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Sci Rep. 2017 Apr 28;7:45040. doi: 10.1038/srep45040.

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

Gorski M1,2, van der Most PJ3, Teumer A4, Chu AY5,6, Li M7,8, Mijatovic V9, Nolte IM3, Cocca M10,11, Taliun D12, Gomez F13, Li Y14, Tayo B15, Tin A7, Feitosa MF13, Aspelund T16,17, Attia J18,19, Biffar R20, Bochud M21, Boerwinkle E22, Borecki I23, Bottinger EP24, Chen MH5, Chouraki V25, Ciullo M26,27, Coresh J7, Cornelis MC28, Curhan GC29,30, d'Adamo AP31, Dehghan A32, Dengler L2, Ding J33, Eiriksdottir G16, Endlich K34, Enroth S35, Esko T36, Franco OH32, Gasparini P37,38, Gieger C39,40,41, Girotto G37,38, Gottesman O24, Gudnason V16,42, Gyllensten U35, Hancock SJ18,43, Harris TB44, Helmer C45,46, Höllerer S1, Hofer E47,48, Hofman A32, Holliday EG19, Homuth G49, Hu FB50, Huth C41,51, Hutri-Kähönen N52, Hwang SJ5, Imboden M53,54, Johansson Å35, Kähönen M55,56, König W57,58,59, Kramer H15, Krämer BK60, Kumar A53,54,61, Kutalik Z21, Lambert JC25, Launer LJ44, Lehtimäki T62,63, de Borst M64, Navis G64, Swertz M64, Liu Y33, Lohman K33, Loos RJF24,65, Lu Y24, Lyytikäinen LP62,63, McEvoy MA18, Meisinger C41, Meitinger T66,67, Metspalu A36, Metzger M68, Mihailov E36, Mitchell P69, Nauck M70,71, Oldehinkel AJ72, Olden M1,5, Wjh Penninx B73, Pistis G10, Pramstaller PP12, Probst-Hensch N53,54, Raitakari OT74,75, Rettig R76, Ridker PM6,77, Rivadeneira F78, Robino A38, Rosas SE79, Ruderfer D24, Ruggiero D26, Saba Y80, Sala C10, Schmidt H80, Schmidt R47, Scott RJ81,82, Sedaghat S32, Smith AV16,42, Sorice R26,27, Stengel B68, Stracke S83, Strauch K39,84, Toniolo D10, Uitterlinden AG78, Ulivi S38, Viikari JS85,86, Völker U49,71, Vollenweider P87, Völzke H4,71,88, Vuckovic D37,38, Waldenberger M40,41, Jin Wang J69, Yang Q89, Chasman DI6,90,91, Tromp G92, Snieder H3, Heid IM1, Fox CS5, Köttgen A14,93, Pattaro C12, Böger CA2, Fuchsberger C12.

