Genome-wide association study of kidney function decline in individuals of European descent
Identifieur interne : 002D56 ( Pmc/Corpus ); précédent : 002D55; suivant : 002D57Genome-wide association study of kidney function decline in individuals of European descent
Auteurs : 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 ; Tammara B. Harris ; Lenore J. Launer ; Albert V. Smith ; Braxton D. Mitchell ; Jeffrey 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. Kr Mer ; Holly Kramer ; Sylvia E. Rosas ; Ilja M. Nolte ; Brenda W. Penninx ; Harold Snieder ; 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 Lehtim Ki ; Leo-Pekka Lyytik Inen ; Olli Raitakari ; Andrew Johnson ; Afshin Parsa ; Murielle Bochud ; Iris M. Heid ; Wolfram Goessling ; Anna Köttgen ; H. Linda Kao ; Caroline S. Fox ; Carsten A. BögerSource :
- Kidney international [ 0085-2538 ] ; 2014.
Abstract
Genome wide association studies (GWAS) 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, SNPs at
Url:
DOI: 10.1038/ki.2014.361
PubMed: 25493955
PubMed Central: 4425568
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PMC:4425568Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome-wide association study of kidney function decline in individuals of European descent</title><author><name sortKey="Gorski, Mathias" sort="Gorski, Mathias" uniqKey="Gorski M" first="Mathias" last="Gorski">Mathias Gorski</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Tin, Adrienne" sort="Tin, Adrienne" uniqKey="Tin A" first="Adrienne" last="Tin">Adrienne Tin</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation></author><author><name sortKey="Garnaas, Maija" sort="Garnaas, Maija" uniqKey="Garnaas M" first="Maija" last="Garnaas">Maija Garnaas</name><affiliation><nlm:aff id="A4">Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff></affiliation></author><author><name sortKey="Mcmahon, Gearoid M" sort="Mcmahon, Gearoid M" uniqKey="Mcmahon G" first="Gearoid M." last="Mcmahon">Gearoid M. Mcmahon</name><affiliation><nlm:aff id="A5">Brigham and Women's Hospital Division of Nephrology, 75 Francis St, Boston MA 02115</nlm:aff></affiliation><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Tayo, Bamidele O" sort="Tayo, Bamidele O" uniqKey="Tayo B" first="Bamidele O." last="Tayo">Bamidele O. Tayo</name><affiliation><nlm:aff id="A8">Department of Public Health Services, Loyola Medical Center, 2160 S First Avenue, Maywood, IL 60153, 2160 S First Avenue, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Pattaro, Cristian" sort="Pattaro, Cristian" uniqKey="Pattaro C" first="Cristian" last="Pattaro">Cristian Pattaro</name><affiliation><nlm:aff id="A9">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy, Affiliated Institute of the University of Lübeck, Germany, Viale Druso, 1 - 39100 Bolzano (Italy)</nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="A10">Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Friedrich-Ludwig-Jahn-Str 15a, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I." last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation><nlm:aff id="A11">The George Institute for Global Health, University of Sydney, PO Box M201 Missenden Rd, Sydney NSW 2050 Australia</nlm:aff></affiliation></author><author><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><affiliation><nlm:aff id="A12">Centre de recherche du Centre hospitalier de l’Université de Montréal, University of Montreal, Canada, 2901 Rachel street East, Montreal (PQ) H1W 4A4, Canada</nlm:aff></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="A13">CHUM Research Center- Technopôle Angus, 2901 Rachel Street office 301, Montreal (Québec) H1W4A4</nlm:aff></affiliation></author><author><name sortKey="Woodward, Marc" sort="Woodward, Marc" uniqKey="Woodward M" first="Marc" last="Woodward">Marc Woodward</name><affiliation><nlm:aff id="A11">The George Institute for Global Health, University of Sydney, PO Box M201 Missenden Rd, Sydney NSW 2050 Australia</nlm:aff></affiliation></author><author><name sortKey="Aspelund, Thor" sort="Aspelund, Thor" uniqKey="Aspelund T" first="Thor" last="Aspelund">Thor Aspelund</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Harris, Tammara B" sort="Harris, Tammara B" uniqKey="Harris T" first="Tammara B." last="Harris">Tammara B. Harris</name><affiliation><nlm:aff id="A16">Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, 3C-309, Bethesda MD 20892 USA</nlm:aff></affiliation></author><author><name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name><affiliation><nlm:aff id="A16">Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, 3C-309, Bethesda MD 20892 USA</nlm:aff></affiliation></author><author><name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D." last="Mitchell">Braxton D. Mitchell</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="O Connell, Jeffrey R" sort="O Connell, Jeffrey R" uniqKey="O Connell J" first="Jeffrey R." last="O'Connell">Jeffrey R. O'Connell</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Shuldiner, Alan R" sort="Shuldiner, Alan R" uniqKey="Shuldiner A" first="Alan R." last="Shuldiner">Alan R. Shuldiner</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Coresh, Josef" sort="Coresh, Josef" uniqKey="Coresh J" first="Josef" last="Coresh">Josef Coresh</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Welch Center for Prevention, Epidmiology and Clinical Research, 2024 E Monument St, Suite 2-600, Baltimore, MD 21287</nlm:aff></affiliation></author><author><name sortKey="Li, Man" sort="Li, Man" uniqKey="Li M" first="Man" last="Li">Man Li</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation></author><author><name sortKey="Freudenberger, Paul" sort="Freudenberger, Paul" uniqKey="Freudenberger P" first="Paul" last="Freudenberger">Paul Freudenberger</name><affiliation><nlm:aff id="A20">Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria, Harrachgasse 21, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Hofer, Edith" sort="Hofer, Edith" uniqKey="Hofer E" first="Edith" last="Hofer">Edith Hofer</name><affiliation><nlm:aff id="A21">Department of Neurology and Institute for Medical Informatics, Statistics and Documentation Medical University Graz, Austria, Auenbruggerplatz 22 and Auenbruggerplatz2, 8036 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name><affiliation><nlm:aff id="A20">Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria, Harrachgasse 21, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name><affiliation><nlm:aff id="A22">Department of Neurology, Medical University Graz, Austria, Auenbruggerplatz 22, 8036 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Holliday, Elizabeth G" sort="Holliday, Elizabeth G" uniqKey="Holliday E" first="Elizabeth G." last="Holliday">Elizabeth G. Holliday</name><affiliation><nlm:aff id="A23">University of Newcastle, Centre for Clinical Epidemiology & Biostatistics, CReDITSS, HMRI, C/-University Drive, Callaghan NSW 2308, Australia</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Paul" sort="Mitchell, Paul" uniqKey="Mitchell P" first="Paul" last="Mitchell">Paul Mitchell</name><affiliation><nlm:aff id="A24">University of Sydney, Westmead Millennium Institute, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead Hospital, NSW 2145 Australia</nlm:aff></affiliation></author><author><name sortKey="Wang, Jie Jin" sort="Wang, Jie Jin" uniqKey="Wang J" first="Jie Jin" last="Wang">Jie Jin Wang</name><affiliation><nlm:aff id="A24">University of Sydney, Westmead Millennium Institute, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead Hospital, NSW 2145 Australia</nlm:aff></affiliation></author><author><name sortKey="De Boer, Ian H" sort="De Boer, Ian H" uniqKey="De Boer I" first="Ian H." last="De Boer">Ian H. De Boer</name><affiliation><nlm:aff id="A25">University of Washington, Box 359606, 325 9th Ave, Seattle, WA 98104</nlm:aff></affiliation></author><author><name sortKey="Li, Guo" sort="Li, Guo" uniqKey="Li G" first="Guo" last="Li">Guo Li</name><affiliation><nlm:aff id="A26">Cardiovascular Health Research Unit, University of Washington, Seattle</nlm:aff></affiliation></author><author><name sortKey="Siscovick, David S" sort="Siscovick, David S" uniqKey="Siscovick D" first="David S." last="Siscovick">David S. Siscovick</name><affiliation><nlm:aff id="A27">Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA (USA)</nlm:aff></affiliation></author><author><name sortKey="Kutalik, Zoltan" sort="Kutalik, Zoltan" uniqKey="Kutalik Z" first="Zoltan" last="Kutalik">Zoltan Kutalik</name><affiliation><nlm:aff id="A28">Service of Medical Genetics, Lausanne University Hospital, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="A29">Swiss Institute of Bioinformatics, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Corre, Tanguy" sort="Corre, Tanguy" uniqKey="Corre T" first="Tanguy" last="Corre">Tanguy Corre</name><affiliation><nlm:aff id="A28">Service of Medical Genetics, Lausanne University Hospital, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="A30">Internal Medicine Department, Lausanne University Hospital, Rue du Bugnon 46, CH-1005 Lausanne</nlm:aff></affiliation></author><author><name sortKey="Waeber, Gerard" sort="Waeber, Gerard" uniqKey="Waeber G" first="Gérard" last="Waeber">Gérard Waeber</name><affiliation><nlm:aff id="A30">Internal Medicine Department, Lausanne University Hospital, Rue du Bugnon 46, CH-1005 Lausanne</nlm:aff></affiliation></author><author><name sortKey="Gupta, Jayanta" sort="Gupta, Jayanta" uniqKey="Gupta J" first="Jayanta" last="Gupta">Jayanta Gupta</name><affiliation><nlm:aff id="A31">The Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics</nlm:aff></affiliation></author><author><name sortKey="Kanetsky, Peter A" sort="Kanetsky, Peter A" uniqKey="Kanetsky P" first="Peter A." last="Kanetsky">Peter A. Kanetsky</name><affiliation><nlm:aff id="A31">The Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics</nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Olden, Matthias" sort="Olden, Matthias" uniqKey="Olden M" first="Matthias" last="Olden">Matthias Olden</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Yang, Qiong" sort="Yang, Qiong" uniqKey="Yang Q" first="Qiong" last="Yang">Qiong Yang</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A32">Boston University School of Public Health, Department of Biostatistics, 715 Albany St, Boston, MA 02118</nlm:aff></affiliation></author><author><name sortKey="De Andrade, Mariza" sort="De Andrade, Mariza" uniqKey="De Andrade M" first="Mariza" last="De Andrade">Mariza De Andrade</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Atkinson, Elizabeth J" sort="Atkinson, Elizabeth J" uniqKey="Atkinson E" first="Elizabeth J." last="Atkinson">Elizabeth J. Atkinson</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Kardia, Sharon L R" sort="Kardia, Sharon L R" uniqKey="Kardia S" first="Sharon L. R." last="Kardia">Sharon L. R. Kardia</name><affiliation><nlm:aff id="A34">University of Michigan, 1415 Washington Heights, #4659, Ann Arbor, MI 48109-2019</nlm:aff></affiliation></author><author><name sortKey="Turner, Stephen T" sort="Turner, Stephen T" uniqKey="Turner S" first="Stephen T." last="Turner">Stephen T. Turner</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Stafford, Jeanette M" sort="Stafford, Jeanette M" uniqKey="Stafford J" first="Jeanette M." last="Stafford">Jeanette M. Stafford</name><affiliation><nlm:aff id="A35">Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Ding, Jingzhong" sort="Ding, Jingzhong" uniqKey="Ding J" first="Jingzhong" last="Ding">Jingzhong Ding</name><affiliation><nlm:aff id="A36">Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Liu, Yongmei" sort="Liu, Yongmei" uniqKey="Liu Y" first="Yongmei" last="Liu">Yongmei Liu</name><affiliation><nlm:aff id="A37">Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Barlassina, Cristina" sort="Barlassina, Cristina" uniqKey="Barlassina C" first="Cristina" last="Barlassina">Cristina Barlassina</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation></author><author><name sortKey="Cusi, Daniele" sort="Cusi, Daniele" uniqKey="Cusi D" first="Daniele" last="Cusi">Daniele Cusi</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A39">Division of Nephrology, San Paolo Hospital, Via A Di Rudiní, 8 20142 MILANO</nlm:aff></affiliation></author><author><name sortKey="Salvi, Erika" sort="Salvi, Erika" uniqKey="Salvi E" first="Erika" last="Salvi">Erika Salvi</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation></author><author><name sortKey="Staessen, Jan A" sort="Staessen, Jan A" uniqKey="Staessen J" first="Jan A" last="Staessen">Jan A. Staessen</name><affiliation><nlm:aff id="A40">Department of Epidemiology, Maastricht University, Maastricht, Netherlands, PO Box 616, 6200 MD Maastricht, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A41">Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Block d, Level 00, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M" last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Grallert, Harald" sort="Grallert, Harald" uniqKey="Grallert H" first="Harald" last="Grallert">Harald Grallert</name><affiliation><nlm:aff id="A42">Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A43">Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A44">German Center for Diabetes Research, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Meisinger, Christa" sort="Meisinger, Christa" uniqKey="Meisinger C" first="Christa" last="Meisinger">Christa Meisinger</name><affiliation><nlm:aff id="A42">Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation><nlm:aff id="A45">DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A46">Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A47">Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A48">Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Kr Mer, Bernhard K" sort="Kr Mer, Bernhard K" uniqKey="Kr Mer B" first="Bernhard K." last="Kr Mer">Bernhard K. Kr Mer</name><affiliation><nlm:aff id="A49">University Medical Centre Mannheim, 5th Department of Medicine, University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167, Mannheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Kramer, Holly" sort="Kramer, Holly" uniqKey="Kramer H" first="Holly" last="Kramer">Holly Kramer</name><affiliation><nlm:aff id="A8">Department of Public Health Services, Loyola Medical Center, 2160 S First Avenue, Maywood, IL 60153, 2160 S First Avenue, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Rosas, Sylvia E" sort="Rosas, Sylvia E" uniqKey="Rosas S" first="Sylvia E." last="Rosas">Sylvia E. Rosas</name><affiliation><nlm:aff id="A50">Joslin Diabetes Center and Beth Israel Medical Center, Harvard Medical School, MA</nlm:aff></affiliation></author><author><name sortKey="Nolte, Ilja M" sort="Nolte, Ilja M" uniqKey="Nolte I" first="Ilja M." last="Nolte">Ilja M. Nolte</name><affiliation><nlm:aff id="A51">Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Penninx, Brenda W" sort="Penninx, Brenda W" uniqKey="Penninx B" first="Brenda W." last="Penninx">Brenda W. Penninx</name><affiliation><nlm:aff id="A52">Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands, EMGO Institute Vumc, NESDA, AJ Ernststraat 1187, 1081 HL Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name><affiliation><nlm:aff id="A51">Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Del Greco, Fabiola" sort="Del Greco, Fabiola" uniqKey="Del Greco F" first="Fabiola" last="Del Greco">Fabiola Del Greco</name><affiliation><nlm:aff id="A53">Center for Biomedicine, European Academy of Bolzano (EURAC), Viale Druso, 1 - 39100 Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Franke, Andre" sort="Franke, Andre" uniqKey="Franke A" first="Andre" last="Franke">Andre Franke</name><affiliation><nlm:aff id="A54">Institute of Clinical Molecular Biology, Schittenhelmstr 12, 24105 Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Nothlings, Ute" sort="Nothlings, Ute" uniqKey="Nothlings U" first="Ute" last="Nöthlings">Ute Nöthlings</name><affiliation><nlm:aff id="A55">popgen Biobank, University Hospital Schleswig-Holstein, Niemannsweg 11, 24105 Kiel, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A56">Section for Epidemiology, Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Niemannsweg 11, 24105 Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Lieb, Wolfgang" sort="Lieb, Wolfgang" uniqKey="Lieb W" first="Wolfgang" last="Lieb">Wolfgang Lieb</name><affiliation><nlm:aff id="A57">Institute of Epidemiology and Biobank popgen, Christian-Albrechts University, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Bakker, Stephan J L" sort="Bakker, Stephan J L" uniqKey="Bakker S" first="Stephan J. L." last="Bakker">Stephan J. L. Bakker</name><affiliation><nlm:aff id="A58">University Medical Center Groningen, University of Groningen, Dept. of Nephrology Groningen, The Netherlands, Dept Nephrology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gansevoort, Ron T" sort="Gansevoort, Ron T" uniqKey="Gansevoort R" first="Ron T." last="Gansevoort">Ron T. Gansevoort</name><affiliation><nlm:aff id="A58">University Medical Center Groningen, University of Groningen, Dept. of Nephrology Groningen, The Netherlands, Dept Nephrology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="A59">University Medical Center Groningen, University of Groningen, Dept. of Cardiology, Groningen, The Netherlands, Dept Cardiology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar H" sort="Franco, Oscar H" uniqKey="Franco O" first="Oscar H." last="Franco">Oscar H. Franco</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Sedaghat, Sanaz" sort="Sedaghat, Sanaz" uniqKey="Sedaghat S" first="Sanaz" last="Sedaghat">Sanaz Sedaghat</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Kollerits, Barbara" sort="Kollerits, Barbara" uniqKey="Kollerits B" first="Barbara" last="Kollerits">Barbara Kollerits</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="A62">First Department of Internal Medicine, Paracelsus