/ASN.2016020131
[Indexed for MEDLINE]
Free PMC Article

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