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

Mathias Gorski, Adrienne Tin, Maija Garnaas, Gearoid M. McMahon, Audrey Y. Chu, Bamidele O. Tayo, Cristian Pattaro, Alexander Teumer, Daniel I. Chasman, John Chalmers, Pavel Hamet, Johanne Tremblay, Marc Woodward, Thor Aspelund, Gudny Eiriksdottir, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Braxton D. MitchellJeffrey R. O'Connell, Alan R. Shuldiner, Josef Coresh, Man Li, Paul Freudenberger, Edith Hofer, Helena Schmidt, Reinhold Schmidt, Elizabeth G. Holliday, Paul Mitchell, Jie Jin Wang, Ian H. De Boer, Guo Li, David S. Siscovick, Zoltan Kutalik, Tanguy Corre, Peter Vollenweider, Gérard Waeber, Jayanta Gupta, Peter A. Kanetsky, Shih Jen Hwang, Matthias Olden, Qiong Yang, Mariza De Andrade, Elizabeth J. Atkinson, Sharon L.R. Kardia, Stephen T. Turner, Jeanette M. Stafford, Jingzhong Ding, Yongmei Liu, Cristina Barlassina, Daniele Cusi, Erika Salvi, Jan A. Staessen, Paul M. Ridker, Harald Grallert, Christa Meisinger, Martina Müller-Nurasyid, Bernhard K. Krämer, Holly Kramer, Sylvia E. Rosas, Ilja M. Nolte, Brenda W. Penninx, Harold Snieder, M. Fabiola Del Greco, Andre Franke, Ute Nöthlings, Wolfgang Lieb, Stephan J.L. Bakker, Ron T. Gansevoort, Pim Van Der Harst, Abbas Dehghan, Oscar H. Franco, Albert Hofman, Fernando Rivadeneira, Sanaz Sedaghat, André G. Uitterlinden, Stefan Coassin, Margot Haun, Barbara Kollerits, Florian Kronenberg, Bernhard Paulweber, Nicole Aumann, Karlhans Endlich, Mike Pietzner, Uwe Völker, Rainer Rettig, Vincent Chouraki, Catherine Helmer, Jean Charles Lambert, Marie Metzger, Benedicte Stengel, Terho Lehtimäki, Leo Pekka Lyytikäinen, Olli Raitakari, Andrew Johnson, Afshin Parsa, Murielle Bochud, Iris M. Heid, Wolfram Goessling, Anna Köttgen, W. H.Linda Kao, Caroline S. Fox, Carsten A. Böger

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1017-1029
Number of pages13
JournalKidney international
Volume87
Issue number5
DOIs
StatePublished - May 11 2015
Externally publishedYes

Bibliographical note

Funding Information:
HYPERGENES (FP7—HEALTH-F4-2007-201550); INTEROMICS (MIUR—CNR Italian Flagship Project); IC15-CT98-0329-EPOGH; LSHM-CT-2006-037093; HEALTH-2011-278249-EU-MASCARA; and ERC Advanced Grant-2011-294713-EPLORE and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen; Ministry of the Flemish Community; Brussels; Belgium (grants G.0575.06 and G.0734.09)

Funding Information:
The Health Aging and Body Composition Study (Health ABC) was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

Funding Information:
GENOA: This research was partially supported by the National Heart Lung and Blood Institute of the National Institutes of Health (R01 HL-87660).

Funding Information:
NESDA was supported by the Geestkracht program of ZonMW (grant 10-000-1002), matching funds from universities and mental health-care institutes involved in NESDA. Funding support was also provided by the Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717), Centre for Medical Systems Biology (NWO Genomics), the Neuroscience Campus Amsterdam, the EMGO institute, the European Union (EU/WLRT-2001-01254), and by NIMH (RO1 MH059160). Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802) and the Center for Molecular and Systems Biology. Genotype data were obtained from dbGaP ( http://www.ncbi.nlm.nih.gov/dbgap ), accession number phs000020.v1.p1. Statistical analyses were partly conducted at the Genetic Cluster Computer ( http://www.geneticcluster.org ), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation.

Funding Information:
The CHS research reported in this article was supported by contract numbers N01-HC-85079–01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm . DNA handling and genotyping were supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Funding Information:
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. AK was supported by the grant KO3598/2-1 (Emmy Noether Programme) of the German Research Foundation.

Funding Information:
Rotterdam Study II: The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and by the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Dr Michael Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners, and the pharmacists. We thank Dr Tobias A Knoch, Luc V de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundes-ministerium für Forschung und Technology under grants #01 AK 803 A-H and #01 IG 07015 G, for access to their grid resources. AD is supported by NWO grant (vici, 918-76-619).