Private Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg</nlm:aff></affiliation></author><author><name sortKey="Aumann, Nicole" sort="Aumann, Nicole" uniqKey="Aumann N" first="Nicole" last="Aumann">Nicole Aumann</name><affiliation><nlm:aff id="A63">Institute for Community Medicine, Walther-Rathenau-Str 48, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Endlich, Karlhans" sort="Endlich, Karlhans" uniqKey="Endlich K" first="Karlhans" last="Endlich">Karlhans Endlich</name><affiliation><nlm:aff id="A64">Institute of Anatomy and Cell Biology, Friedrich-Loeffler-Str 23d, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Pietzner, Mike" sort="Pietzner, Mike" uniqKey="Pietzner M" first="Mike" last="Pietzner">Mike Pietzner</name><affiliation><nlm:aff id="A65">Institute for Clinical Chemistry and Laboratory Medicine, Ferdinant-Sauerbruch-Str, 17475 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="A10">Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Friedrich-Ludwig-Jahn-Str 15a, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Rettig, Rainer" sort="Rettig, Rainer" uniqKey="Rettig R" first="Rainer" last="Rettig">Rainer Rettig</name><affiliation><nlm:aff id="A66">Institute of Physiology University of Greifswald, Greifswalder Str 11c, 17495 Greifswald-Karlsburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name><affiliation><nlm:aff id="A67">Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, CHR&U de Lille, Service d'épidémiologie régional, CHRU Lille, France</nlm:aff></affiliation></author><author><name sortKey="Helmer, Catherine" sort="Helmer, Catherine" uniqKey="Helmer C" first="Catherine" last="Helmer">Catherine Helmer</name><affiliation><nlm:aff id="A68">Inserm, U897, Université Bordeaux 2, ISPED, ISPED, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France</nlm:aff></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><nlm:aff id="A69">Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, INSTITUT PASTEUR, 1 RUE DU PROFESSEUR CALMETTE,BP 245,59019 LILLE, CX France</nlm:aff></affiliation></author><author><name sortKey="Metzger, Marie" sort="Metzger, Marie" uniqKey="Metzger M" first="Marie" last="Metzger">Marie Metzger</name><affiliation><nlm:aff id="A70">Inserm, Univ Paris Sud, CESP, UMRS 1018, Team 10, Inserm U1018,CESP,Team 10, 16, avenue P Vaillant Couturier, 94 807 Villejuif cedex, France</nlm:aff></affiliation></author><author><name sortKey="Stengel, Benedicte" sort="Stengel, Benedicte" uniqKey="Stengel B" first="Benedicte" last="Stengel">Benedicte Stengel</name><affiliation><nlm:aff id="A70">Inserm, Univ Paris Sud, CESP, UMRS 1018, Team 10, Inserm U1018,CESP,Team 10, 16, avenue P Vaillant Couturier, 94 807 Villejuif cedex, France</nlm:aff></affiliation></author><author><name sortKey="Lehtim Ki, Terho" sort="Lehtim Ki, Terho" uniqKey="Lehtim Ki T" first="Terho" last="Lehtim Ki">Terho Lehtim Ki</name><affiliation><nlm:aff id="A71">Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland, Department of Clinical Chemistry, Fimlab Laboratories, Finn-Medi 2, 3th floor, PO Box 66, FI-33101 Tampere, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Lyytik Inen, Leo Pekka" sort="Lyytik Inen, Leo Pekka" uniqKey="Lyytik Inen L" first="Leo-Pekka" last="Lyytik Inen">Leo-Pekka Lyytik Inen</name><affiliation><nlm:aff id="A71">Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland, Department of Clinical Chemistry, Fimlab Laboratories, Finn-Medi 2, 3th floor, PO Box 66, FI-33101 Tampere, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Raitakari, Olli" sort="Raitakari, Olli" uniqKey="Raitakari O" first="Olli" last="Raitakari">Olli Raitakari</name><affiliation><nlm:aff id="A72">Department of Clinical Physiology, Turku University Hospital, Turku 20521, Finland, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, POBox 52, 20521 Turku, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Johnson, Andrew" sort="Johnson, Andrew" uniqKey="Johnson A" first="Andrew" last="Johnson">Andrew Johnson</name><affiliation><nlm:aff id="A73">NHLBI Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Parsa, Afshin" sort="Parsa, Afshin" uniqKey="Parsa A" first="Afshin" last="Parsa">Afshin Parsa</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Bochud, Murielle" sort="Bochud, Murielle" uniqKey="Bochud M" first="Murielle" last="Bochud">Murielle Bochud</name><affiliation><nlm:aff id="A74">Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 2, CH-1066 Epalinges, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Heid, Iris M" sort="Heid, Iris M" uniqKey="Heid I" first="Iris M." last="Heid">Iris M. Heid</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A46">Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Goessling, Wolfram" sort="Goessling, Wolfram" uniqKey="Goessling W" first="Wolfram" last="Goessling">Wolfram Goessling</name><affiliation><nlm:aff id="A75">Divisions of Genetics and Gastroenterology, Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="A76">Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States of America</nlm:aff></affiliation></author><author><name sortKey="Kottgen, Anna" sort="Kottgen, Anna" uniqKey="Kottgen A" first="Anna" last="Köttgen">Anna Köttgen</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A77">Renal Division, Freiburg University Clinic, Germany, Berliner Allee 29, 79110 Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kao, H Linda" sort="Kao, H Linda" uniqKey="Kao H" first="H. Linda" last="Kao">H. Linda Kao</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Welch Center for Prevention, Epidmiology and Clinical Research, 2024 E Monument St, Suite 2-600, Baltimore, MD 21287</nlm:aff></affiliation></author><author><name sortKey="Fox, Caroline S" sort="Fox, Caroline S" uniqKey="Fox C" first="Caroline S." last="Fox">Caroline S. Fox</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A78">Brigham and Women's Hospital Department of Endocrinology, 221 Longwood Ave, Boston MA 02115</nlm:aff></affiliation></author><author><name sortKey="Boger, Carsten A" sort="Boger, Carsten A" uniqKey="Boger C" first="Carsten A." last="Böger">Carsten A. Böger</name><affiliation><nlm:aff id="A2">Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25493955</idno><idno type="pmc">4425568</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425568</idno><idno type="RBID">PMC:4425568</idno><idno type="doi">10.1038/ki.2014.361</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002D56</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002D56</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide association study of kidney function decline in individuals of European descent</title><author><name sortKey="Gorski, Mathias" sort="Gorski, Mathias" uniqKey="Gorski M" first="Mathias" last="Gorski">Mathias Gorski</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Tin, Adrienne" sort="Tin, Adrienne" uniqKey="Tin A" first="Adrienne" last="Tin">Adrienne Tin</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation></author><author><name sortKey="Garnaas, Maija" sort="Garnaas, Maija" uniqKey="Garnaas M" first="Maija" last="Garnaas">Maija Garnaas</name><affiliation><nlm:aff id="A4">Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff></affiliation></author><author><name sortKey="Mcmahon, Gearoid M" sort="Mcmahon, Gearoid M" uniqKey="Mcmahon G" first="Gearoid M." last="Mcmahon">Gearoid M. Mcmahon</name><affiliation><nlm:aff id="A5">Brigham and Women's Hospital Division of Nephrology, 75 Francis St, Boston MA 02115</nlm:aff></affiliation><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Tayo, Bamidele O" sort="Tayo, Bamidele O" uniqKey="Tayo B" first="Bamidele O." last="Tayo">Bamidele O. Tayo</name><affiliation><nlm:aff id="A8">Department of Public Health Services, Loyola Medical Center, 2160 S First Avenue, Maywood, IL 60153, 2160 S First Avenue, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Pattaro, Cristian" sort="Pattaro, Cristian" uniqKey="Pattaro C" first="Cristian" last="Pattaro">Cristian Pattaro</name><affiliation><nlm:aff id="A9">Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy, Affiliated Institute of the University of Lübeck, Germany, Viale Druso, 1 - 39100 Bolzano (Italy)</nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="A10">Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Friedrich-Ludwig-Jahn-Str 15a, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I." last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Chalmers, John" sort="Chalmers, John" uniqKey="Chalmers J" first="John" last="Chalmers">John Chalmers</name><affiliation><nlm:aff id="A11">The George Institute for Global Health, University of Sydney, PO Box M201 Missenden Rd, Sydney NSW 2050 Australia</nlm:aff></affiliation></author><author><name sortKey="Hamet, Pavel" sort="Hamet, Pavel" uniqKey="Hamet P" first="Pavel" last="Hamet">Pavel Hamet</name><affiliation><nlm:aff id="A12">Centre de recherche du Centre hospitalier de l’Université de Montréal, University of Montreal, Canada, 2901 Rachel street East, Montreal (PQ) H1W 4A4, Canada</nlm:aff></affiliation></author><author><name sortKey="Tremblay, Johanne" sort="Tremblay, Johanne" uniqKey="Tremblay J" first="Johanne" last="Tremblay">Johanne Tremblay</name><affiliation><nlm:aff id="A13">CHUM Research Center- Technopôle Angus, 2901 Rachel Street office 301, Montreal (Québec) H1W4A4</nlm:aff></affiliation></author><author><name sortKey="Woodward, Marc" sort="Woodward, Marc" uniqKey="Woodward M" first="Marc" last="Woodward">Marc Woodward</name><affiliation><nlm:aff id="A11">The George Institute for Global Health, University of Sydney, PO Box M201 Missenden Rd, Sydney NSW 2050 Australia</nlm:aff></affiliation></author><author><name sortKey="Aspelund, Thor" sort="Aspelund, Thor" uniqKey="Aspelund T" first="Thor" last="Aspelund">Thor Aspelund</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Harris, Tammara B" sort="Harris, Tammara B" uniqKey="Harris T" first="Tammara B." last="Harris">Tammara B. Harris</name><affiliation><nlm:aff id="A16">Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, 3C-309, Bethesda MD 20892 USA</nlm:aff></affiliation></author><author><name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name><affiliation><nlm:aff id="A16">Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, 3C-309, Bethesda MD 20892 USA</nlm:aff></affiliation></author><author><name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name><affiliation><nlm:aff id="A14">Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</nlm:aff></affiliation><affiliation><nlm:aff id="A15">University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D." last="Mitchell">Braxton D. Mitchell</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="O Connell, Jeffrey R" sort="O Connell, Jeffrey R" uniqKey="O Connell J" first="Jeffrey R." last="O'Connell">Jeffrey R. O'Connell</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Shuldiner, Alan R" sort="Shuldiner, Alan R" uniqKey="Shuldiner A" first="Alan R." last="Shuldiner">Alan R. Shuldiner</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Coresh, Josef" sort="Coresh, Josef" uniqKey="Coresh J" first="Josef" last="Coresh">Josef Coresh</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Welch Center for Prevention, Epidmiology and Clinical Research, 2024 E Monument St, Suite 2-600, Baltimore, MD 21287</nlm:aff></affiliation></author><author><name sortKey="Li, Man" sort="Li, Man" uniqKey="Li M" first="Man" last="Li">Man Li</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation></author><author><name sortKey="Freudenberger, Paul" sort="Freudenberger, Paul" uniqKey="Freudenberger P" first="Paul" last="Freudenberger">Paul Freudenberger</name><affiliation><nlm:aff id="A20">Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria, Harrachgasse 21, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Hofer, Edith" sort="Hofer, Edith" uniqKey="Hofer E" first="Edith" last="Hofer">Edith Hofer</name><affiliation><nlm:aff id="A21">Department of Neurology and Institute for Medical Informatics, Statistics and Documentation Medical University Graz, Austria, Auenbruggerplatz 22 and Auenbruggerplatz2, 8036 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name><affiliation><nlm:aff id="A20">Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria, Harrachgasse 21, 8010 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name><affiliation><nlm:aff id="A22">Department of Neurology, Medical University Graz, Austria, Auenbruggerplatz 22, 8036 Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Holliday, Elizabeth G" sort="Holliday, Elizabeth G" uniqKey="Holliday E" first="Elizabeth G." last="Holliday">Elizabeth G. Holliday</name><affiliation><nlm:aff id="A23">University of Newcastle, Centre for Clinical Epidemiology & Biostatistics, CReDITSS, HMRI, C/-University Drive, Callaghan NSW 2308, Australia</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Paul" sort="Mitchell, Paul" uniqKey="Mitchell P" first="Paul" last="Mitchell">Paul Mitchell</name><affiliation><nlm:aff id="A24">University of Sydney, Westmead Millennium Institute, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead Hospital, NSW 2145 Australia</nlm:aff></affiliation></author><author><name sortKey="Wang, Jie Jin" sort="Wang, Jie Jin" uniqKey="Wang J" first="Jie Jin" last="Wang">Jie Jin Wang</name><affiliation><nlm:aff id="A24">University of Sydney, Westmead Millennium Institute, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead Hospital, NSW 2145 Australia</nlm:aff></affiliation></author><author><name sortKey="De Boer, Ian H" sort="De Boer, Ian H" uniqKey="De Boer I" first="Ian H." last="De Boer">Ian H. De Boer</name><affiliation><nlm:aff id="A25">University of Washington, Box 359606, 325 9th Ave, Seattle, WA 98104</nlm:aff></affiliation></author><author><name sortKey="Li, Guo" sort="Li, Guo" uniqKey="Li G" first="Guo" last="Li">Guo Li</name><affiliation><nlm:aff id="A26">Cardiovascular Health Research Unit, University of Washington, Seattle</nlm:aff></affiliation></author><author><name sortKey="Siscovick, David S" sort="Siscovick, David S" uniqKey="Siscovick D" first="David S." last="Siscovick">David S. Siscovick</name><affiliation><nlm:aff id="A27">Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA (USA)</nlm:aff></affiliation></author><author><name sortKey="Kutalik, Zoltan" sort="Kutalik, Zoltan" uniqKey="Kutalik Z" first="Zoltan" last="Kutalik">Zoltan Kutalik</name><affiliation><nlm:aff id="A28">Service of Medical Genetics, Lausanne University Hospital, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="A29">Swiss Institute of Bioinformatics, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Corre, Tanguy" sort="Corre, Tanguy" uniqKey="Corre T" first="Tanguy" last="Corre">Tanguy Corre</name><affiliation><nlm:aff id="A28">Service of Medical Genetics, Lausanne University Hospital, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="A30">Internal Medicine Department, Lausanne University Hospital, Rue du Bugnon 46, CH-1005 Lausanne</nlm:aff></affiliation></author><author><name sortKey="Waeber, Gerard" sort="Waeber, Gerard" uniqKey="Waeber G" first="Gérard" last="Waeber">Gérard Waeber</name><affiliation><nlm:aff id="A30">Internal Medicine Department, Lausanne University Hospital, Rue du Bugnon 46, CH-1005 Lausanne</nlm:aff></affiliation></author><author><name sortKey="Gupta, Jayanta" sort="Gupta, Jayanta" uniqKey="Gupta J" first="Jayanta" last="Gupta">Jayanta Gupta</name><affiliation><nlm:aff id="A31">The Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics</nlm:aff></affiliation></author><author><name sortKey="Kanetsky, Peter A" sort="Kanetsky, Peter A" uniqKey="Kanetsky P" first="Peter A." last="Kanetsky">Peter A. Kanetsky</name><affiliation><nlm:aff id="A31">The Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics</nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Olden, Matthias" sort="Olden, Matthias" uniqKey="Olden M" first="Matthias" last="Olden">Matthias Olden</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Yang, Qiong" sort="Yang, Qiong" uniqKey="Yang Q" first="Qiong" last="Yang">Qiong Yang</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A32">Boston University School of Public Health, Department of Biostatistics, 715 Albany St, Boston, MA 02118</nlm:aff></affiliation></author><author><name sortKey="De Andrade, Mariza" sort="De Andrade, Mariza" uniqKey="De Andrade M" first="Mariza" last="De Andrade">Mariza De Andrade</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Atkinson, Elizabeth J" sort="Atkinson, Elizabeth J" uniqKey="Atkinson E" first="Elizabeth J." last="Atkinson">Elizabeth J. Atkinson</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Kardia, Sharon L R" sort="Kardia, Sharon L R" uniqKey="Kardia S" first="Sharon L. R." last="Kardia">Sharon L. R. Kardia</name><affiliation><nlm:aff id="A34">University of Michigan, 1415 Washington Heights, #4659, Ann Arbor, MI 48109-2019</nlm:aff></affiliation></author><author><name sortKey="Turner, Stephen T" sort="Turner, Stephen T" uniqKey="Turner S" first="Stephen T." last="Turner">Stephen T. Turner</name><affiliation><nlm:aff id="A33">Mayo Clinic, 200 First Street SW, Rochester, MN 55905</nlm:aff></affiliation></author><author><name sortKey="Stafford, Jeanette M" sort="Stafford, Jeanette M" uniqKey="Stafford J" first="Jeanette M." last="Stafford">Jeanette M. Stafford</name><affiliation><nlm:aff id="A35">Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Ding, Jingzhong" sort="Ding, Jingzhong" uniqKey="Ding J" first="Jingzhong" last="Ding">Jingzhong Ding</name><affiliation><nlm:aff id="A36">Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Liu, Yongmei" sort="Liu, Yongmei" uniqKey="Liu Y" first="Yongmei" last="Liu">Yongmei Liu</name><affiliation><nlm:aff id="A37">Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</nlm:aff></affiliation></author><author><name sortKey="Barlassina, Cristina" sort="Barlassina, Cristina" uniqKey="Barlassina C" first="Cristina" last="Barlassina">Cristina