Format

Send to

Choose Destination
Kidney Int. 2015 May;87(5):1017-29. doi: 10.1038/ki.2014.361. Epub 2014 Dec 10.

Genome-wide association study of kidney function decline in individuals of European descent.

Author information

1
1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany [2] Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
2
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
3
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
1] Division of Nephrology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA [2] NHLBI's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA.
5
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Department of Public Health Services, Loyola Medical Center, Loyola University Chicago, Maywood, Illinois, USA.
7
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy.
8
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
9
George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia.
10
Centre de recherche du Centre hospitalier de l'Université de Montréal, University of Montreal, Montreal, Quebec, Canada.
11
CHUM Research Center- Technopôle Angus, Montreal, Québec, Canada.
12
1] Icelandic Heart Association, Research Institute, Kopavogur, Iceland [2] University of Iceland, Reykjavik, Iceland.
13
Icelandic Heart Association, Research Institute, Kopavogur, Iceland.
14
Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
15
1] Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA [2] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.
16
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
17
1] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA [2] Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland, USA.
18
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
19
Department of Neurology, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria.
20
Department of Neurology, Medical University Graz, Graz, Austria.
21
Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, CReDITSS, HMRI, Callaghan, New South Wales, Australia.
22
Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
23
University of Washington, Seattle, Washington, USA.
24
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.
25
1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA [2] New York Academy of Medicine, New York, New York, USA.
26
1] Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland [2] Department of Medical Genetics, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
27
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
28
Internal Medicine Department, Lausanne University Hospital, Lausanne, Switzerland.
29
Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics.
30
NHLBI's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA.
31
1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany [2] NHLBI's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA.
32
1] NHLBI's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
33
Mayo Clinic, Rochester, Minnesota, USA.
34
University of Michigan, Ann Arbor, Michigan, USA.
35
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
36
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
37
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
38
Department of Health Science, University of Milano, Milano, Italy.
39
1] Department of Health Science, University of Milano, Milano, Italy [2] Division of Nephrology, San Paolo Hospital, Milano, Italy.
40
1] Department of Epidemiology, Maastricht University, Maastricht, The Netherlands [2] Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
41
1] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany [2] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany [3] German Center for Diabetes Research, Neuherberg, Germany.
42
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
43
1] DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany [2] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany [3] Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany [4] Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
44
University Medical Centre Mannheim, 5th Department of Medicine, University of Heidelberg, Mannheim, Germany.
45
Joslin Diabetes Center and Beth Israel Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
46
1] Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, Groningen, The Netherlands.
47
1] Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands [2] EMGO Institute Vumc, NESDA, Amsterdam, The Netherlands.
48
Institute of Clinical Molecular Biology, Kiel, Germany.
49
1] Popgen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany [2] Section for Epidemiology, Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
50
Institute of Epidemiology and Biobank popgen, Christian-Albrechts University, Kiel, Germany.
51
University Medical Center Groningen, Department of Nephrology, University of Groningen, Groningen, The Netherlands.
52
University Medical Center Groningen, Department of Cardiology, University of Groningen, Groningen, The Netherlands.
53
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
54
Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.
55
First Department of Internal Medicine, Paracelsus Private Medical University Salzburg, Salzburg, Austria.
56
Department SHIP/KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
57
Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
58
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
59
Institute of Physiology, University of Greifswald, Greifswald-Karlsburg, Germany.
60
Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, CHR&U de Lille, Service d'épidémiologie régional, CHRU, Lille, France.
61
Inserm, U897, Université Bordeaux 2, ISPED, ISPED, Université Bordeaux 2, Bordeaux, France.
62
Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, Institut Pasteur, Lille, France.
63
Inserm, U1018, University Paris-Sud, CESP Team 10, Villejuif, France.
64
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
65
1] Department of Clinical Physiology, Turku University Hospital, Turku, Finland [2] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
66
NHLBI Cardiovascular Epidemiology and Human Genomics Branch, Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA.
67
Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Epalinges, Switzerland.
68
1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany [2] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
69
1] Divisions of Genetics and Gastroenterology, Department of Medicine, Brigham and Women's Hospital, and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA [2] Harvard Stem Cell Institute, Harvard University and Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
70
1] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA [2] Renal Division, Freiburg University Clinic, Germany, Freiburg, Germany.
71
1] NHLBI's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA [2] Department of Endocrinology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
72
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.

Abstract

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

PMID:
25493955
PMCID:
PMC4425568
DOI:
10.1038/ki.2014.361
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center