Funding Information:
The Blue Mountains Eye Study (BMES) was supported by the Australian National Health and Medical Research Council (NHMRC), Canberra Australia (NHMRC project grant IDs 974159, 211069, and 302068, and Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye, grant ID 529923). The BMES GWAS and genotyping costs were supported by Australian NHMRC, Canberra Australia (NHMRC project grant IDs 512423, 475604, and 529912), and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster, grant IDs 085475/B/08/Z and 085475/08/Z). EGH is supported by the NHMRC Fellowship scheme.

Funding Information:
KORA studies: The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, USA (HEW, IMH, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (HEW 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kröner-Fresenius-Stiftung (P48/08//A11/08 to CAB and BKK; 2012_A147 to CAB and IMH). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius-Stiftung (CAB, BKK) and the Regensburg University Medical Center, Germany, and in F4 by the University of Ulm, Germany (WK). Genome-wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (CAB, BKK). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (CAB, IMH). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research, and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation was funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center.

Funding Information:
The CoLaus study received financial contributions from GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne; and the Swiss National Science Foundation (33CSCO-122661; 3200BO-111361/2; 3100AO-116323/1;310000-112552). MB is supported by the Swiss School of Public Health Plus.

Funding Information:
The SAPHIR study was partially supported by a grant from the Kamillo Eisner Stiftung to B Paulweber and by grants from the ‘Genomics of Lipid-associated Disorders—GOLD’ of the ‘Austrian Genome Research Programme GEN-AU’ to F Kronenberg.

Funding Information:
ASPS: The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The authors thank the staff and the participants of the ASPS for their valuable contributions. We thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA bank.

Funding Information:
FHS: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.

Funding Information:
KORA studies: The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, USA (HEW, IMH, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (HEW, 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kröner-Fresenius-Stiftung (P48/08//A11/08 to CAB and BKK; 2012_A147 to CAB and IMH). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius-Stiftung (CAB, BKK) and the Regensburg University Medical Center, Germany, and those in F4 by the University of Ulm, Germany (WK). Genome-wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (CAB, BKK). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (CAB, IMH). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research, and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation was funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center.

Funding Information:
The Young Finns Study has been financially supported by the Academy of Finland grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere, and Turku University Hospital Medical Funds (grants 9M048 and 9N035 for TeLeht), the Juho Vainio Foundation, the Paavo Nurmi Foundation, the Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, the Tampere Tuberculosis Foundation, and the Emil Aaltonen Foundation (TL). The expert technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen is gratefully acknowledged.

Funding Information:
AGES: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. We are indebted to the participants for their willingness to participate in the study.

Funding Information:
AMISH: The Amish studies are supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (PAPI Study), U01 HL072515-06 (HAPI Study), U01 HL084756 and NIH K12RR023250 (University of Maryland MCRDP), NIH P30 DK072488 (Clinical Nutrition Research Unit), the University of Maryland General Clinical Research Center, grant M01 RR 16500, and the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center. We thank our Amish research volunteers for their long-standing partnership in research, and the research staff at the Amish Research Clinic for their hard work and dedication.

Funding Information:
SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG.

Funding Information:
The PREVEND Study was financially supported by several grants from the Dutch Kidney Foundation.

Funding Information:
Rotterdam Study 1: The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Dr Michael Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners, and the pharmacists. We thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundes-ministerium für Forschung und Technology under grants #01 AK 803 A-H and #01 IG 07015 G, for access to their grid resources. AD is supported by an NWO grant (vici, 918-76-619).

Funding Information:
Three Cities: The work was made possible by the generous participation of the control subjects, the patients, and their families. We thank Dr Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University, and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France, and the joint French Ministry of Research/INSERM ‘Cohortes et collections de données biologiques’ program. Lille Génopôle received an unconditional grant from Eisai.

Funding Information:
POPGEN: This study was funded by the German National Genome Research Network (NGFN; Federal Ministry of Education and Research, grant numbers 1GS0121, 01GS0171, and 01GR0468) and by the DFG Excellence Cluster ‘Inflammation at Interfaces’ (EXC 306).

Funding Information:
ADVANCE: The genetic epidemiological work was funded by Prognomix Inc. and by grants from Genome Quebec and Canadian Institutes for Health Research. The clinical study was managed by the George Institute for International Health (Sydney, Australia) with grants received from Les Laboratoires Servier, France, and from Medical Research Council of Australia. The genotyping was performed at the genomic platform of CRCHUM. We acknowledge the technical help of Carole Long and Mounsif Haloui and the bioinformatic analyses performed by Gilles Godefroid, François-Christophe Blanchet-Marois, and François Harvey. The members of the genetic substudy of ADVANCE, Stephen Harrap, and Michel Marre are also acknowledged.

Keywords

  • chronic kidney disease
  • genome-wide association study
  • kidney development
  • kidney function decline
  • population genetics
  • single nucleotide polymorphism
  • zebrafish

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