Barlassina</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation></author><author><name sortKey="Cusi, Daniele" sort="Cusi, Daniele" uniqKey="Cusi D" first="Daniele" last="Cusi">Daniele Cusi</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A39">Division of Nephrology, San Paolo Hospital, Via A Di Rudiní, 8 20142 MILANO</nlm:aff></affiliation></author><author><name sortKey="Salvi, Erika" sort="Salvi, Erika" uniqKey="Salvi E" first="Erika" last="Salvi">Erika Salvi</name><affiliation><nlm:aff id="A38">Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</nlm:aff></affiliation></author><author><name sortKey="Staessen, Jan A" sort="Staessen, Jan A" uniqKey="Staessen J" first="Jan A" last="Staessen">Jan A. Staessen</name><affiliation><nlm:aff id="A40">Department of Epidemiology, Maastricht University, Maastricht, Netherlands, PO Box 616, 6200 MD Maastricht, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A41">Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Block d, Level 00, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M" last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="A7">Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</nlm:aff></affiliation></author><author><name sortKey="Grallert, Harald" sort="Grallert, Harald" uniqKey="Grallert H" first="Harald" last="Grallert">Harald Grallert</name><affiliation><nlm:aff id="A42">Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A43">Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A44">German Center for Diabetes Research, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Meisinger, Christa" sort="Meisinger, Christa" uniqKey="Meisinger C" first="Christa" last="Meisinger">Christa Meisinger</name><affiliation><nlm:aff id="A42">Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation><nlm:aff id="A45">DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A46">Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A47">Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A48">Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Kr Mer, Bernhard K" sort="Kr Mer, Bernhard K" uniqKey="Kr Mer B" first="Bernhard K." last="Kr Mer">Bernhard K. Kr Mer</name><affiliation><nlm:aff id="A49">University Medical Centre Mannheim, 5th Department of Medicine, University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167, Mannheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Kramer, Holly" sort="Kramer, Holly" uniqKey="Kramer H" first="Holly" last="Kramer">Holly Kramer</name><affiliation><nlm:aff id="A8">Department of Public Health Services, Loyola Medical Center, 2160 S First Avenue, Maywood, IL 60153, 2160 S First Avenue, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Rosas, Sylvia E" sort="Rosas, Sylvia E" uniqKey="Rosas S" first="Sylvia E." last="Rosas">Sylvia E. Rosas</name><affiliation><nlm:aff id="A50">Joslin Diabetes Center and Beth Israel Medical Center, Harvard Medical School, MA</nlm:aff></affiliation></author><author><name sortKey="Nolte, Ilja M" sort="Nolte, Ilja M" uniqKey="Nolte I" first="Ilja M." last="Nolte">Ilja M. Nolte</name><affiliation><nlm:aff id="A51">Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Penninx, Brenda W" sort="Penninx, Brenda W" uniqKey="Penninx B" first="Brenda W." last="Penninx">Brenda W. Penninx</name><affiliation><nlm:aff id="A52">Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands, EMGO Institute Vumc, NESDA, AJ Ernststraat 1187, 1081 HL Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name><affiliation><nlm:aff id="A51">Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Del Greco, Fabiola" sort="Del Greco, Fabiola" uniqKey="Del Greco F" first="Fabiola" last="Del Greco">Fabiola Del Greco</name><affiliation><nlm:aff id="A53">Center for Biomedicine, European Academy of Bolzano (EURAC), Viale Druso, 1 - 39100 Bolzano, Italy</nlm:aff></affiliation></author><author><name sortKey="Franke, Andre" sort="Franke, Andre" uniqKey="Franke A" first="Andre" last="Franke">Andre Franke</name><affiliation><nlm:aff id="A54">Institute of Clinical Molecular Biology, Schittenhelmstr 12, 24105 Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Nothlings, Ute" sort="Nothlings, Ute" uniqKey="Nothlings U" first="Ute" last="Nöthlings">Ute Nöthlings</name><affiliation><nlm:aff id="A55">popgen Biobank, University Hospital Schleswig-Holstein, Niemannsweg 11, 24105 Kiel, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A56">Section for Epidemiology, Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Niemannsweg 11, 24105 Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Lieb, Wolfgang" sort="Lieb, Wolfgang" uniqKey="Lieb W" first="Wolfgang" last="Lieb">Wolfgang Lieb</name><affiliation><nlm:aff id="A57">Institute of Epidemiology and Biobank popgen, Christian-Albrechts University, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Bakker, Stephan J L" sort="Bakker, Stephan J L" uniqKey="Bakker S" first="Stephan J. L." last="Bakker">Stephan J. L. Bakker</name><affiliation><nlm:aff id="A58">University Medical Center Groningen, University of Groningen, Dept. of Nephrology Groningen, The Netherlands, Dept Nephrology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gansevoort, Ron T" sort="Gansevoort, Ron T" uniqKey="Gansevoort R" first="Ron T." last="Gansevoort">Ron T. Gansevoort</name><affiliation><nlm:aff id="A58">University Medical Center Groningen, University of Groningen, Dept. of Nephrology Groningen, The Netherlands, Dept Nephrology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="A59">University Medical Center Groningen, University of Groningen, Dept. of Cardiology, Groningen, The Netherlands, Dept Cardiology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar H" sort="Franco, Oscar H" uniqKey="Franco O" first="Oscar H." last="Franco">Oscar H. Franco</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Sedaghat, Sanaz" sort="Sedaghat, Sanaz" uniqKey="Sedaghat S" first="Sanaz" last="Sedaghat">Sanaz Sedaghat</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="A60">Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Kollerits, Barbara" sort="Kollerits, Barbara" uniqKey="Kollerits B" first="Barbara" last="Kollerits">Barbara Kollerits</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name><affiliation><nlm:aff id="A61">Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="A62">First Department of Internal Medicine, Paracelsus Private Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg</nlm:aff></affiliation></author><author><name sortKey="Aumann, Nicole" sort="Aumann, Nicole" uniqKey="Aumann N" first="Nicole" last="Aumann">Nicole Aumann</name><affiliation><nlm:aff id="A63">Institute for Community Medicine, Walther-Rathenau-Str 48, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Endlich, Karlhans" sort="Endlich, Karlhans" uniqKey="Endlich K" first="Karlhans" last="Endlich">Karlhans Endlich</name><affiliation><nlm:aff id="A64">Institute of Anatomy and Cell Biology, Friedrich-Loeffler-Str 23d, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Pietzner, Mike" sort="Pietzner, Mike" uniqKey="Pietzner M" first="Mike" last="Pietzner">Mike Pietzner</name><affiliation><nlm:aff id="A65">Institute for Clinical Chemistry and Laboratory Medicine, Ferdinant-Sauerbruch-Str, 17475 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="A10">Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Friedrich-Ludwig-Jahn-Str 15a, 17487 Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Rettig, Rainer" sort="Rettig, Rainer" uniqKey="Rettig R" first="Rainer" last="Rettig">Rainer Rettig</name><affiliation><nlm:aff id="A66">Institute of Physiology University of Greifswald, Greifswalder Str 11c, 17495 Greifswald-Karlsburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name><affiliation><nlm:aff id="A67">Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, CHR&U de Lille, Service d'épidémiologie régional, CHRU Lille, France</nlm:aff></affiliation></author><author><name sortKey="Helmer, Catherine" sort="Helmer, Catherine" uniqKey="Helmer C" first="Catherine" last="Helmer">Catherine Helmer</name><affiliation><nlm:aff id="A68">Inserm, U897, Université Bordeaux 2, ISPED, ISPED, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France</nlm:aff></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><nlm:aff id="A69">Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, INSTITUT PASTEUR, 1 RUE DU PROFESSEUR CALMETTE,BP 245,59019 LILLE, CX France</nlm:aff></affiliation></author><author><name sortKey="Metzger, Marie" sort="Metzger, Marie" uniqKey="Metzger M" first="Marie" last="Metzger">Marie Metzger</name><affiliation><nlm:aff id="A70">Inserm, Univ Paris Sud, CESP, UMRS 1018, Team 10, Inserm U1018,CESP,Team 10, 16, avenue P Vaillant Couturier, 94 807 Villejuif cedex, France</nlm:aff></affiliation></author><author><name sortKey="Stengel, Benedicte" sort="Stengel, Benedicte" uniqKey="Stengel B" first="Benedicte" last="Stengel">Benedicte Stengel</name><affiliation><nlm:aff id="A70">Inserm, Univ Paris Sud, CESP, UMRS 1018, Team 10, Inserm U1018,CESP,Team 10, 16, avenue P Vaillant Couturier, 94 807 Villejuif cedex, France</nlm:aff></affiliation></author><author><name sortKey="Lehtim Ki, Terho" sort="Lehtim Ki, Terho" uniqKey="Lehtim Ki T" first="Terho" last="Lehtim Ki">Terho Lehtim Ki</name><affiliation><nlm:aff id="A71">Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland, Department of Clinical Chemistry, Fimlab Laboratories, Finn-Medi 2, 3th floor, PO Box 66, FI-33101 Tampere, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Lyytik Inen, Leo Pekka" sort="Lyytik Inen, Leo Pekka" uniqKey="Lyytik Inen L" first="Leo-Pekka" last="Lyytik Inen">Leo-Pekka Lyytik Inen</name><affiliation><nlm:aff id="A71">Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland, Department of Clinical Chemistry, Fimlab Laboratories, Finn-Medi 2, 3th floor, PO Box 66, FI-33101 Tampere, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Raitakari, Olli" sort="Raitakari, Olli" uniqKey="Raitakari O" first="Olli" last="Raitakari">Olli Raitakari</name><affiliation><nlm:aff id="A72">Department of Clinical Physiology, Turku University Hospital, Turku 20521, Finland, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, POBox 52, 20521 Turku, FINLAND</nlm:aff></affiliation></author><author><name sortKey="Johnson, Andrew" sort="Johnson, Andrew" uniqKey="Johnson A" first="Andrew" last="Johnson">Andrew Johnson</name><affiliation><nlm:aff id="A73">NHLBI Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation></author><author><name sortKey="Parsa, Afshin" sort="Parsa, Afshin" uniqKey="Parsa A" first="Afshin" last="Parsa">Afshin Parsa</name><affiliation><nlm:aff id="A17">Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</nlm:aff></affiliation></author><author><name sortKey="Bochud, Murielle" sort="Bochud, Murielle" uniqKey="Bochud M" first="Murielle" last="Bochud">Murielle Bochud</name><affiliation><nlm:aff id="A74">Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 2, CH-1066 Epalinges, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Heid, Iris M" sort="Heid, Iris M" uniqKey="Heid I" first="Iris M." last="Heid">Iris M. Heid</name><affiliation><nlm:aff id="A1">Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A46">Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Goessling, Wolfram" sort="Goessling, Wolfram" uniqKey="Goessling W" first="Wolfram" last="Goessling">Wolfram Goessling</name><affiliation><nlm:aff id="A75">Divisions of Genetics and Gastroenterology, Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="A76">Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States of America</nlm:aff></affiliation></author><author><name sortKey="Kottgen, Anna" sort="Kottgen, Anna" uniqKey="Kottgen A" first="Anna" last="Köttgen">Anna Köttgen</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A77">Renal Division, Freiburg University Clinic, Germany, Berliner Allee 29, 79110 Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kao, H Linda" sort="Kao, H Linda" uniqKey="Kao H" first="H. Linda" last="Kao">H. Linda Kao</name><affiliation><nlm:aff id="A3">Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Welch Center for Prevention, Epidmiology and Clinical Research, 2024 E Monument St, Suite 2-600, Baltimore, MD 21287</nlm:aff></affiliation></author><author><name sortKey="Fox, Caroline S" sort="Fox, Caroline S" uniqKey="Fox C" first="Caroline S." last="Fox">Caroline S. Fox</name><affiliation><nlm:aff id="A6">NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A78">Brigham and Women's Hospital Department of Endocrinology, 221 Longwood Ave, Boston MA 02115</nlm:aff></affiliation></author><author><name sortKey="Boger, Carsten A" sort="Boger, Carsten A" uniqKey="Boger C" first="Carsten A." last="Böger">Carsten A. Böger</name><affiliation><nlm:aff id="A2">Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany</nlm:aff></affiliation></author></analytic><series><title level="j">Kidney international</title><idno type="ISSN">0085-2538</idno><idno type="eISSN">1523-1755</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P3">Genome wide association studies (GWAS) 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, SNPs at <italic>MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1</italic> and <italic>CDH23</italic> showed the strongest associations for at least one trait, in addition to the known <italic>UMOD</italic> locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at <italic>UMOD</italic> was replicated. Associations at <italic>GALNT11</italic> with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m<sup>2</sup> or more), and <italic>CDH23</italic> with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for <italic>UMOD, GALNT11</italic> and <italic>CDH23</italic>. Morpholino knockdowns of <italic>galnt11</italic> and <italic>cdh23</italic> in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to 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 <italic>GALNT11</italic> and <italic>CDH23</italic>, and show that the <italic>UMOD</italic> locus is significantly associated with kidney function decline.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Coresh, J" uniqKey="Coresh J">J Coresh</name></author><author><name sortKey="Selvin, E" uniqKey="Selvin E">E Selvin</name></author><author><name sortKey="Stevens, La" uniqKey="Stevens L">LA Stevens</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meguid El Nahas, A" uniqKey="Meguid El Nahas A">A Meguid El Nahas</name></author><author><name sortKey="Bello, Ak" uniqKey="Bello A">AK Bello</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Matsushita, K" uniqKey="Matsushita K">K Matsushita</name></author><author><name sortKey="Selvin, E" uniqKey="Selvin E">E 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K" uniqKey="Wang K">K Wang</name></author><author><name sortKey="Li, M" uniqKey="Li M">M Li</name></author><author><name sortKey="Hakonarson, H" uniqKey="Hakonarson H">H Hakonarson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lash, Jp" uniqKey="Lash J">JP Lash</name></author><author><name sortKey="Go, As" uniqKey="Go A">AS Go</name></author><author><name sortKey="Appel, Lj" uniqKey="Appel L">LJ Appel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reznichenko, A" uniqKey="Reznichenko A">A Reznichenko</name></author><author><name sortKey="Boger, Ca" uniqKey="Boger C">CA Böger</name></author><author><name sortKey="Snieder, H" uniqKey="Snieder H">H Snieder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Lipkowitz, Ms" uniqKey="Lipkowitz M">MS Lipkowitz</name></author><author><name sortKey="Salem, Rm" uniqKey="Salem R">RM Salem</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Mahata, M" uniqKey="Mahata M">M Mahata</name></author><author><name sortKey="Rao, F" uniqKey="Rao F">F Rao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Salem, Rm" uniqKey="Salem R">RM Salem</name></author><author><name sortKey="Rao, F" uniqKey="Rao F">F Rao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fung, Mm" uniqKey="Fung M">MM Fung</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Lipkowitz, Ms" uniqKey="Lipkowitz M">MS Lipkowitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cooper Worobey, C" uniqKey="Cooper Worobey C">C Cooper Worobey</name></author><author><name sortKey="Fisher, Nd" uniqKey="Fisher N">ND Fisher</name></author><author><name sortKey="Cox, D" uniqKey="Cox D">D Cox</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jorsal, A" uniqKey="Jorsal A">A Jorsal</name></author><author><name sortKey="Tarnow, L" uniqKey="Tarnow L">L Tarnow</name></author><author><name sortKey="Lajer, M" uniqKey="Lajer M">M Lajer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sandholm, N" uniqKey="Sandholm N">N Sandholm</name></author><author><name sortKey="Salem, Rm" uniqKey="Salem R">RM Salem</name></author><author><name sortKey="Mcknight, Aj" uniqKey="Mcknight A">AJ McKnight</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, W" uniqKey="Cheng W">W Cheng</name></author><author><name sortKey="Zhou, X" uniqKey="Zhou X">X Zhou</name></author><author><name sortKey="Zhu, L" uniqKey="Zhu L">L 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sortKey="Yuan, S" uniqKey="Yuan S">S Yuan</name></author><author><name sortKey="Pedersen, Nb" uniqKey="Pedersen N">NB Pedersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schwander, M" uniqKey="Schwander M">M Schwander</name></author><author><name sortKey="Xiong, W" uniqKey="Xiong W">W Xiong</name></author><author><name sortKey="Tokita, J" uniqKey="Tokita J">J Tokita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bolz, H" uniqKey="Bolz H">H Bolz</name></author><author><name sortKey="Von Brederlow, B" uniqKey="Von Brederlow B">B von Brederlow</name></author><author><name sortKey="Ramirez, A" uniqKey="Ramirez A">A Ramirez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bork, Jm" uniqKey="Bork J">JM Bork</name></author><author><name sortKey="Peters, Lm" uniqKey="Peters L">LM Peters</name></author><author><name sortKey="Riazuddin, S" uniqKey="Riazuddin S">S 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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0323470</journal-id><journal-id journal-id-type="pubmed-jr-id">5428</journal-id><journal-id journal-id-type="nlm-ta">Kidney Int</journal-id><journal-id journal-id-type="iso-abbrev">Kidney Int.