Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Alexander Teumer (), Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro () and Anna Köttgen ()
Additional contact information
Alexander Teumer: University Medicine Greifswald
Yong Li: Faculty of Medicine and Medical Center - University of Freiburg
Sahar Ghasemi: University Medicine Greifswald
Bram P. Prins: University of Cambridge
Matthias Wuttke: Faculty of Medicine and Medical Center - University of Freiburg
Tobias Hermle: Faculty of Medicine and Medical Center - University of Freiburg
Ayush Giri: Vanderbilt University Medical Center
Karsten B. Sieber: Target Sciences - Genetics, GlaxoSmithKline
Chengxiang Qiu: University of Pennsylvania
Holger Kirsten: University of Leipzig
Adrienne Tin: Johns Hopkins Bloomberg School of Public Health
Audrey Y. Chu: Genetics, Merck & Co., Inc.
Nisha Bansal: University of Washington
Mary F. Feitosa: Washington University School of Medicine
Lihua Wang: Washington University School of Medicine
Jin-Fang Chai: National University of Singapore and National University Health System
Massimiliano Cocca: Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”
Christian Fuchsberger: Institute for Biomedicine (affiliated to the University of Lübeck)
Mathias Gorski: University Hospital Regensburg
Anselm Hoppmann: Faculty of Medicine and Medical Center - University of Freiburg
Katrin Horn: University of Leipzig
Man Li: University of Utah
Jonathan Marten: University of Edinburgh
Damia Noce: Institute for Biomedicine (affiliated to the University of Lübeck)
Teresa Nutile: Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” - CNR
Sanaz Sedaghat: Erasmus MC, University Medical Center Rotterdam
Gardar Sveinbjornsson: deCODE Genetics, Amgen Inc.
Bamidele O. Tayo: Loyola University Chicago
Peter J. van der Most: University of Groningen, University Medical Center Groningen
Yizhe Xu: University of Utah
Zhi Yu: Johns Hopkins Bloomberg School of Public Health
Lea Gerstner: Faculty of Medicine and Medical Center - University of Freiburg
Johan Ärnlöv: Karolinska Institutet
Stephan J. L. Bakker: University of Groningen, University Medical Center Groningen
Daniela Baptista: Cardiology, Geneva University Hospitals
Mary L. Biggs: University of Washington
Eric Boerwinkle: University of Texas Health Science Centre
Hermann Brenner: German Cancer Research Centre (DKFZ)
Ralph Burkhardt: University of Leipzig
Robert J. Carroll: Vanderbilt University Medical Center
Miao-Li Chee: Singapore National Eye Centre
Miao-Ling Chee: Singapore National Eye Centre
Mengmeng Chen: Faculty of Medicine and Medical Center - University of Freiburg
Ching-Yu Cheng: Singapore National Eye Centre
James P. Cook: University of Liverpool
Josef Coresh: Johns Hopkins Bloomberg School of Public Health
Tanguy Corre: University of Lausanne
John Danesh: University of Cambridge
Martin H. de Borst: University of Groningen, University Medical Center Groningen
Alessandro De Grandi: Institute for Biomedicine (affiliated to the University of Lübeck)
Renée de Mutsert: Leiden University Medical Centre
Aiko P. J. de Vries: Leiden University Medical Centre
Frauke Degenhardt: Christian-Albrechts-University of Kiel
Katalin Dittrich: University of Leipzig
Jasmin Divers: Wake Forest School of Medicine
Kai-Uwe Eckardt: Intensive Care Medicine, Charité
Georg Ehret: Cardiology, Geneva University Hospitals
Karlhans Endlich: Partner Site Greifswald
Janine F. Felix: Erasmus MC, University Medical Center Rotterdam
Oscar H. Franco: Erasmus MC, University Medical Center Rotterdam
Andre Franke: Christian-Albrechts-University of Kiel
Barry I. Freedman: Wake Forest School of Medicine
Sandra Freitag-Wolf: Kiel University, University Hospital Schleswig-Holstein
Ron T. Gansevoort: University of Groningen, University Medical Center Groningen
Vilmantas Giedraitis: Uppsala University
Martin Gögele: Institute for Biomedicine (affiliated to the University of Lübeck)
Franziska Grundner-Culemann: Faculty of Medicine and Medical Center - University of Freiburg
Daniel F. Gudbjartsson: deCODE Genetics, Amgen Inc.
Vilmundur Gudnason: Icelandic Heart Association
Pavel Hamet: Montreal University Hospital Research Centre, CHUM
Tamara B. Harris: National Institutes of Health
Andrew A. Hicks: Institute for Biomedicine (affiliated to the University of Lübeck)
Hilma Holm: deCODE Genetics, Amgen Inc.
Valencia Hui Xian Foo: Singapore National Eye Centre
Shih-Jen Hwang: NHLBI’s Framingham Heart Study
M. Arfan Ikram: Erasmus MC, University Medical Center Rotterdam
Erik Ingelsson: Stanford University School of Medicine
Vincent W. V. Jaddoe: Erasmus MC, University Medical Center Rotterdam
Johanna Jakobsdottir: Icelandic Heart Association, Holtasmari 1
Navya Shilpa Josyula: Biomedical and Translational Informatics Institute
Bettina Jung: University Hospital Regensburg
Mika Kähönen: Tampere University Hospital
Chiea-Chuen Khor: Singapore National Eye Centre
Wieland Kiess: University of Leipzig
Wolfgang Koenig: Deutsches Herzzentrum München, Technische Universität München
Antje Körner: University of Leipzig
Peter Kovacs: University of Leipzig
Holly Kramer: Loyola University Chicago
Bernhard K. Krämer: 5th Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg
Florian Kronenberg: Medical University of Innsbruck
Leslie A. Lange: Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver - Anschutz Medical Campus
Carl D. Langefeld: Wake Forest School of Medicine
Jeannette Jen-Mai Lee: National University of Singapore and National University Health System
Terho Lehtimäki: Fimlab Laboratories
Wolfgang Lieb: Kiel University
Su-Chi Lim: National University of Singapore and National University Health System
Lars Lind: Uppsala University
Cecilia M. Lindgren: University of Oxford
Jianjun Liu: Agency for Science Technology and Research
Markus Loeffler: University of Leipzig
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Anubha Mahajan: University of Oxford
Joseph C. Maranville: MRL, Merck & Co., Inc.