Author information

1
Department of Genetic Epidemiology, University Regensburg, Regensburg, Germany.
2
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
3
Department of Epidemiology, University of Groningen, University Medical Center Groningen, P.O. box 30.001, 9700 RB Groningen, The Netherlands.
4
Institute for Community Medicine, University Medicine Greifswald, Walther-Rathenau-Str. 48, 17475 Greifswald, Germany.
5
NHLBI's Framingham Heart Study, Framingham, MA 01702, USA.
6
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02215, USA.
7
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615N Wolfe St, Baltimore, MD, 21205, USA.
8
Division of Nephrology and Department of Human Genetics, University of Utah, USA.
9
Department of Life and Reproduction Sciences, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.
10
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132, Milano, Italy.
11
Department of Medical, Surgical and Health Sciences, University of Trieste, 34100, Trieste, Italy.
12
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy.
13
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63108, USA.
14
Division of Genetic Epidemiology, Medical Center and Faculty of Medicine - University of Freiburg, Freiburg, Germany.
15
Loyola University Chicago, 2160 South First Avenue, Bldg 105, Maywood, IL 60153, USA.
16
Icelandic Heart Association, Kopavogur, Iceland.
17
University of Iceland, Reykjavik, Iceland.
18
School of Medicine and Public Health, University of Newcastle, Australia.
19
Public Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
20
Clinic for Prosthodontic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
21
Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Route de la Corniche 10, 1010, Lausanne, Switzerland.
22
University of Texas Health Science Center at Houston, USA.
23
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
24
The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, USA.
25
Inserm U1167, Lille University, Institut Pasteur de Lille, Lille, France.
26
Institute of Genetics and Biophysics, "Adriano Buzzati-Traverso"-CNR, Via P. Castellino 111, 80131 Napoli, Italy.
27
IRCCS Neuromed, via dell'Elettronica, Pozzilli (Is), Italy.
28
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1400 Chicago, IL 60611, USA.
29
Renal Division, Brigham and Women's Hospital, USA.
30
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
31
Clinical Department of Medical, Surgical and Health Science, University of Trieste, Italy.
32
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
33
Wake Forest School of Medicine, USA.
34
Institute of Anatomy and Cell Biology, University Medicine Greifswald, Friedrich-Loeffler-Str. 23c, 17475 Greifswald, Germany.
35
Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden.
36
Estonian Genome Center, University of Tartu, Tartu, Estonia.
37
Department of Medical Sciences, Chirurgical and Health Department, University of Trieste, Trieste, Italy.
38
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
39
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
40
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
41
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
42
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
43
Health Services Research Group, University of Newcastle, Australia.
44
Intramural Research Program, Laboratory of Epidemiology and Population Studies, National Institute on Aging, USA.
45
INSERM, Centre INSERM Research Center U1219, Bordeaux, France.
46
University Bordeaux, ISPED, Bordeaux, France.
47
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria.
48
Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria.
49
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15a, 17475 Greifswald, Germany.
50
Department of Nutrition, Harvard School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, USA.
51
German Center for Diabetes Research (DZD), Neuherberg, Germany.
52
Department of Pediatrics, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland.
53
Unit Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
54
University of Basel, Switzerland.
55
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland.
56
Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland.
57
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
58
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
59
Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany.
60
University Medical Centre Mannheim, 5th Department of Medicine, University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany.
61
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
62
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland.
63
Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland.
64
University Medical Center Groningen, University of Groningen, The Netherlands.
65
The Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, USA.
66
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
67
Institute of Human Genetics, Technische Universität München, Munich, Germany.
68
Inserm U1018, University Paris-Sud, UVSQ, University Paris-Saclay, Villejuif, France.
69
Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney C24, NSW, 2145, Australia.
70
Institute of Clinical Chemistry and Laboratory Medicine-University Medicine Greifswald, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
71
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
72
Department of Psychiatry, University of Groningen, University Medical Center Groningen, P.O. box 30.001, 9700 RB, Groningen, The Netherlands.
73
Department of Psychiatry, Vrije Universiteit, VU University Medical Center, NESDA, A.J. Ernststraat 1187, 1081HL Amsterdam, The Netherlands.
74
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland.
75
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
76
Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany.
77
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA.
78
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
79
Joslin Diabetes Center. Harvard Medical School, Boston, MA, USA.
80
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Austria.
81
School of Biomedical Sciences and Pharmacy, University of Newcastle, Australia.
82
Molecular Medicine, Pathology North Ph. 0409926764, Newcastle, Australia.
83
Clinic for Internal Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
84
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
85
Division of Medicine, Turku University Hospital, Turku 20521, Finland.
86
Department of Medicine, University of Turku, Turku 20520, Finland.
87
Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
88
DZD (German Center for Diabetes Research), Site Greifswald, Greifswald, Germany.
89
Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA.
90
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
91
Broad Institute of MIT and Harvard, Cambridge MA 02142 USA.
92
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA.
93
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.

Abstract

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

PMID:
28452372
PMCID:
PMC5408227
DOI:
10.1038/srep45040
[Indexed for MEDLINE]
Free PMC Article

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