</journal-id><journal-title-group><journal-title>Kidney international</journal-title></journal-title-group><issn pub-type="ppub">0085-2538</issn><issn pub-type="epub">1523-1755</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25493955</article-id><article-id pub-id-type="pmc">4425568</article-id><article-id pub-id-type="doi">10.1038/ki.2014.361</article-id><article-id pub-id-type="manuscript">NIHMS638325</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Genome-wide association study of kidney function decline in individuals of European descent</article-title></title-group><contrib-group><contrib 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contrib-type="author"><name><surname>Hamet</surname><given-names>Pavel</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Tremblay</surname><given-names>Johanne</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Woodward</surname><given-names>Marc</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Aspelund</surname><given-names>Thor</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A14">14</xref><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Eiriksdottir</surname><given-names>Gudny</given-names></name><degrees>MSc</degrees><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Gudnason</surname><given-names>Vilmundur</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A14">14</xref><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Harris</surname><given-names>Tammara B.</given-names></name><degrees>MD MSc</degrees><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Launer</surname><given-names>Lenore J.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Albert V.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A14">14</xref><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Mitchell</surname><given-names>Braxton D.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A17">17</xref><xref ref-type="aff" 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rid="A51">51</xref></contrib><contrib contrib-type="author"><name><surname>Penninx</surname><given-names>Brenda W.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A52">52</xref></contrib><contrib contrib-type="author"><name><surname>Snieder</surname><given-names>Harold</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A51">51</xref></contrib><contrib contrib-type="author"><name><surname>Del Greco</surname><given-names>Fabiola</given-names></name><degrees>M. 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contrib-type="author"><name><surname>van der Harst</surname><given-names>Pim</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A59">59</xref></contrib><contrib contrib-type="author"><name><surname>Dehghan</surname><given-names>Abbas</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A60">60</xref></contrib><contrib contrib-type="author"><name><surname>Franco</surname><given-names>Oscar H.</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A60">60</xref></contrib><contrib contrib-type="author"><name><surname>Hofman</surname><given-names>Albert</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A60">60</xref></contrib><contrib contrib-type="author"><name><surname>Rivadeneira</surname><given-names>Fernando</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A60">60</xref></contrib><contrib 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contrib-type="author"><name><surname>Stengel</surname><given-names>Benedicte</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A70">70</xref></contrib><contrib contrib-type="author"><name><surname>Lehtimäki</surname><given-names>Terho</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A71">71</xref></contrib><contrib contrib-type="author"><name><surname>Lyytikäinen</surname><given-names>Leo-Pekka</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A71">71</xref></contrib><contrib contrib-type="author"><name><surname>Raitakari</surname><given-names>Olli</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A72">72</xref></contrib><contrib contrib-type="author"><name><surname>Johnson</surname><given-names>Andrew</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A73">73</xref></contrib><contrib contrib-type="author"><name><surname>Parsa</surname><given-names>Afshin</given-names></name><degrees>MD MPH</degrees><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Bochud</surname><given-names>Murielle</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A74">74</xref></contrib><contrib contrib-type="author"><name><surname>Heid</surname><given-names>Iris M.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A46">46</xref></contrib><contrib contrib-type="author"><name><surname>Goessling</surname><given-names>Wolfram</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A75">75</xref><xref ref-type="aff" rid="A76">76</xref></contrib><contrib contrib-type="author"><name><surname>Köttgen</surname><given-names>Anna</given-names></name><degrees>MD MPH</degrees><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A77">77</xref></contrib><contrib contrib-type="author"><name><surname>Kao</surname><given-names>H. Linda</given-names></name><degrees>PhD MHS</degrees><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A19">19</xref><xref ref-type="author-notes" rid="FN2">§</xref></contrib><contrib contrib-type="author"><name><surname>Fox</surname><given-names>Caroline S.</given-names></name><degrees>MD MPH</degrees><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A78">78</xref></contrib><contrib contrib-type="author"><name><surname>Böger</surname><given-names>Carsten A.</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, 93042 Regensburg, Germany</aff><aff id="A2"><label>2</label>Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany</aff><aff id="A3"><label>3</label>Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA</aff><aff id="A4"><label>4</label>Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</aff><aff id="A5"><label>5</label>Brigham and Women's Hospital Division of Nephrology, 75 Francis St, Boston MA 02115</aff><aff id="A6"><label>6</label>NHLBI's Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</aff><aff id="A7"><label>7</label>Brigham and Women's Hospital, Division of Preventive Medicine, 900 Commonwealth Ave, 3rd Floor, Boston MA 02215</aff><aff id="A8"><label>8</label>Department of Public Health Services, Loyola Medical Center, 2160 S First Avenue, Maywood, IL 60153, 2160 S First Avenue, Maywood, IL 60153</aff><aff id="A9"><label>9</label>Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy, Affiliated Institute of the University of Lübeck, Germany, Viale Druso, 1 - 39100 Bolzano (Italy)</aff><aff id="A10"><label>10</label>Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Friedrich-Ludwig-Jahn-Str 15a, 17487 Greifswald, Germany</aff><aff id="A11"><label>11</label>The George Institute for Global Health, University of Sydney, PO Box M201 Missenden Rd, Sydney NSW 2050 Australia</aff><aff id="A12"><label>12</label>Centre de recherche du Centre hospitalier de l’Université de Montréal, University of Montreal, Canada, 2901 Rachel street East, Montreal (PQ) H1W 4A4, Canada</aff><aff id="A13"><label>13</label>CHUM Research Center- Technopôle Angus, 2901 Rachel Street office 301, Montreal (Québec) H1W4A4</aff><aff id="A14"><label>14</label>Icelandic Heart Association, Research Institute, Holtasmari 1, 201 Kopavogur, Iceland</aff><aff id="A15"><label>15</label>University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland</aff><aff id="A16"><label>16</label>Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, 3C-309, Bethesda MD 20892 USA</aff><aff id="A17"><label>17</label>Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</aff><aff id="A18"><label>18</label>Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, University of Maryland School of Medicine, 660 W Redwood St, RM 492, Baltimore, MD, 21212</aff><aff id="A19"><label>19</label>Welch Center for Prevention, Epidmiology and Clinical Research, 2024 E Monument St, Suite 2-600, Baltimore, MD 21287</aff><aff id="A20"><label>20</label>Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria, Harrachgasse 21, 8010 Graz, Austria</aff><aff id="A21"><label>21</label>Department of Neurology and Institute for Medical Informatics, Statistics and Documentation Medical University Graz, Austria, Auenbruggerplatz 22 and Auenbruggerplatz2, 8036 Graz, Austria</aff><aff id="A22"><label>22</label>Department of Neurology, Medical University Graz, Austria, Auenbruggerplatz 22, 8036 Graz, Austria</aff><aff id="A23"><label>23</label>University of Newcastle, Centre for Clinical Epidemiology & Biostatistics, CReDITSS, HMRI, C/-University Drive, Callaghan NSW 2308, Australia</aff><aff id="A24"><label>24</label>University of Sydney, Westmead Millennium Institute, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead Hospital, NSW 2145 Australia</aff><aff id="A25"><label>25</label>University of Washington, Box 359606, 325 9th Ave, Seattle, WA 98104</aff><aff id="A26"><label>26</label>Cardiovascular Health Research Unit, University of Washington, Seattle</aff><aff id="A27"><label>27</label>Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA (USA)</aff><aff id="A28"><label>28</label>Service of Medical Genetics, Lausanne University Hospital, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</aff><aff id="A29"><label>29</label>Swiss Institute of Bioinformatics, DGM, rue du Bugnon 27, 1005,Lausanne, Switzerland</aff><aff id="A30"><label>30</label>Internal Medicine Department, Lausanne University Hospital, Rue du Bugnon 46, CH-1005 Lausanne</aff><aff id="A31"><label>31</label>The Perelman School of Medicine at the University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics</aff><aff id="A32"><label>32</label>Boston University School of Public Health, Department of Biostatistics, 715 Albany St, Boston, MA 02118</aff><aff id="A33"><label>33</label>Mayo Clinic, 200 First Street SW, Rochester, MN 55905</aff><aff id="A34"><label>34</label>University of Michigan, 1415 Washington Heights, #4659, Ann Arbor, MI 48109-2019</aff><aff id="A35"><label>35</label>Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</aff><aff id="A36"><label>36</label>Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157</aff><aff id="A37"><label>37</label>Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157</aff><aff id="A38"><label>38</label>Department of Health Science, University of Milano, Viale Ortles 22/4, 20139, Milano, Italy</aff><aff id="A39"><label>39</label>Division of Nephrology, San Paolo Hospital, Via A Di Rudiní, 8 20142 MILANO</aff><aff id="A40"><label>40</label>Department of Epidemiology, Maastricht University, Maastricht, Netherlands, PO Box 616, 6200 MD Maastricht, The Netherlands</aff><aff id="A41"><label>41</label>Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Block d, Level 00, B-3000 Leuven, Belgium</aff><aff id="A42"><label>42</label>Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="A43"><label>43</label>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="A44"><label>44</label>German Center for Diabetes Research, Neuherberg, Germany</aff><aff id="A45"><label>45</label>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</aff><aff id="A46"><label>46</label>Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany</aff><aff id="A47"><label>47</label>Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany</aff><aff id="A48"><label>48</label>Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany</aff><aff id="A49"><label>49</label>University Medical Centre Mannheim, 5th Department of Medicine, University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167, Mannheim, Germany</aff><aff id="A50"><label>50</label>Joslin Diabetes Center and Beth Israel Medical Center, Harvard Medical School, MA</aff><aff id="A51"><label>51</label>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology (FA40), University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</aff><aff id="A52"><label>52</label>Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands, EMGO Institute Vumc, NESDA, AJ Ernststraat 1187, 1081 HL Amsterdam, The Netherlands</aff><aff id="A53"><label>53</label>Center for Biomedicine, European Academy of Bolzano (EURAC), Viale Druso, 1 - 39100 Bolzano, Italy</aff><aff id="A54"><label>54</label>Institute of Clinical Molecular Biology, Schittenhelmstr 12, 24105 Kiel, Germany</aff><aff id="A55"><label>55</label>popgen Biobank, University Hospital Schleswig-Holstein, Niemannsweg 11, 24105 Kiel, Germany</aff><aff id="A56"><label>56</label>Section for Epidemiology, Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Niemannsweg 11, 24105 Kiel, Germany</aff><aff id="A57"><label>57</label>Institute of Epidemiology and Biobank popgen, Christian-Albrechts University, Kiel, Germany</aff><aff id="A58"><label>58</label>University Medical Center Groningen, University of Groningen, Dept. of Nephrology Groningen, The Netherlands, Dept Nephrology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</aff><aff id="A59"><label>59</label>University Medical Center Groningen, University of Groningen, Dept. of Cardiology, Groningen, The Netherlands, Dept Cardiology, UMC Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands</aff><aff id="A60"><label>60</label>Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands</aff><aff id="A61"><label>61</label>Innsbruck Medical University, Division of Genetic Epidemiology, Schöpfstraße 41, 6020 Innsbruck, AUSTRIA</aff><aff id="A62"><label>62</label>First Department of Internal Medicine, Paracelsus Private Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg</aff><aff id="A63"><label>63</label>Institute for Community Medicine, Walther-Rathenau-Str 48, 17487 Greifswald, Germany</aff><aff id="A64"><label>64</label>Institute of Anatomy and Cell Biology, Friedrich-Loeffler-Str 23d, 17487 Greifswald, Germany</aff><aff id="A65"><label>65</label>Institute for Clinical Chemistry and Laboratory Medicine, Ferdinant-Sauerbruch-Str, 17475 Greifswald, Germany</aff><aff id="A66"><label>66</label>Institute of Physiology University of Greifswald, Greifswalder Str 11c, 17495 Greifswald-Karlsburg, Germany</aff><aff id="A67"><label>67</label>Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, CHR&U de Lille, Service d'épidémiologie régional, CHRU Lille, France</aff><aff id="A68"><label>68</label>Inserm, U897, Université Bordeaux 2, ISPED, ISPED, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France</aff><aff id="A69"><label>69</label>Inserm, U744, Institut Pasteur de Lille, Université Lille-Nord de France, INSTITUT PASTEUR, 1 RUE DU PROFESSEUR CALMETTE,BP 245,59019 LILLE, CX France</aff><aff id="A70"><label>70</label>Inserm, Univ Paris Sud, CESP, UMRS 1018, Team 10, Inserm U1018,CESP,Team 10, 16, avenue P Vaillant Couturier, 94 807 Villejuif cedex, France</aff><aff id="A71"><label>71</label>Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland, Department of Clinical Chemistry, Fimlab Laboratories, Finn-Medi 2, 3th floor, PO Box 66, FI-33101 Tampere, FINLAND</aff><aff id="A72"><label>72</label>Department of Clinical Physiology, Turku University Hospital, Turku 20521, Finland, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, POBox 52, 20521 Turku, FINLAND</aff><aff id="A73"><label>73</label>NHLBI Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt Wayte Ave Suite #2, Framingham MA 01702, USA</aff><aff id="A74"><label>74</label>Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 2, CH-1066 Epalinges, Switzerland</aff><aff id="A75"><label>75</label>Divisions of Genetics and Gastroenterology, Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America</aff><aff id="A76"><label>76</label>Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States of America</aff><aff id="A77"><label>77</label>Renal Division, Freiburg University Clinic, Germany, Berliner Allee 29, 79110 Freiburg, Germany</aff><aff id="A78"><label>78</label>Brigham and Women's Hospital Department of Endocrinology, 221 Longwood Ave, Boston MA 02115</aff><author-notes><fn id="FN1" fn-type="equal"><label>*</label><p id="P1">These authors contributed equally.</p></fn><fn id="FN2" fn-type="deceased"><label>§</label><p id="P2">deceased while manuscript was in revision.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>25</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>10</day><month>12</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>5</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>11</month><year>2015</year></pub-date><volume>87</volume><issue>5</issue><fpage>1017</fpage><lpage>1029</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ki.2014.361</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link></license-p></license></permissions><abstract><p id="P3">Genome wide association studies (GWAS) 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, SNPs at <italic>MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1</italic> and <italic>CDH23</italic> showed the strongest associations for at least one trait, in addition to the known <italic>UMOD</italic> locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at <italic>UMOD</italic> was replicated. Associations at <italic>GALNT11</italic> with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m<sup>2</sup> or more), and <italic>CDH23</italic> with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for <italic>UMOD, GALNT11</italic> and <italic>CDH23</italic>. Morpholino knockdowns of <italic>galnt11</italic> and <italic>cdh23</italic> in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to 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 <italic>GALNT11</italic> and <italic>CDH23</italic>, and show that the <italic>UMOD</italic> locus is significantly associated with kidney function decline.