Deborah Mascalzoni: Institute for Biomedicine (affiliated to the University of Lübeck)
Barbara McMullen: Vanderbilt University School of Medicine
Christa Meisinger: German Research Centre for Environmental Health
Thomas Meitinger: Partner Site Munich Heart Alliance
Kozeta Miliku: Erasmus MC, University Medical Center Rotterdam
Dennis O. Mook-Kanamori: Leiden University Medical Centre
Martina Müller-Nurasyid: Helmholtz Zentrum München - German Research Centre for Environmental Health
Josyf C. Mychaleckyj: University of Virginia
Matthias Nauck: Partner Site Greifswald
Kjell Nikus: Tampere University Hospital
Boting Ning: Boston University School of Public Health
Raymond Noordam: Leiden University Medical Centre
Jeffrey O’ Connell: University of Maryland School of Medicine
Isleifur Olafsson: Landspitali University Hospital
Nicholette D. Palmer: Biochemistry, Wake Forest School of Medicine
Annette Peters: Partner Site Munich Heart Alliance
Anna I. Podgornaia: Genetics, Merck & Co., Inc.
Belen Ponte: Service de Néphrologie, Geneva University Hospitals
Tanja Poulain: University of Leipzig
Peter P. Pramstaller: Institute for Biomedicine (affiliated to the University of Lübeck)
Ton J. Rabelink: Leiden University Medical Centre
Laura M. Raffield: University of North Carolina
Dermot F. Reilly: Genetics, Merck & Co., Inc.
Rainer Rettig: University Medicine Greifswald
Myriam Rheinberger: University Hospital Regensburg
Kenneth M. Rice: University of Washington
Fernando Rivadeneira: Erasmus MC, University Medical Center Rotterdam
Heiko Runz: MRL, Merck & Co., Inc.
Kathleen A. Ryan: University of Maryland School of Medicine
Charumathi Sabanayagam: Singapore National Eye Centre
Kai-Uwe Saum: German Cancer Research Centre (DKFZ)
Ben Schöttker: German Cancer Research Centre (DKFZ)
Christian M. Shaffer: Vanderbilt University Medical Center
Yuan Shi: Singapore National Eye Centre
Albert V. Smith: University of Iceland
Konstantin Strauch: Helmholtz Zentrum München - German Research Centre for Environmental Health
Michael Stumvoll: University of Leipzig
Benjamin B. Sun: University of Cambridge
Silke Szymczak: Kiel University, University Hospital Schleswig-Holstein
E-Shyong Tai: National University of Singapore and National University Health System
Nicholas Y. Q. Tan: Singapore National Eye Centre
Kent D. Taylor: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Andrej Teren: University of Leipzig
Yih-Chung Tham: Singapore National Eye Centre
Joachim Thiery: University of Leipzig
Chris H. L. Thio: University of Groningen, University Medical Center Groningen
Hauke Thomsen: German Cancer Research Centre (DKFZ)
Unnur Thorsteinsdottir: deCODE Genetics, Amgen Inc.
Anke Tönjes: University of Leipzig
Johanne Tremblay: Montreal University Hospital Research Centre, CHUM
André G. Uitterlinden: Erasmus MC, University Medical Center Rotterdam
Pim van der Harst: University of Groningen, University Medical Center Groningen
Niek Verweij: University of Groningen, University Medical Center Groningen
Suzanne Vogelezang: Erasmus MC, University Medical Center Rotterdam
Uwe Völker: Partner Site Greifswald
Melanie Waldenberger: Partner Site Munich Heart Alliance
Chaolong Wang: Agency for Science Technology and Research
Otis D. Wilson: Division of Nephrology & Hypertension
Charlene Wong: National University of Singapore and National University Health System
Tien-Yin Wong: Singapore National Eye Centre
Qiong Yang: Boston University School of Public Health
Masayuki Yasuda: Singapore National Eye Centre
Shreeram Akilesh: University of Washington
Murielle Bochud: University of Lausanne
Carsten A. Böger: University Hospital Regensburg
Olivier Devuyst: University of Zurich
Todd L. Edwards: Vanderbilt University Medical Centre
Kevin Ho: Kidney Health Research Institute (KHRI), Geisinger
Andrew P. Morris: University of Liverpool
Afshin Parsa: National Institutes of Health
Sarah A. Pendergrass: Biomedical and Translational Informatics Institute
Bruce M. Psaty: University of Washington
Jerome I. Rotter: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Kari Stefansson: deCODE Genetics, Amgen Inc.
James G. Wilson: University of Mississippi Medical Centre
Katalin Susztak: University of Pennsylvania
Harold Snieder: University of Groningen, University Medical Center Groningen
Iris M. Heid: University of Regensburg
Markus Scholz: University of Leipzig
Adam S. Butterworth: University of Cambridge
Adriana M. Hung: Division of Nephrology & Hypertension
Cristian Pattaro: Institute for Biomedicine (affiliated to the University of Lübeck)
Anna Köttgen: Faculty of Medicine and Medical Center - University of Freiburg

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Date: 2019
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DOI: 10.1038/s41467-019-11576-0

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