</p></abstract><kwd-group><kwd>chronic kidney disease</kwd><kwd>kidney development</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="S1"><title>Introduction</title><p id="P4">Chronic kidney disease (CKD) is an important public health problem affecting up to 10% of adults world-wide [<xref rid="R1" ref-type="bibr">1</xref>–<xref rid="R3" ref-type="bibr">3</xref>]. Faster rates of decline in estimated glomerular filtration rate (eGFR), and entry into CKD stages of increasing severity are associated with an increased risk of cardiovascular and all-cause mortality [<xref rid="R4" ref-type="bibr">4</xref>–<xref rid="R9" ref-type="bibr">9</xref>]. Thus, recently issued guidelines on the evaluation and management of patients with CKD have highlighted the importance of evaluating longitudinal measures of renal function in addition to determining eGFR and urinary albumin excretion at discrete time points [<xref rid="R3" ref-type="bibr">3</xref>].</p><p id="P5">Traditional risk factors for CKD include diabetes and hypertension, but these do not fully account for CKD risk [<xref rid="R10" ref-type="bibr">10</xref>]. There is evidence for considerable clustering of CKD within families [<xref rid="R11" ref-type="bibr">11</xref>] and the heritability of eGFR has been estimated at up to 36–75% in population-based studies [<xref rid="R12" ref-type="bibr">12</xref>]. Using genome-wide association studies (GWAS), multiple loci have been identified in association with eGFR and CKD in both European [<xref rid="R13" ref-type="bibr">13</xref>–<xref rid="R16" ref-type="bibr">16</xref>] and non-European populations [<xref rid="R17" ref-type="bibr">17</xref>,<xref rid="R18" ref-type="bibr">18</xref>] using data from one time point. However, multiple lines of evidence suggest that there may be unique genetic contributions to renal function decline above and beyond baseline renal function. First, there is substantial variability in the rate of eGFR decline in studies of healthy persons as well as among those with CKD [<xref rid="R3" ref-type="bibr">3</xref>,<xref rid="R4" ref-type="bibr">4</xref>,<xref rid="R19" ref-type="bibr">19</xref>,<xref rid="R20" ref-type="bibr">20</xref>]. Second, we have previously shown that some genetic loci associated with cross-sectional eGFR are also associated with incident CKD even after accounting for baseline eGFR [<xref rid="R21" ref-type="bibr">21</xref>]. Finally, genetic background has been shown to affect CKD progression in animal models [<xref rid="R22" ref-type="bibr">22</xref>,<xref rid="R23" ref-type="bibr">23</xref>].</p><p id="P6">Taken together, these data suggest that unique loci may exist for renal function decline in addition to those identified for a one-time measure of eGFR. Thus, we conducted a genome-wide association study (GWAS) meta-analysis among participants from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts.</p></sec><sec sec-type="results" id="S2"><title>Results</title><sec id="S3"><title>Study participants</title><p id="P7">Changes in renal function over time were derived from 45,530 individuals who participated in stage 1 meta-analysis of study-specific GWAS, and an additional 18,028 independent individuals who participated in stage 2 meta-analysis (<xref ref-type="table" rid="T1">Table 1</xref>). Details on study design and genotyping are provided in <xref ref-type="supplementary-material" rid="SD1">Supplementary Tables 1 and 2</xref> respectively.</p><p id="P8">At the baseline examination, the prevalence of CKD, defined as eGFR<60 ml/min/1.73m<sup>2</sup>, ranged from 3.2% to 21.4% in stage 1 cohorts and from 0.2% to 23.9% in stage 2 replication cohorts. As expected, cohorts with lower mean age at baseline tended to have a lower baseline prevalence of CKD. Four kidney function decline traits were derived from serial eGFR values in each study participant to model mechanisms underlying different rates of kidney function change over time: 1) annual decline of eGFR (eGFRchange, in ml/min/1.73m<sup>2</sup> decline per year; a positive value represents a decline in eGFR, whilst a negative value represents a rise in eGFR over time), 2) incident CKD to select individuals with a decline in kidney function to the clinical outcome CKD stage 3 or higher (CKDi, cases defined as those free of CKD at baseline but eGFR<60ml/min/1.73m<sup>2</sup> during follow-up), 3) incident CKD with additionally at least a 25% eGFR decline from baseline to select individuals reaching CKD stage 3 after a sizeable decline in kidney function (CKDi25,) [<xref rid="R24" ref-type="bibr">24</xref>], and 4) rapid eGFR-decline to select individuals with the highest risk of adverse outcomes (Rapid Decline, cases defined as those with annual eGFR-decline≥3ml/min/1.73m<sup>2</sup>) [<xref rid="R5" ref-type="bibr">5</xref>]. Most cohorts showed a decline in kidney function over time (<xref ref-type="table" rid="T1">Table 1</xref>). The distribution of all four traits in stage 1 and stage 2 cohorts can be found in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 3</xref>.</p></sec><sec id="S4"><title>Heritability of eGFR change</title><p id="P9">The heritability of eGFR change in the Framingham Heart Study was estimated as 38%, after adjusting for age, sex, and baseline eGFR.</p><sec id="S5"><title>Stage 1 meta-analysis of GWAS of measures of kidney function change over time</title><p id="P10">Stage 1 GWAS meta-analysis was performed in all samples for all four traits. Two secondary association analyses were performed to account for potentially different rates of kidney function decline in those with and without CKD: 1) eGFRchange stratified by baseline CKD status and 2) Rapid Decline in only those without baseline CKD; too few individuals with CKD fulfilled Rapid Decline criteria to perform this analysis. <xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 1</xref> shows the Manhattan and QQ-plots of the stage 1 meta-analysis of each trait. The genomic control factor ranged from 1.007 – 1.05, suggesting negligible evidence for population stratification.</p><p id="P11">In GWAS meta-analysis of stage 1 cohorts, the minor T allele of rs12917707 at the <italic>UMOD</italic> locus, previously identified by GWAS to be associated with higher eGFR in cross-sectional analysis [<xref rid="R14" ref-type="bibr">14</xref>], was associated with an increase in eGFR over time at a genome-wide significant level (p=2.6×10<sup>−14</sup>, <xref ref-type="table" rid="T2">Table 2</xref>), and showed at least nominally significant, direction consistent association with all other analyzed phenotypes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4</xref>). In addition, SNPs at the novel <italic>CDH23, GALNTL5/GALNT11, MEOX2, IL1RAP/OSTN, C2orf48/HPCAL1</italic> and <italic>NPPB/NPPA</italic> loci were associated with at least one of the analyzed traits at a significance level of p<10<sup>−6</sup> (<xref ref-type="table" rid="T2">Table 2</xref>). Thus, a total of 7 SNPs were moved forward to stage 2 meta-analysis. These SNPs mostly showed high imputation quality in each cohort or were genotyped de-novo (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 5</xref>), and low between-study heterogeneity (I<sup>2</sup><25%).</p></sec><sec id="S6"><title>Stage 2 meta-analysis</title><p id="P12">Of the seven loci moved forward for stage 2 meta-analysis, only rs12917707 at <italic>UMOD</italic> was significantly associated with the stage 1 trait after correcting for multiple testing (p=4.7*×10<sup>−5</sup>). Two further SNPs showed suggestive significance (one-sided p<0.05) with their respective stage 1 trait: rs875860 in <italic>CDH23</italic> with eGFRchange in those with CKD at baseline, and rs1019173 at <italic>GALNTL5/GALNT11</italic> with Rapid Decline (<xref ref-type="table" rid="T2">Table 2</xref>). There was no significant heterogeneity between studies for these two SNPs (rs875860: I<sup>2</sup>=9.7%, p=0.34; rs1019173: I<sup>2</sup>=32.4%, p=0.12) or for the other SNPs analyzed in stage 2 meta-analysis (I<sup>2</sup> <30.0%).</p><p id="P13">The SNP rs1019173 is located in an intron in the <italic>GALNTL5</italic> gene, and lies in a linkage disequilibrium (LD) block spanning the genes <italic>GALNT11, MLL3, CCT8L</italic>, and part of the <italic>GALNTL5</italic> gene (<xref ref-type="fig" rid="F1">Figure 1a</xref>). The SNP in <italic>CDH23</italic>, rs875860, is an intronic SNP in an LD block whose boundaries lie within the coding region of the <italic>CDH23</italic> gene (<xref ref-type="fig" rid="F1">Figure 1b</xref>).</p><p id="P14">In the combined meta-analysis of these three SNPs from both stage 1 and stage 2 cohorts, there was no evidence of between-study heterogeneity in the combined metaanalysis (I<sup>2</sup><25%). Only the SNP at <italic>UMOD</italic> showed genome-wide significant association (rs12917707, p=1.2×10<sup>−16</sup>) in the combined stage 1 and stage 2 analysis, whereas there was suggestive evidence of significance for the two novel loci identified in stage 1 (rs875860 in <italic>CDH23:</italic> p=1.5×10<sup>−6</sup> for the association with eGFRchange in those with CKD; rs1019173 at <italic>GALNTL5/GALNT11</italic>: OR=0.91 for the A allele, p=2.2×10<sup>−7</sup> for the association with Rapid Decline).</p></sec></sec><sec id="S7"><title>Functional validation of novel loci in zebrafish</title><p id="P15">To investigate the role of the two suggestive novel loci in vertebrate kidney development and function and to bolster confidence in the nominally significant statistical associations in the replication studies, we knocked down the corresponding genes in the zebrafish using antisense morpholino (MO) technology. We focused on the <italic>CDH23</italic> region and the block containing <italic>GALNTL5, GALNT11, MLL3 and CCT8L1</italic>. For the latter region, we focused on <italic>GALNT11</italic> and <italic>MLL3</italic>, because there are no zebrafish <italic>GALNTL5 and CCT8L1</italic> orthologs. Further, we investigated the effect of MO knockdown of <italic>umod</italic>. Following MO injection at the 1-cell stage, we performed <italic>in situ</italic> hybridization for the established renal markers <italic>pax2a</italic> (global kidney) and <italic>nephrin</italic> (podocytes) at 48 hours post-fertilization (hpf). Compared to control embryos, <italic>cdh23, galnt11, mll3a, mll3b</italic> and <italic>umod</italic> morphants did not display significant defects in glomerular or tubule gene expression (<xref ref-type="fig" rid="F2">Figure 2A</xref>, n>25 embryos per MO injection).</p><p id="P16">It is possible that morphant embryos develop a kidney function decline phenotype only after exposure to a nephrotoxin, despite observing no differences in renal marker expression at 48 hpf. Accordingly, after MO injection, we injected embryos with gentamicin at 48 hpf and observed edema prevalence and severity over the next three days. In control embryos, gentamicin injection predictably resulted in a majority of embryos developing minor (cardiac) edema by 24 hours post-injection (hpi) (<xref ref-type="fig" rid="F2">Figure 2B–D</xref>). In comparison, <italic>cdh23</italic> and <italic>galnt11</italic> morphants developed significantly more severe (cardiac, intestinal, and ocular) and more frequent edema (<xref ref-type="fig" rid="F2">Figure 2B–D</xref>). Specifically, whereas 10% of control embryos developed severe edema by 72 hpi, 43% of <italic>cdh23</italic> morphants (p=0.009) and 55% of <italic>galnt11</italic> morphants (p=0.001) developed severe edema at this time point. Additionally, a significant proportion of <italic>cdh23</italic> (33%, p=0.035) and <italic>galnt11</italic> morphant embryos (46%, p=0.005) injected with gentamicin developed edema earlier compared to controls at 5 hpi. In contrast, knockdown of <italic>mll3</italic> or <italic>umod</italic> affected neither kidney development nor susceptibility to gentamicin (<xref ref-type="fig" rid="F2">Figure 2B–C</xref>). Taken together, these data demonstrate that knockdown of <italic>cdh23</italic> and <italic>galnt11</italic> results in altered renal function after a nephrotoxic insult.</p></sec><sec id="S8"><title>Interrogation of novel loci in eSNP databases and the CRIC Study</title><p id="P17">We interrogated eSNP data bases for evidence of SNPs at the <italic>CDH23</italic> and <italic>GALNTL5/GALNT11</italic> loci to evaluate an effect on gene expression [<xref rid="R25" ref-type="bibr">25</xref>] but found no relevant associations. Similarly, annotation information provided by ANNOVAR [<xref rid="R26" ref-type="bibr">26</xref>] did not yield genetic variants of potential functional interest within 500kb of and in linkage disequilibrium (r2 > 0.8 based on HapMap release 22) with the index SNPs.</p><p id="P18">In Caucasian participants of the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective study of patients with CKD at baseline [<xref rid="R27" ref-type="bibr">27</xref>], neither SNPs in <italic>GALNTL5/GALNT11</italic> or <italic>CDH23</italic> were associated with eGFRchange (n=1476) or time to a composite renal event that consisted of incident end stage renal disease or halving of eGFR (n=1585, with a total of n=178 events; results not shown).</p></sec></sec><sec sec-type="discussion" id="S9"><title>Discussion</title><sec id="S10"><title>Key findings</title><p id="P19">Our key findings are fourfold. First, we estimate the heritability of eGFR decline as being 38% in the general population of European descent, providing a rationale to search for genetic variants associated with kidney function decline. Second, we extend evidence of a known locus (<italic>UMOD</italic>) previously associated with incident CKD and ESRD [<xref rid="R21" ref-type="bibr">21</xref>,<xref rid="R28" ref-type="bibr">28</xref>] by showing genome-wide significant association with kidney function change. Third, we have identified two novel genetic loci (<italic>CDH23</italic> and <italic>GALNTL5/GALNT11</italic>) with suggestive association with kidney function decline phenotypes. Finally, we show that knock-down of the two novel loci in zebrafish renders the nephron susceptible to a nephrotoxic insult.</p></sec><sec id="S11"><title>Our findings in the context of the literature</title><p id="P20">We extend the current literature by performing the first large-scale GWAS of renal function decline traits in the general population. Previous studies analyzing progression of renal disease in African Americans [<xref rid="R29" ref-type="bibr">29</xref>−<xref rid="R32" ref-type="bibr">32</xref>], individuals of European descent [<xref rid="R21" ref-type="bibr">21</xref>], healthy nurses [<xref rid="R33" ref-type="bibr">33</xref>], and patients with diabetes [<xref rid="R34" ref-type="bibr">34</xref>,<xref rid="R35" ref-type="bibr">35</xref>], hypertension [<xref rid="R31" ref-type="bibr">31</xref>], IgA nephropathy [<xref rid="R36" ref-type="bibr">36</xref>,<xref rid="R37" ref-type="bibr">37</xref>] and ESRD [<xref rid="R21" ref-type="bibr">21</xref>] focused only on candidate genes.</p><p id="P21">The SNP in <italic>UMOD</italic> has previously been identified in a GWAS of eGFR measured at one time point [<xref rid="R14" ref-type="bibr">14</xref>], and was significantly associated with incident CKD and ESRD in a candidate gene study [<xref rid="R21" ref-type="bibr">21</xref>] and with salt-sensitive hypertension and kidney damage in rodents and humans [<xref rid="R38" ref-type="bibr">38</xref>]. Our data extend this knowledge base by providing strong evidence that genetic variation at the <italic>UMOD</italic> locus affects different definitions of kidney function decline.</p><p id="P22">For Rapid Decline, the associated region on chromosome 7 contains the genes <italic>GALNTL5, GALNT11, MLL3</italic>, and <italic>CCT8L1</italic>, with our zebrafish data suggesting <italic>GALNTL5</italic> and <italic>GALNT11</italic> as the genes of interest. <italic>GALNTL5</italic> encodes the putative polypeptide N-acetylgalactosaminyltransferase-like protein 5, which by similarity has a presumed role in O-linked oligosaccharide biosynthesis. Polypeptide N-acetylgalactosaminyltransferase 11, encoded by <italic>GALNT11</italic>, is a glycosyl transferase that catalyzes the initial reaction in O-linked oligosaccharide biosynthesis. Studies in <italic>Xenopus</italic> support a role of the gene product in left-right patterning by modulating Notch1 signaling and thus establishing the crucial balance between motile and immotile cilia, and it is also expressed in the developing kidney of zebrafish [<xref rid="R39" ref-type="bibr">39</xref>,<xref rid="R40" ref-type="bibr">40</xref>]. Our data suggest that <italic>galnt11</italic> is not essential for kidney development, but protects against susceptibility from nephrotoxins.</p><p id="P23">The region of chromosome 7 also contains a locus (rs7805747 in <italic>PRKAG2</italic>) that was previously identified in a GWAS meta-analysis of cross-sectional eGFR [<xref rid="R15" ref-type="bibr">15</xref>]. However, this SNP is independent of rs1019173 (r<sup>2</sup>=0.002, D’=0.061 in the 1000 Genomes Pilot Version 1, hg18); therefore, the novel locus identified in the present study is unlikely tagging the <italic>PRKAG2</italic> locus. Moreover, conditional analysis using genotypes from both SNPs from individual level data from the ARIC study showed that the association between rs1019173 and Rapid Decline is unchanged when controlling for rs7805747 (data not shown).</p><p id="P24">The other locus identified from this study is an intronic SNP in <italic>CDH23</italic> that is nominally associated with eGFR change in those with CKD at baseline. <italic>CDH23</italic> encodes cadherin 23, a glycoprotein of the cadherin family. Cadherin 23 and protocadherin 15, encoded by <italic>PCDH15</italic>, form the tip-links spanning the stereocilia of the inner ear’s hair cells. These tip-links are key contributors to the mechanosensory transduction in hair cells required for hearing [<xref rid="R41" ref-type="bibr">41</xref>]. Rare mutations of <italic>CDH23</italic> cause progressive, nonsyndromic deafness (DFNB12, MIM # 601386) [<xref rid="R42" ref-type="bibr">42</xref>−<xref rid="R44" ref-type="bibr">44</xref>] or Usher Syndrome 1D, characterized by profound deafness, vestibular dysfunction and retinitis pigmentosa (MIM # 601067). The transmembrane protein cadherin 23 is expressed in many tissues, including the kidney [<xref rid="R44" ref-type="bibr">44</xref>,<xref rid="R45" ref-type="bibr">45</xref>], where it is found predominantly in the tubulointerstitium [<xref rid="R46" ref-type="bibr">46</xref>]. While a kidney phenotype has not been reported for patients with DFNB12 or Usher syndrome, our zebrafish data provide evidence that cadherin 23 plays a role in protecting from susceptibility to nephrotoxins, while not being essential for nephrogenesis.</p></sec><sec id="S12"><title>Implications</title><p id="P25">Our GWAS findings point towards two novel gene loci, <italic>CDH23</italic> and <italic>GALNTL5/GALNT11</italic>, and one previously identified locus (<italic>UMOD</italic>) as being associated with kidney function decline. The zebrafish experiments support a role of the two newly identified loci in increasing renal susceptibility to nephrotoxic insults and may indicate that a perturbation model could serve as a model of longitudinal kidney function decline. In previous work, we have shown that knockdown of two genes identified by GWAS of cross-sectional eGFR, <italic>mpped2</italic> and <italic>casp9</italic>, resulted in abnormal kidney development, with susceptibility to gentamicin only in <italic>casp9</italic> knockdown [<xref rid="R16" ref-type="bibr">16</xref>]. Taken together, our current and previous data highlight the differential role of genes in affecting kidney development, function and susceptibility to damage.</p></sec><sec id="S13"><title>Strengths and Limitations</title><p id="P26">Strengths of this study include the large sample size of renal function decline traits, follow-up in independent samples, analysis of several definitions of kidney function decline and validation in zebrafish. Some limitations warrant mention. Even though we addressed inter-assay differences of serum creatinine measurement by calibrating creatinine to representative NHANES standards, several other factors causing imprecision in defining kidney function decline phenotypes may have reduced our statistical power to identify genome-wide significant associations: 1) despite our use of different renal function decline definitions all featured in current guideline statements [<xref rid="R3" ref-type="bibr">3</xref>], there is no standard definition of renal function decline, 2) kidney function trajectories are less well-defined with two vs. several serum creatinine measurements given that renal function change may not be linear over time [<xref rid="R3" ref-type="bibr">3</xref>] and there may be day-to-day alterations in GFR, 3) GFR estimation equations are known to be imprecise especially at a GFR>60 ml/min/1.73m<sup>2</sup>, 4) we observed heterogeneity in design between studies including a wide range of length of follow-up. We cannot rule out that low statistical power also accounts for the negative finding in the CRIC study. Further, our findings, obtained mainly in general population cohorts, provide novel insights into mechanisms of kidney function decline, but may not be generalizable to cohorts enriched for CKD. This limitation deserves particular attention due to the unexpected observation that in most cohorts, the subgroup with baseline CKD (defined as eGFR<60 ml/min/1.73m<sup>2</sup>) showed a mean increase in eGFR over time irrespective of length of follow-up interval. This may indicate that in the CKD subgroup of these cohorts, a baseline eGFR<60 ml/min/1.73m<sup>2</sup> may not represent progressive CKD with active disease but rather stable disease or imprecise GFR estimation. This highlights that more work with expanded datasets and functional models are necessary to further elucidate the genetics of CKD initiation and progression in population-based studies. Finally, the role of genes contributing to aging and chronic disease in humans may not be entirely modeled by transient morpholino knockdown and observation of a developmental phenotype: while zebrafish allows high throughput modeling of the effects of gene knockdown in a vertebrate organism, the developmental role of specific genes may well be different from homeostatic organ maintenance in the adult. Specifically, <italic>umod</italic> may not play a relevant role in zebrafish renal development or toxin susceptibility.</p></sec><sec id="S14" sec-type="conclusions"><title>Conclusion</title><p id="P27">In a large GWAS of kidney function decline phenotypes in individuals of European descent, we showed that a SNP in <italic>UMOD</italic> is associated with kidney function decline phenotypes, and that there is suggestive statistical evidence for two novel loci (<italic>GALNTL5/GALNT11</italic> and <italic>CDH23</italic>). Zebrafish experiments at the two novel loci suggest roles in the deterioration of kidney function after acute injury. Given the complexity of the kidney function decline phenotype, further interrogation of these regions is warranted.</p></sec></sec><sec sec-type="materials|methods" id="S15"><title>Materials and Methods</title><sec id="S16"><title>Ethics Statement</title><p id="P28">In all studies, all participants gave informed consent. All studies were approved by their responsible Research Ethics Committees.</p></sec><sec id="S17"><title>Phenotype definition</title><p id="P29">Serum creatinine was measured at a minimum of 2 time points spaced several years apart (2.0 – 22.2 years, median 5.6 years). In almost all studies, there were only two serum creatinine measurements in total. To be consistent across studies, we used each individual’s two creatinine measurements with the longest follow-up in between for phenotype creation in all cohorts (see below). Baseline and follow-up serum creatinine were calibrated to the US nationally representative National Health and Nutrition Examination Study (NHANES) data in all discovery and replication studies to account for between-laboratory variation [<xref rid="R47" ref-type="bibr">47</xref>]. In order to be consistent with our prior work, GFR based on serum creatinine (eGFRcrea) was estimated using the four-variable MDRD Study Equation. eGFRcrea values <15 ml/min/1.73m<sup>2</sup> were set to 15, and those >200 were set to 200 ml/min/1.73m<sup>2</sup>.</p><p id="P30">Several phenotypes were used to model different mechanisms involved in change of renal function over time, using each individual’s two serum creatinine measurements with the longest follow-up. The continuous phenotype <bold>eGFRchange</bold>, modeling annual change in kidney function, was calculated by subtracting the eGFR at follow-up from the eGFR at baseline, and then dividing by the number of years of follow-up for each participant. Thus, a positive value of eGFRchange corresponds to a decline in kidney function over time, whereas a negative value of eGFRchange corresponds to an increase in kidney function over time. Three dichotomous phenotypes were calculated to model kidney function decline phenotypes with different clinical implications [<xref rid="R5" ref-type="bibr">5</xref>,<xref rid="R24" ref-type="bibr">24</xref>]: For <bold>Rapid Decline</bold>, cases were defined as individuals with a rapid decline in kidney function >= 3ml/min/1.73 m<sup>2</sup> per year, and controls as those with a kidney function decline < 3ml/min/1.73 m<sup>2</sup> per year [<xref rid="R6" ref-type="bibr">6</xref>]. For incident CKD (<bold>CKDi</bold>), cases were defined as participants with eGFR at baseline >= 60 ml/min/1.73m<sup>2</sup> declining to an eGFR at follow-up < 60ml/min/1.73 m<sup>2</sup>; a more stringent definition of incident CKD (<bold>CKDi25</bold>) is restricted to incident CKD cases with a decline of eGFR >= 25% at follow-up. For both CKDi and CKDi25, controls were defined as those with an eGFR >= 60ml/min/1.73 m<sup>2</sup> at baseline and follow-up.</p></sec><sec id="S18"><title>Heritability of eGFR in the Framingham Heart Study</title><p id="P31">Heritability of eGFRchange was calculated with family data of the Framingham Heart Study using the variance components analysis implemented in SOLAR [<xref rid="R48" ref-type="bibr">48</xref>]. eGFRchange was calculated by taking follow-up eGFR (obtained between 2005−2008) and subtracting baseline eGFR (obtained in 1995−1998), divided by the number of years of follow-up. Residuals were created after adjusting for age, sex, baseline eGFR, and principal components as necessary. With residuals as response variable, a variance components model with an additive genetic and a random environmental variance components was fitted, where the correlation among relatives attributable to the genetic component is assumed proportional to the kinship coefficient matrix. Heritability is calculated as the ratio of the estimated genetic variance to the total phenotypic variance.</p></sec><sec id="S19"><title>Definition of strata</title><p id="P32">Kidney function decline is known to differ depending on level of baseline eGFR. Thus, <bold>eGFRchange</bold> was analyzed (<bold>A</bold>) in the overall sample [eGFRchange overall], (<bold>B</bold>) in those with eGFR >= 60 ml/min/1.73m<sup>2</sup> at baseline [eGFRchange noCKD], and (<bold>C</bold>) in those with eGFR < 60 ml/min/1.73m<sup>2</sup> at baseline [eGFRchange withCKD]. <bold>Rapid Decline</bold> was analyzed in the overall sample [Rapid Decline overall] and in those with eGFR >= 60 ml/min/1.73m<sup>2</sup> at baseline [Rapid Decline noCKD]. <bold>CKDi</bold> and <bold>CKDi25</bold> were analyzed in the overall sample only.</p><sec id="S20"><title>Stage 1 genome-wide association analyses</title><p id="P33">All participating studies used a uniform analysis plan and each trait was created using standard programming commands that were provided to collaborating studies. The continuous trait (eGFRchange) was analyzed by linear regression, the dichotomous traits by logistic regression (Rapid Decline, CKDi, CKDi25). Models included the allelic dosage at each marker from imputed study data consisting of 2.5 million HapMap-II SNPs [<xref rid="R49" ref-type="bibr">49</xref>] on average, based on imputations with different programs and reference panels. Details of genotyping and imputation in each study are shown in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 2</xref>. We used the additive genetic model, adjusted for age and sex, baseline eGFR and, where applicable, for study site and principal components.</p></sec><sec id="S21"><title>Stage 1 meta-analysis</title><p id="P34">For our stage 1 analysis, we used aggregated statistics of 16 population-based GWA studies of individuals of European ancestry for each of the longitudinal traits: eGFRchange overall, eGFRchange noCKD, eGFRchange with CKD, Rapid Decline overall, Rapid Decline noCKD, CKDi and CKDi25. All 16 stage 1 studies contributed data to every trait, except for the AMISH study, which provided data to eGFRchange overall and eGFRchange no CKD only due to low number of CKD cases at baseline and follow-up.</p><p id="P35">All input files underwent quality control using the GWAtoolbox package in R (<ext-link ext-link-type="uri" xlink:href="http://www.eurac.edu/GWAtoolbox.html">www.eurac.edu/GWAtoolbox.html</ext-link>) [<xref rid="R50" ref-type="bibr">50</xref>], before including them into meta-analysis. Study data was meta-analyzed assuming fixed effects and using inverse-variance weighting. Thus the pooled effect β<sub>pooled</sub> is estimated as <inline-formula><mml:math id="M1" overflow="scroll"><mml:msub><mml:mo>∑</mml:mo><mml:mi>i</mml:mi></mml:msub><mml:mfrac><mml:mrow><mml:msub><mml:mi mathvariant="normal">β</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>/</mml:mo><mml:mi>S</mml:mi><mml:msubsup><mml:mi>E</mml:mi><mml:mi>i</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow><mml:mrow><mml:mn>1</mml:mn><mml:mo>/</mml:mo><mml:mi>S</mml:mi><mml:msubsup><mml:mi>E</mml:mi><mml:mi>i</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:mfrac></mml:math></inline-formula>, where β and SE are the effect and standard error of the SNP on the outcome in the i<sub>th</sub> study. The meta-analyses were performed by METAL. We performed genomic control correction if the inflation factor λ in the study files was greater than 1 (1<sup>st</sup> GC correction) or if it was greater than 1 in the meta-analysis result (2<sup>nd</sup> GC correction) [<xref rid="R51" ref-type="bibr">51</xref>].</p><p id="P36">Next, we created a list of independent SNPs (pairwise r<sup>2</sup><0.2, HAPMAP II release 22) that had a genomic control corrected p-value <10<sup>−6</sup> and minor allele frequency > 5% in stage 1 meta-analysis and were present in at least 85% of the contributing studies.</p></sec><sec id="S22"><title>Stage 2 meta-analysis</title><p id="P37">The stage 2 meta-analysis of SNPs identified in stage 1 was performed on the same phenotypes and using the same analysis plan as the stage 1 analysis, and was based on <italic>in silico</italic> genetic data or on <italic>de novo</italic> genotyped variants. Details on each stage 2 study’s genotyping and imputation platforms are shown in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 2</xref>. In addition, we also performed a combined inverse-variance weighted fixed-effects stage 1 and stage 2 meta-analysis using individual study files as input. Studies with less than 50 cases for a dichotomous trait or with an overall sample size of less than 50 for a continuous trait were excluded from the meta-analyses of the corresponding trait. SNPs with a stage 2 meta-analysis one-sided p-value <0.05 and effect direction consistency with the stage 1 meta-analysis effect direction were defined as showing nominally significant evidence of replication. The I<sup>2</sup> statistic was computed to assess heterogeneity between studies.</p></sec></sec><sec id="S23"><title>Zebrafish functional experiments</title><p id="P38">Zebrafish were maintained according to established IACUC protocols. Zebrafish were injected at the 1-cell stage with 2 nl of 400 uM morpholinos (MO; GeneTools, Philomath, OR) designed to block the ATG start site or an exon-intron splice site of the target gene (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>). Embryos were fixed in 4% PFA at the appropriate stages for in situ hybridization using well established protocols (<ext-link ext-link-type="uri" xlink:href="http://zfin.org/ZFIN/Methods/ThisseProtocol.html">http://zfin.org/ZFIN/Methods/ThisseProtocol.html</ext-link>). Renal gene expression was visualized using established markers for <italic>pax2a</italic> (global kidney) and <italic>nephrin</italic> (podocytes) [<xref rid="R52" ref-type="bibr">52</xref>,<xref rid="R53" ref-type="bibr">53</xref>]. The number of embryos displaying abnormal renal gene expression was compared to uninjected control embryos, and statistical significance was determined by Fisher’s exact test. For the gentamicin nephrotoxin experiment, embryos were injected with MO at the 1-cell stage and then injected with 5 nl of 10 mg/ml gentamicin prepared from one stock solution in the cardiac sinus venosus at 48 hpf after being anesthetized in a 1:20 dilution of 4 mg/ml Tricaine in embryo water. Live embryo development and edema prevalence was documented over the next three days.</p></sec></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>01</label><media xlink:href="NIHMS638325-supplement-01.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d37e2350" position="anchor"></media></supplementary-material></sec></body><back><ack id="S24"><title>Acknowledgements</title><p id="P39">Stage 1 cohorts:</p><p id="P40">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. The researchers are indebted to the participants for their willingness to participate in the study</p><p id="P41">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.</p><p id="P42">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. The authors 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. A.K. was supported by the grant KO3598/2-1 (Emmy Noether Programme) of the German Research Foundation.</p><p id="P43">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.</p><p id="P44">The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-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 <ext-link ext-link-type="uri" xlink:href="http://www.chs-nhlbi.org/pi.htm">http://www.chs-nhlbi.org/pi.htm</ext-link>. DNA handling and genotyping was 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.</p><p id="P45">The CoLaus study received financial contributions from GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne; the Swiss National Science Foundation (33CSCO-122661; 3200BO-111361/2; 3100AO-116323/1;310000-112552). M.B is supported by the Swiss School of Public Health Plus.</p><p id="P46">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.</p><p id="P47">GENOA: This research was partially supported by the National Heart Lung and Blood Institute of the National Institutes of Health R01 HL-87660.</p><p id="P48">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.</p><p id="P49">The JUPITER trial and the genotyping were supported by AstraZeneca</p><p id="P50">KORA studies: The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 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 C.A.B. and B.K.K.; 2012_A147 to CAB and IMH). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., 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. Geno-typing 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.</p><p id="P51">MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung and Blod Institute (NHLBI) in collaboration with MESA Investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and CTSA UL1-RR-024156</p><p id="P52">Rotterdam Study 1: The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 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 nr. 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, 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. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. We would like to 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. Abbas Dehghan is supported by NWO grant (vici, 918-76-619).</p><p id="P53">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.</p><p id="P54">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 donnees biologiques” programme. Lille Génopôle received an unconditional grant from Eisai.</p><p id="P55">Stage 2 cohorts:</p><p id="P56">ADVANCE: The genetic epidemiological work was funded by Prognomix Inc. and by grants from Genome Quebec and Canadian Institutes for Health Research (CIHR). 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. The authors 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 sub-study of ADVANCE, Stephen Harrap and Michel Marre are also acknowledged.</p><p id="P57">The Blue Mountains Eye Study (BMES) was supported by the Australian National Health & Medical Research Council (NHMRC), Canberra Australia (NHMRC project grant IDs 974159, 211069, 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 was 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.</p><p id="P58">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)</p><p id="P59">KORA studies: The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 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 C.A.B. and B.K.K.; 2012_A147 to CAB and IMH). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., 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. Geno-typing 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.</p><p id="P60">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 and the EMGO institute; the European Union (EU/WLRT-2001-01254), 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 were supported by grants from GAIN and the NIMH (MH081802) and the Center for Molecular and Systems Biology (CMSB).</p><p id="P61">Genotype data were obtained from dbGaP (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/dbgap">http://www.ncbi.nlm.nih.gov/dbgap</ext-link>, accession number phs000020.v1.p1. Statistical analyses were partly conducted at the Genetic Cluster Computer (<ext-link ext-link-type="uri" xlink:href="http://www.geneticcluster.org">http://www.geneticcluster.org</ext-link>), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation.</p><p id="P62">POPGEN: This study was funded by the German National Genome Research Network (NGFN; Federal Ministry of Education and Research, grant numbers 1GS0121, 01GS0171, 01GR0468) and by the DFG Excellence Cluster ‘Inflammation at Interfaces’ (EXC 306).</p><p id="P63">The PREVEND Study was financially supported by several grants from the Dutch Kidney Foundation.</p><p id="P64">The PREVEND Study was financially supported by several grants from the Dutch Kidney Foundation.</p><p id="P65">Rotterdam Study II: The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 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 nr. 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, 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. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. We would like to 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. Abbas Dehghan is supported by NWO grant (vici, 918-76-619).</p><p id="P66">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.</p><p id="P67">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 (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T.L). The expert technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen is gratefully acknowledged.</p></ack><fn-group><fn id="FN3" fn-type="con"><p id="P68">Author contributions</p><p id="P69"><bold>Study design</bold>: ATi, ARSh, AHo, AGUi, AKö, BTa, BSt, BDMi, BWPe, CSFo, CHe, DSSi, GEi, HKr, IHdeB, JDi, JCh, JCo, KEn, LJLa, MWo, MdAn, ORa, PMRi, PHa, RRe, RSc, SERo, TBHa, THa, TLe, UNö, UVö, VGu, PVo, GWa, WHLKa, YLi,</p><p id="P70"><bold>Study Management</bold>: ARSh, AHo, AFr, AGUi, BPa, MBo, BDMi, BWPe, CSFo, CHe, DSSi, GEi, JJWa, JDi, JTr, JCh, MWo, MPi, NAu, ORa, OHFr, PMRi, PMi, PHa, RSc, SLRKa, STTu, THa, TLe, UNo, VGu, PVo, YLi,</p><p id="P71"><bold>Subject Recruitment</bold>: ARSh, AHo, BPa, BDMi, CSFo, CHe, CMe, CBa, DCu, DSSi, FKr, GEi, JCh, JASt, NAu, ORa, PMa, PMRi, PMi, PHa, RSc, STTu, THa, TLe, UNö, VGu, PVo, GWa</p><p id="P72"><bold>Zebra fish experiments:</bold> MGa, WGoe.</p><p id="P73"><bold>Interpretation of Results</bold>: ADe, ATi, APa, AVSm, AKö, AYCh, BTa, BPa, MBo, CSFo, CABö, CPa, DICh, GMMc, HKr, IHdeB, IMHe, JDi, JTr, JCh, KEn, MGa, MWo, MGo, MPi, NAu, ORa, PHa, PvdHa, RRe, RTGa, SSe, SJLBa, SERo, THa, TLe, TAs, UVö, WGoe, WHLKa, YLi</p><p id="P74"><bold>Drafting of manuscript</bold>: ATi, AKö, CSFo, CABö, GMMc, IMHe, MGa, MGo, WGoe, WHLKa.</p><p id="P75"><bold>Statistical Methods and Analysis</bold>: ADe, ATi, APa, AVSm, ATe, AKö, AYCh, BTa, BKo, BSt, BPa, CSFö, CABo, CPa, DICh, EHo, EGHo, ESa, FDGM, FKr, GMMc, GLi, HKr, IMNo, IMHe, JGu, JAn, LJROC, JDi, JCh, L-PLy, MLi, MWo, MMe, MM-Nu, MGo, MOl, MOl, PAKa, SSe, S-JHw, SCo, TCo, TAs, WHLKa, YLi, ZKo</p><p id="P76"><bold>Genotyping</bold>: ARSh, AVSm, ATe, AFr, AGUi, BKo, BDMi, CSFö, CABo, CBa, DICh, EJAt, FRi, FKr, GLi, HGr, HSc, JGu, J-CL, LJROC, JTr, L-PLy, MHa, MdAn, PFr, PHa, PAKa, PvdHa, STTu, SLRKa, TLe, UVö, YLi</p><p id="P77"><bold>Bioinformatics</bold>: AVSm, ATe, AFr, AJo, BTa, CABö, CPa, DICh, EHo, ESa, FRi, FKr, GMMc, GLi, HSc, HKr, IMHe, JGu, J-CL, JAn, LJROC, L-PLy, MWo, MGo, MOl, PFr, PAKa, QYa, S-JHw, SCo, VCh</p><p id="P78"><bold>Critical review and final approval of manuscript</bold>: all.</p></fn><fn id="FN4"><p id="P79">Financial disclosures</p><p id="P80">Johanne Tremblay: Consultant Servier; Pavel Hamet: Cconsultant Servier, John Chalmers: Grant Servier.</p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Coresh</surname><given-names>J</given-names></name><name><surname>Selvin</surname><given-names>E</given-names></name><name><surname>Stevens</surname><given-names>LA</given-names></name><etal></etal></person-group><article-title>Prevalence of chronic kidney disease in the United States</article-title><source>JAMA</source><year>2007</year><volume>298</volume><fpage>2038</fpage><lpage>2047</lpage><pub-id pub-id-type="pmid">17986697</pub-id></element-citation></ref><ref 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person-group-type="author"><name><surname>Kramer-Zucker</surname><given-names>AG</given-names></name><name><surname>Wiessner</surname><given-names>S</given-names></name><name><surname>Jensen</surname><given-names>AM</given-names></name><name><surname>Drummond</surname><given-names>IA</given-names></name></person-group><article-title>Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes</article-title><source>Dev Biol</source><year>2005</year><volume>285</volume><fpage>316</fpage><lpage>329</lpage><pub-id pub-id-type="pmid">16102746</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><p id="P81">Regional Association Plots of the novel loci identified by GWAS of kidney function decline traits. Negative log10 pvalues are plotted versus genomic position (build 36, hg18). The lead SNP in each region is labeled. Other SNPs in each region are color-coded based on their LD to the lead SNP. Light blue lines indicate recombination rate (cM/Mb). (A) <italic>GALNTL5/GALNT11</italic> locus. (B) <italic>CDH23</italic> locus.</p></caption><graphic xlink:href="nihms638325f1a"></graphic><graphic xlink:href="nihms638325f1b"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title><italic>Cdh23 and galnt11</italic> knockdowns exacerbate nephrotoxic injury in zebrafish embryos</title><p id="P82">(A) Whole mount in situ hybridization for the global kidney marker <italic>pax2a</italic> (arrowhead denotes the glomerulus, bracket denotes the tubule) and the podocyte marker <italic>nephrin</italic> demonstrates that morpholino (MO) knockdowns of <italic>cdh23, galnt11, mll3a</italic>, and <italic>mll3b</italic> do not result in changes in kidney gene expression compared to control embryos at 48 hours post-fertilization (hpf). Similar results were obtained for MO knockdowns of <italic>umod</italic> (images not shown). (B) Morpholino knockdown of <italic>cdh23</italic> and <italic>galnt11</italic> causes embryos to develop edema at a higher frequency than control embryos following gentamicin challenge. Data are presented as number of observed abnormalities per total number of embryos scored at 5, 24, 48, and 72 hours post-gentamicin injection (hpi), normalized to control experiments. *p < 0.05, **p < 0.005 by Fisher’s exact test. (C) Graphical representation of edema prevalence in embryos injected with gentamicin in (B). (D) Control embryos develop minor (cardiac) edema whereas <italic>cdh23</italic> and <italic>galnt11</italic> MO-injected embryos develop severe (cardiac, intestinal, ocular) edema 72 hours after gentamicin injection.</p></caption><graphic xlink:href="nihms638325f2"></graphic></fig><table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label><caption><p id="P83">Stage 1 and Stage 2 cohort characteristics.</p></caption><table frame="void" rules="rows"><thead><tr><th align="center" rowspan="1" colspan="1"></th><th align="center" valign="bottom" rowspan="1" colspan="1">n</th><th align="center" valign="bottom" rowspan="1" colspan="1">Age at<break></break>baseline,<break></break>years</th><th align="center" valign="bottom" rowspan="1" colspan="1">% women,<break></break>n</th><th align="center" valign="bottom" rowspan="1" colspan="1">%HTN at<break></break>baseline,<break></break>n</th><th align="center" valign="bottom" rowspan="1" colspan="1">%DM at<break></break>baseline,<break></break>n</th><th align="center" valign="bottom" rowspan="1" colspan="1">%CKD at<break></break>baseline,<break></break>n</th><th align="center" valign="bottom" rowspan="1" colspan="1">eGFR<break></break>baseline,<break></break>ml/min/1.73m2</th><th align="center" valign="bottom" rowspan="1" colspan="1">eGFR follow-<break></break>up,<break></break>ml/min/1.73m2</th><th align="center" rowspan="1" colspan="1">Duration<break></break>between<break></break>baseline and<break></break>follow-up<break></break>(Years)<break></break>mean, SD</th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1"><bold>Stage 1 discovery cohorts</bold></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>AGES</bold></td><td align="center" rowspan="1" colspan="1">3219</td><td align="center" rowspan="1" colspan="1">54.2 (8.98)</td><td align="center" rowspan="1" colspan="1">58.0, 1867</td><td align="center" rowspan="1" colspan="1">21.6, 694</td><td align="center" rowspan="1" colspan="1">3.2, 103</td><td align="center" rowspan="1" colspan="1">3.2, 104</td><td align="center" rowspan="1" colspan="1">89.6 (19.3)</td><td align="center" rowspan="1" colspan="1">73.0 (20.0)</td><td align="center" rowspan="1" colspan="1">22.2 (6.7)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>Amish</bold></td><td align="center" rowspan="1" colspan="1">458</td><td align="center" rowspan="1" colspan="1">46.9 (14.3)</td><td align="center" rowspan="1" colspan="1">54.4, 249</td><td align="center" rowspan="1" colspan="1">8.7, 40</td><td align="center" rowspan="1" colspan="1">4.2, 19</td><td align="center" rowspan="1" colspan="1">NA</td><td align="center" rowspan="1" colspan="1">95.9 (24.3)</td><td align="center" rowspan="1" colspan="1">89.2 (19.4)</td><td align="center" rowspan="1" colspan="1">5.2 (2.6)</td></tr><tr><td align="center" valign="bottom" rowspan="1" colspan="1"><bold>ARIC</bold></td><td align="center" valign="bottom" rowspan="1" colspan="1">9049</td><td align="center" valign="bottom" rowspan="1" colspan="1">54.5 (5.7)</td><td align="center" valign="bottom" rowspan="1" colspan="1">52.9, 4793</td><td align="center" valign="bottom" rowspan="1" colspan="1">26.9, 2427</td><td align="center" valign="bottom" rowspan="1" colspan="1">8.6, 780</td><td align="center" valign="bottom" rowspan="1" colspan="1">2.9, 260</td><td align="center" valign="bottom" rowspan="1" colspan="1">89.7 (17.0)</td><td align="center" rowspan="1" colspan="1">83.5 (17.1)<sup>A</sup><break></break>80.6 (17.1)<sup>B</sup></td><td align="center" valign="bottom" rowspan="1" colspan="1">8.0 (2.2)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>ASPS</bold></td><td align="center" rowspan="1" colspan="1">848</td><td align="center" rowspan="1" colspan="1">65.8 (8.1)</td><td align="center" rowspan="1" colspan="1">56.8, 482</td><td align="center" rowspan="1" colspan="1">72.5, 615</td><td align="center" rowspan="1" colspan="1">9.8, 83</td><td align="center" rowspan="1" colspan="1">12.7, 108</td><td align="center" rowspan="1" colspan="1">80.2 (20.2)</td><td align="center" rowspan="1" colspan="1">74.6 (15.1)</td><td align="center" rowspan="1" colspan="1">5.5 (2.0)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>CHS</bold></td><td align="center" rowspan="1" colspan="1">2820</td><td align="center" rowspan="1" colspan="1">71.9 (5.0)</td><td align="center" rowspan="1" colspan="1">61.3, 1729</td><td align="center" rowspan="1" colspan="1">34.5, 966</td><td align="center" rowspan="1" colspan="1">11.0, 310</td><td align="center" rowspan="1" colspan="1">7.9, 224</td><td align="center" rowspan="1" colspan="1">77.3 (20.8)</td><td align="center" rowspan="1" colspan="1">75.4 (20.2)</td><td align="center" rowspan="1" colspan="1">5.9 (1.8)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>CoLaus</bold></td><td align="center" rowspan="1" colspan="1">1918</td><td align="center" rowspan="1" colspan="1">53.9 (10.8)</td><td align="center" rowspan="1" colspan="1">54.9, 1053</td><td align="center" rowspan="1" colspan="1">35.4, 679</td><td align="center" rowspan="1" colspan="1">6.31, 121</td><td align="center" rowspan="1" colspan="1">5.0, 95</td><td align="center" rowspan="1" colspan="1">91.5 (20.4)</td><td align="center" rowspan="1" colspan="1">84.9 (18.2)</td><td align="center" rowspan="1" colspan="1">5.58 (0.29)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>FHS (Offspring and Cohort)</bold></td><td align="center" rowspan="1" colspan="1">2523</td><td align="center" rowspan="1" colspan="1">58.1 (8.6)</td><td align="center" rowspan="1" colspan="1">55.6, 1405</td><td align="center" rowspan="1" colspan="1">36.8, 927</td><td align="center" rowspan="1" colspan="1">8.1, 206</td><td align="center" rowspan="1" colspan="1">8.3, 210</td><td align="center" rowspan="1" colspan="1">88.7 (25.5)</td><td align="center" rowspan="1" colspan="1">79.5 (19.1)</td><td align="center" rowspan="1" colspan="1">11.1 (3.6)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>GENOA</bold></td><td align="center" rowspan="1" colspan="1">1041</td><td align="center" rowspan="1" colspan="1">54.7 (10.3)</td><td align="center" rowspan="1" colspan="1">55.6, 579</td><td align="center" rowspan="1" colspan="1">71.7, 746</td><td align="center" rowspan="1" colspan="1">8.8, 92</td><td align="center" rowspan="1" colspan="1">4.3, 45</td><td align="center" rowspan="1" colspan="1">92.1 (20.7)</td><td align="center" rowspan="1" colspan="1">89.8 (22.8)</td><td align="center" rowspan="1" colspan="1">4.0 (1.1)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>HABC</bold></td><td align="center" rowspan="1" colspan="1">888</td><td align="center" rowspan="1" colspan="1">73.4 (2.8)</td><td align="center" rowspan="1" colspan="1">48.5, 431</td><td align="center" rowspan="1" colspan="1">33.1, 294</td><td align="center" rowspan="1" colspan="1">8.5, 75</td><td align="center" rowspan="1" colspan="1">21.4, 190</td><td align="center" rowspan="1" colspan="1">71.8 (13.2)</td><td align="center" rowspan="1" colspan="1">72.9 (21.2)</td><td align="center" rowspan="1" colspan="1">9.0 (0.3)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>JUPITER</bold></td><td align="center" rowspan="1" colspan="1">8780</td><td align="center" rowspan="1" colspan="1">66.1 (7.8)</td><td align="center" rowspan="1" colspan="1">32.2, 2826</td><td align="center" rowspan="1" colspan="1">63.8, 5602</td><td align="center" rowspan="1" colspan="1">0.6, 54</td><td align="center" rowspan="1" colspan="1">11.5, 1008</td><td align="center" rowspan="1" colspan="1">80.1 (18.1)</td><td align="center" rowspan="1" colspan="1">78.2 (17.7)</td><td align="center" rowspan="1" colspan="1">2.6 (1.0)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>KORA3</bold></td><td align="center" rowspan="1" colspan="1">1641</td><td align="center" rowspan="1" colspan="1">52.5 (10.1)</td><td align="center" rowspan="1" colspan="1">49.5, 813</td><td align="center" rowspan="1" colspan="1">38.3, 629</td><td align="center" rowspan="1" colspan="1">4.3, 71</td><td align="center" rowspan="1" colspan="1">3.2, 53</td><td align="center" rowspan="1" colspan="1">91.3 (18.0)</td><td align="center" rowspan="1" colspan="1">83.9 (21.0)</td><td align="center" rowspan="1" colspan="1">10 (0)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>KORA4</bold></td><td align="center" rowspan="1" colspan="1">1807</td><td align="center" rowspan="1" colspan="1">53.8 (8.9)</td><td align="center" rowspan="1" colspan="1">51.3, 927</td><td align="center" rowspan="1" colspan="1">33.7, 606</td><td align="center" rowspan="1" colspan="1">3.7, 66</td><td align="center" rowspan="1" colspan="1">3.9, 70</td><td align="center" rowspan="1" colspan="1">89.5 (17.5)</td><td align="center" rowspan="1" colspan="1">85.1 (20.2)</td><td align="center" rowspan="1" colspan="1">7.1 (0.4)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>MESA</bold></td><td align="center" rowspan="1" colspan="1">2324</td><td align="center" rowspan="1" colspan="1">63.2 (10.1)</td><td align="center" rowspan="1" colspan="1">51.7, 1201</td><td align="center" rowspan="1" colspan="1">37.3, 866</td><td align="center" rowspan="1" colspan="1">5.5, 135</td><td align="center" rowspan="1" colspan="1">13.3, 310</td><td align="center" rowspan="1" colspan="1">74.2 (13.9)</td><td align="center" rowspan="1" colspan="1">70.7 (15.1)</td><td align="center" rowspan="1" colspan="1">4.8 (0.5)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>The Rotterdam Study (RS-I)</bold></td><td align="center" rowspan="1" colspan="1">2422</td><td align="center" rowspan="1" colspan="1">66.5 (7.0)</td><td align="center" rowspan="1" colspan="1">60.2, 1459</td><td align="center" rowspan="1" colspan="1">50.8, 1230</td><td align="center" rowspan="1" colspan="1">7.5, 182</td><td align="center" rowspan="1" colspan="1">7.7, 186</td><td align="center" rowspan="1" colspan="1">79.9 (15.5)</td><td align="center" rowspan="1" colspan="1">73.7 (15.8)</td><td align="center" rowspan="1" colspan="1">6.5 (0.4)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>SHIP</bold></td><td align="center" rowspan="1" colspan="1">3203</td><td align="center" rowspan="1" colspan="1">49.2 (15.3)</td><td align="center" rowspan="1" colspan="1">51.8, 1659</td><td align="center" rowspan="1" colspan="1">24.3, 778</td><td align="center" rowspan="1" colspan="1">7.0, 225</td><td align="center" rowspan="1" colspan="1">3.7, 119</td><td align="center" rowspan="1" colspan="1">92.4 (19.8)</td><td align="center" rowspan="1" colspan="1">90.6 (23.6)</td><td align="center" rowspan="1" colspan="1">5.3 (0.7)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>Three Cities (3C)</bold></td><td align="center" rowspan="1" colspan="1">2589</td><td align="center" rowspan="1" colspan="1">73.0 (4.5)</td><td align="center" rowspan="1" colspan="1">61.9, 1602</td><td align="center" rowspan="1" colspan="1">76.7, 1986</td><td align="center" rowspan="1" colspan="1">8.6, 223</td><td align="center" rowspan="1" colspan="1">18.9, 489</td><td align="center" rowspan="1" colspan="1">73.1 (16.1)</td><td align="center" rowspan="1" colspan="1">71.0 (16.8)</td><td align="center" rowspan="1" colspan="1">3.8 (0.3)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>Stage 2 replication cohorts</bold></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>ADVANCE</bold></td><td align="center" rowspan="1" colspan="1">2034</td><td align="center" rowspan="1" colspan="1">67.0 (6.6)</td><td align="center" rowspan="1" colspan="1">31.9, 649</td><td align="center" rowspan="1" colspan="1">55.2, 1123</td><td align="center" rowspan="1" colspan="1">100, 2034</td><td align="center" rowspan="1" colspan="1">16.0, 325</td><td align="center" rowspan="1" colspan="1">84.1 (28.1)</td><td align="center" rowspan="1" colspan="1">84.8 (34.5)</td><td align="center" rowspan="1" colspan="1">4.9 (0.9)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>BMES</bold></td><td align="center" rowspan="1" colspan="1">1304</td><td align="center" rowspan="1" colspan="1">62.9 (7.7)</td><td align="center" rowspan="1" colspan="1">60.1, 784</td><td align="center" rowspan="1" colspan="1">67.1, 875</td><td align="center" rowspan="1" colspan="1">5.4, 71</td><td align="center" rowspan="1" colspan="1">23.9, 312</td><td align="center" rowspan="1" colspan="1">82.6 (31.7)</td><td align="center" rowspan="1" colspan="1">75.5 (34.9)</td><td align="center" rowspan="1" colspan="1">10.4 (0.6)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>COLAUS</bold></td><td align="center" rowspan="1" colspan="1">2238</td><td align="center" rowspan="1" colspan="1">53.1 (10.4)</td><td align="center" rowspan="1" colspan="1">53.9, 1207</td><td align="center" rowspan="1" colspan="1">24.0, 538</td><td align="center" rowspan="1" colspan="1">4.1, 91</td><td align="center" rowspan="1" colspan="1">3.5, 79</td><td align="center" rowspan="1" colspan="1">90.5 (19.5)</td><td align="center" rowspan="1" colspan="1">88.7 (18.7)</td><td align="center" rowspan="1" colspan="1">5.5 (0.3)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>HYPERGENES</bold></td><td align="center" rowspan="1" colspan="1">651</td><td align="center" rowspan="1" colspan="1">53.4 (7.5)</td><td align="center" rowspan="1" colspan="1">45.3, 295</td><td align="center" rowspan="1" colspan="1">13.9, 91</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0.61, 4</td><td align="center" rowspan="1" colspan="1">107.4 (23.5)</td><td align="center" rowspan="1" colspan="1">103.4 (35.1)</td><td align="center" rowspan="1" colspan="1">5.6 ( 3.2)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>KORA3</bold></td><td align="center" rowspan="1" colspan="1">1494</td><td align="center" rowspan="1" colspan="1">51.6 (13.3)</td><td align="center" rowspan="1" colspan="1">52.5, 785</td><td align="center" rowspan="1" colspan="1">29.4, 437</td><td align="center" rowspan="1" colspan="1">5.1, 76</td><td align="center" rowspan="1" colspan="1">2.6, 39</td><td align="center" rowspan="1" colspan="1">98.0 (20.1)</td><td align="center" rowspan="1" colspan="1">92.4 (21.3)</td><td align="center" rowspan="1" colspan="1">9.6 (0.6)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>KORA4</bold></td><td align="center" rowspan="1" colspan="1">1200</td><td align="center" rowspan="1" colspan="1">49.2 (15.4)</td><td align="center" rowspan="1" colspan="1">52.4, 629</td><td align="center" rowspan="1" colspan="1">13.3, 159</td><td align="center" rowspan="1" colspan="1">4, 48</td><td align="center" rowspan="1" colspan="1">5.8, 70</td><td align="center" rowspan="1" colspan="1">97.4 (21.7)</td><td align="center" rowspan="1" colspan="1">92.6 (22.4)</td><td align="center" rowspan="1" colspan="1">7.2 (0.5)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>NESDA</bold></td><td align="center" rowspan="1" colspan="1">1270</td><td align="center" rowspan="1" colspan="1">43.3 (12.3)</td><td align="center" rowspan="1" colspan="1">67.2, 854</td><td align="center" rowspan="1" colspan="1">32.4, 411</td><td align="center" rowspan="1" colspan="1">5.4, 69</td><td align="center" rowspan="1" colspan="1">0.9, 11</td><td align="center" rowspan="1" colspan="1">97.8 (20.4)</td><td align="center" rowspan="1" colspan="1">95.5 (18.5)</td><td align="center" rowspan="1" colspan="1">2.0 (0.3)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>popgen</bold></td><td align="center" rowspan="1" colspan="1">577</td><td align="center" rowspan="1" colspan="1">60.2 (9.4)</td><td align="center" rowspan="1" colspan="1">42.1, 243</td><td align="center" rowspan="1" colspan="1">50.4, 288</td><td align="center" rowspan="1" colspan="1">5.2, 30</td><td align="center" rowspan="1" colspan="1">6.1, 35</td><td align="center" rowspan="1" colspan="1">84.5 (17.2)</td><td align="center" rowspan="1" colspan="1">79.9 (18.4)</td><td align="center" rowspan="1" colspan="1">4.8 (0.8)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>PREVEND (4 year follow-up)</bold></td><td align="center" rowspan="1" colspan="1">791</td><td align="center" rowspan="1" colspan="1">53.0 (13.3)</td><td align="center" rowspan="1" colspan="1">50.8, 402</td><td align="center" rowspan="1" colspan="1">40.8, 323</td><td align="center" rowspan="1" colspan="1">4.2, 33</td><td align="center" rowspan="1" colspan="1">6.0, 47</td><td align="center" rowspan="1" colspan="1">89.2 (19.5)</td><td align="center" rowspan="1" colspan="1">106.4 (34.2)</td><td align="center" rowspan="1" colspan="1">4.3 (0.6)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>PREVEND (9 year follow-up)</bold></td><td align="center" rowspan="1" colspan="1">2169</td><td align="center" rowspan="1" colspan="1">48.0 (11.1)</td><td align="center" rowspan="1" colspan="1">48.0, 1040</td><td align="center" rowspan="1" colspan="1">28.2, 612</td><td align="center" rowspan="1" colspan="1">3.1, 66</td><td align="center" rowspan="1" colspan="1">1.7, 37</td><td align="center" rowspan="1" colspan="1">93.7 (17.7)</td><td align="center" rowspan="1" colspan="1">86.9 (18.6)</td><td align="center" rowspan="1" colspan="1">9.4 (0.84)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>RS-II</bold></td><td align="center" rowspan="1" colspan="1">1243</td><td align="center" rowspan="1" colspan="1">61.8 (5.2)</td><td align="center" rowspan="1" colspan="1">54.6, 679</td><td align="center" rowspan="1" colspan="1">21.4, 266</td><td align="center" rowspan="1" colspan="1">7.8, 97</td><td align="center" rowspan="1" colspan="1">8.6, 186</td><td align="center" rowspan="1" colspan="1">81.2 (17.0)</td><td align="center" rowspan="1" colspan="1">73.7 (15.8)</td><td align="center" rowspan="1" colspan="1">10.6 (0.4)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>SAPHIR</bold></td><td align="center" rowspan="1" colspan="1">1374</td><td align="center" rowspan="1" colspan="1">51.6 (6.0)</td><td align="center" rowspan="1" colspan="1">39.0. 536</td><td align="center" rowspan="1" colspan="1">54.9, 754</td><td align="center" rowspan="1" colspan="1">2.6, 36</td><td align="center" rowspan="1" colspan="1">0.9, 13</td><td align="center" rowspan="1" colspan="1">91.5 (15.8)</td><td align="center" rowspan="1" colspan="1">88.0 (16.0)</td><td align="center" rowspan="1" colspan="1">4.6 (0.7)</td></tr><tr><td align="center" rowspan="1" colspan="1"><bold>YFS</bold></td><td align="center" rowspan="1" colspan="1">1683</td><td align="center" rowspan="1" colspan="1">31.9 (4.9)</td><td align="center" rowspan="1" colspan="1">56.0, 943</td><td align="center" rowspan="1" colspan="1">8.3, 139</td><td align="center" rowspan="1" colspan="1">1.1, 18</td><td align="center" rowspan="1" colspan="1">0.2, 3</td><td align="center" rowspan="1" colspan="1">105.4 (16.4)</td><td align="center" rowspan="1" colspan="1">100.4 (16.0)</td><td align="center" rowspan="1" colspan="1">6.0 (0)</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><p id="P84">Unless indicated otherwise, values are given as mean (SD)</p></fn><fn id="TFN2"><p id="P85"><bold>A:</bold> eGFR at visit 2; <bold>B:</bold> eGFR at visit 4; <bold>DM:</bold> Diabetes; <bold>HTN:</bold> hypertension; <bold>CKD:</bold> Chronic kidney disease (eGFR<60ml/min/1.73m<sup>2</sup>); <bold>eGFR:</bold> estimated glomerular filtration rate; <bold>SD:</bold> standard deviation</p></fn></table-wrap-foot></table-wrap><table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label><caption><p id="P86">Genetic association results of SNPs identified in stage 1 meta-analysis</p></caption><table frame="void" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="2" rowspan="1">discovery stage 1</th><th align="center" colspan="2" rowspan="1">Replication<break></break>stage 2</th><th align="center" colspan="3" rowspan="1">Stage 1 and stage 2<break></break>combined</th></tr><tr><th align="left" valign="bottom" rowspan="1" colspan="1">SNPID</th><th align="left" valign="bottom" rowspan="1" colspan="1">trait</th><th align="left" valign="bottom" rowspan="1" colspan="1">Chr</th><th align="left" valign="bottom" rowspan="1" colspan="1">Position<break></break>(b36)</th><th align="left" valign="bottom" rowspan="1" colspan="1">Locus</th><th align="center" valign="bottom" rowspan="1" colspan="1">coded<break></break>allele</th><th align="center" valign="bottom" rowspan="1" colspan="1">non-<break></break>coded<break></break>allele</th><th align="left" valign="bottom" rowspan="1" colspan="1">AF<break></break>coded<break></break>allele</th><th align="left" valign="bottom" rowspan="1" colspan="1">beta</th><th align="left" valign="bottom" rowspan="1" colspan="1">PVal2G<break></break>C</th><th align="left" valign="bottom" rowspan="1" colspan="1">beta</th><th align="left" valign="bottom" rowspan="1" colspan="1">one-sided<break></break>pval1GC</th><th align="left" valign="bottom" rowspan="1" colspan="1">beta</th><th align="left" valign="bottom" rowspan="1" colspan="1">two-sided<break></break>pval1GC</th><th align="left" valign="bottom" rowspan="1" colspan="1">total<break></break>sample<break></break>size</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">rs12917707</td><td align="left" rowspan="1" colspan="1">eGFRchange overall</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">20275191</td><td align="left" rowspan="1" colspan="1"><italic>UMOD, PDILT</italic></td><td align="center" rowspan="1" colspan="1">t</td><td align="center" rowspan="1" colspan="1">g</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">−0.15</td><td align="left" rowspan="1" colspan="1">2.6×10<sup>−14</sup></td><td align="left" rowspan="1" colspan="1">−0.12</td><td align="left" rowspan="1" colspan="1">4.7×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.14</td><td align="left" rowspan="1" colspan="1">1.8×10<sup>−17</sup></td><td align="left" rowspan="1" colspan="1">59373</td></tr><tr><td align="left" rowspan="1" colspan="1">rs11803049</td><td align="left" rowspan="1" colspan="1">eGFRchange CKD</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">11851482</td><td align="left" rowspan="1" colspan="1"><italic>NPPB, NPPA, KIAA2013, CLCN6</italic></td><td align="center" rowspan="1" colspan="1">a</td><td align="center" rowspan="1" colspan="1">g</td><td align="left" rowspan="1" colspan="1">0.07</td><td align="left" rowspan="1" colspan="1">−0.57</td><td align="left" rowspan="1" colspan="1">3.6×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">0.02</td><td align="left" rowspan="1" colspan="1">0.43<xref ref-type="table-fn" rid="TFN4">*</xref></td><td align="left" rowspan="1" colspan="1">−0.27</td><td align="left" rowspan="1" colspan="1">6.2×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">4116</td></tr><tr><td align="left" rowspan="1" colspan="1">rs875860</td><td align="left" rowspan="1" colspan="1">eGFRchange CKD</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">72979535</td><td align="left" rowspan="1" colspan="1"><bold><italic>CDH23</italic></bold></td><td align="center" rowspan="1" colspan="1">t</td><td align="center" rowspan="1" colspan="1">c</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="left" rowspan="1" colspan="1">−0.49</td><td align="left" rowspan="1" colspan="1">6.2×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">−0.15</td><td align="left" rowspan="1" colspan="1">0.047<xref ref-type="table-fn" rid="TFN4">*</xref></td><td align="left" rowspan="1" colspan="1">−0.31</td><td align="left" rowspan="1" colspan="1">4.6×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">4116</td></tr><tr><td align="left" rowspan="1" colspan="1">rs11764932</td><td align="left" rowspan="1" colspan="1">Rapid Decline overall</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">15699643</td><td align="left" rowspan="1" colspan="1"><italic>MEOX2</italic></td><td align="center" rowspan="1" colspan="1">a</td><td align="center" rowspan="1" colspan="1">g</td><td align="left" rowspan="1" colspan="1">0.36</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="left" rowspan="1" colspan="1">6.8×10<sup>−8</sup></td><td align="left" rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">0.14</td><td align="left" rowspan="1" colspan="1">0.09</td><td align="left" rowspan="1" colspan="1">3.6×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">61078</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1019173</td><td align="left" rowspan="1" colspan="1">Rapid Decline overall</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">151341480</td><td align="left" rowspan="1" colspan="1"><italic><bold>GALNTL5,</bold> GALNT11, MLL3, CCT8L1</italic></td><td align="center" rowspan="1" colspan="1">a</td><td align="center" rowspan="1" colspan="1">g</td><td align="left" rowspan="1" colspan="1">0.63</td><td align="left" rowspan="1" colspan="1">−0.12</td><td align="left" rowspan="1" colspan="1">3.0×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">−0.06</td><td align="left" rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">−0.10</td><td align="left" rowspan="1" colspan="1">2.1×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">61077</td></tr><tr><td align="left" rowspan="1" colspan="1">rs9814367</td><td align="left" rowspan="1" colspan="1">Rapid Decline noCKD</td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">192075180</td><td align="left" rowspan="1" colspan="1"><italic>IL1RAP, OSTN</italic></td><td align="center" rowspan="1" colspan="1">t</td><td align="center" rowspan="1" colspan="1">c</td><td align="left" rowspan="1" colspan="1">0.92</td><td align="left" rowspan="1" colspan="1">−0.20</td><td align="left" rowspan="1" colspan="1">4.1×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">0.02</td><td align="left" rowspan="1" colspan="1">0.39</td><td align="left" rowspan="1" colspan="1">−0.13</td><td align="left" rowspan="1" colspan="1">7.3×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">56687</td></tr><tr><td align="left" rowspan="1" colspan="1">rs759341</td><td align="left" rowspan="1" colspan="1">CKDi25</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">10297660</td><td align="left" rowspan="1" colspan="1"><italic>C2orf48, HPCAL1, RRM2</italic></td><td align="center" rowspan="1" colspan="1">a</td><td align="center" rowspan="1" colspan="1">g</td><td align="left" rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">1.5×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">0.06</td><td align="left" rowspan="1" colspan="1">0.27<xref ref-type="table-fn" rid="TFN5">$</xref></td><td align="left" rowspan="1" colspan="1">0.16</td><td align="left" rowspan="1" colspan="1">2.7×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">41122</td></tr></tbody></table><table-wrap-foot><fn id="TFN3"><p id="P87">“Locus” is based on build 36, hg18. The gene closest to the SNP is listed first and is in boldface if the SNP is located within the gene.</p></fn><fn id="TFN4"><label>*</label><p id="P88">studies included: ADVANCE, BMES, COLAUS, RS-II</p></fn><fn id="TFN5"><label>$</label><p id="P89">studies included: ADVANCE, BMES, RS-II</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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