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

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Listed:
  • Alexander Teumer

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Yong Li

    (Faculty of Medicine and Medical Center - University of Freiburg)

  • Sahar Ghasemi

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Bram P. Prins

    (University of Cambridge)

  • Matthias Wuttke

    (Faculty of Medicine and Medical Center - University of Freiburg
    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
    Tennessee Valley Healthcare System (626)/Vanderbilt University)

  • Karsten B. Sieber

    (Target Sciences - Genetics, GlaxoSmithKline)

  • Chengxiang Qiu

    (University of Pennsylvania)

  • Holger Kirsten

    (University of Leipzig
    University of Leipzig)

  • Adrienne Tin

    (Johns Hopkins Bloomberg School of Public Health
    Welch Centre for Prevention)

  • Audrey Y. Chu

    (Genetics, Merck & Co., Inc.)

  • Nisha Bansal

    (University of Washington
    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
    University of Regensburg)

  • Anselm Hoppmann

    (Faculty of Medicine and Medical Center - University of Freiburg)

  • Katrin Horn

    (University of Leipzig
    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
    Johns Hopkins Bloomberg School of Public Health)

  • Lea Gerstner

    (Faculty of Medicine and Medical Center - University of Freiburg)

  • Johan Ärnlöv

    (Karolinska Institutet
    Dalarna University)

  • Stephan J. L. Bakker

    (University of Groningen, University Medical Center Groningen)

  • Daniela Baptista

    (Cardiology, Geneva University Hospitals)

  • Mary L. Biggs

    (University of Washington
    University of Washington)

  • Eric Boerwinkle

    (University of Texas Health Science Centre)

  • Hermann Brenner

    (German Cancer Research Centre (DKFZ)
    University of Heidelberg)

  • Ralph Burkhardt

    (University of Leipzig
    University of Leipzig
    University Hospital Regensburg)

  • 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
    Duke-NUS Medical School
    National University of Singapore and National University Health System)

  • James P. Cook

    (University of Liverpool)

  • Josef Coresh

    (Johns Hopkins Bloomberg School of Public Health)

  • Tanguy Corre

    (University of Lausanne
    University of Lausanne
    Swiss Institute of Bioinformatics)

  • 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
    University of Leipzig)

  • Jasmin Divers

    (Wake Forest School of Medicine)

  • Kai-Uwe Eckardt

    (Intensive Care Medicine, Charité
    Friedrich-Alexander-University Erlangen-Nürnberg (FAU))

  • Georg Ehret

    (Cardiology, Geneva University Hospitals)

  • Karlhans Endlich

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Janine F. Felix

    (Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam)

  • Oscar H. Franco

    (Erasmus MC, University Medical Center Rotterdam
    University of Bern)

  • 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
    University of Iceland)

  • Pavel Hamet

    (Montreal University Hospital Research Centre, CHUM
    Medpharmgene)

  • 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
    The Centre for Population Studies, NHLBI)

  • M. Arfan Ikram

    (Erasmus MC, University Medical Center Rotterdam)

  • Erik Ingelsson

    (Stanford University School of Medicine
    Stanford University
    Uppsala University
    Stanford University)

  • Vincent W. V. Jaddoe

    (Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam)

  • Johanna Jakobsdottir

    (Icelandic Heart Association, Holtasmari 1
    University of Iceland, Sturlugata 8)

  • Navya Shilpa Josyula

    (Biomedical and Translational Informatics Institute)

  • Bettina Jung

    (University Hospital Regensburg)

  • Mika Kähönen

    (Tampere University Hospital
    Tampere University)

  • Chiea-Chuen Khor

    (Singapore National Eye Centre
    Agency for Science Technology and Research)

  • Wieland Kiess

    (University of Leipzig
    University of Leipzig
    University of Leipzig)

  • Wolfgang Koenig

    (Deutsches Herzzentrum München, Technische Universität München
    Partner Site Munich Heart Alliance
    University of Ulm)

  • Antje Körner

    (University of Leipzig
    University of Leipzig
    University of Leipzig)

  • Peter Kovacs

    (University of Leipzig)

  • Holly Kramer

    (Loyola University Chicago
    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
    Tampere University)

  • Wolfgang Lieb

    (Kiel University)

  • Su-Chi Lim

    (National University of Singapore and National University Health System
    Khoo Teck Puat Hospital)

  • Lars Lind

    (Uppsala University)

  • Cecilia M. Lindgren

    (University of Oxford
    Broad Institute of Harvard and MIT)

  • Jianjun Liu

    (Agency for Science Technology and Research
    National University of Singapore and National University Health System)

  • Markus Loeffler

    (University of Leipzig
    University of Leipzig)

  • Leo-Pekka Lyytikäinen

    (Fimlab Laboratories
    Tampere University)

  • Anubha Mahajan

    (University of Oxford
    University of Oxford)

  • Joseph C. Maranville

    (MRL, Merck & Co., Inc.
    Celgene 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
    Chair of Epidemiology Ludwig- Maximilians-Universität München at UNIKA-T Augsburg)

  • Thomas Meitinger

    (Partner Site Munich Heart Alliance
    Helmholtz Zentrum München
    Technische Universität München)

  • Kozeta Miliku

    (Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam)

  • Dennis O. Mook-Kanamori

    (Leiden University Medical Centre
    Leiden University Medical Centre)

  • Martina Müller-Nurasyid

    (Helmholtz Zentrum München - German Research Centre for Environmental Health
    IBE, Faculty of Medicine, LMU
    Hospital of the Ludwig-Maximilians-University (LMU) Munich)

  • Josyf C. Mychaleckyj

    (University of Virginia)

  • Matthias Nauck

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Kjell Nikus

    (Tampere University Hospital
    Tampere University)

  • 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
    Helmholtz Zentrum München - German Research Centre for Environmental Health
    German Center for Diabetes Research (DZD))

  • 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
    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
    Erasmus MC, University Medical Center Rotterdam)

  • Heiko Runz

    (MRL, Merck & Co., Inc.
    Biogen Inc.)

  • Kathleen A. Ryan

    (University of Maryland School of Medicine)

  • Charumathi Sabanayagam

    (Singapore National Eye Centre
    Duke-NUS Medical School)

  • Kai-Uwe Saum

    (German Cancer Research Centre (DKFZ))

  • Ben Schöttker

    (German Cancer Research Centre (DKFZ)
    University of Heidelberg)

  • Christian M. Shaffer

    (Vanderbilt University Medical Center)

  • Yuan Shi

    (Singapore National Eye Centre
    Duke-NUS Medical School)

  • Albert V. Smith

    (University of Iceland)

  • Konstantin Strauch

    (Helmholtz Zentrum München - German Research Centre for Environmental Health
    IBE, Faculty of Medicine, LMU)

  • 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
    National University of Singapore and National University Health System
    Duke-NUS Medical School)

  • 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
    Heart Centre Leipzig)

  • Yih-Chung Tham

    (Singapore National Eye Centre)

  • Joachim Thiery

    (University of Leipzig
    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
    CRCHUM)

  • André G. Uitterlinden

    (Erasmus MC, University Medical Center Rotterdam)

  • Pim van der Harst

    (University of Groningen, University Medical Center Groningen
    University of Groningen, University Medical Center Groningen
    The Netherlands Heart Institute)

  • Niek Verweij

    (University of Groningen, University Medical Center Groningen)

  • Suzanne Vogelezang

    (Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam
    Erasmus MC, University Medical Center Rotterdam)

  • Uwe Völker

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Melanie Waldenberger

    (Partner Site Munich Heart Alliance
    Helmholtz Zentrum München - German Research Centre for Environmental Health
    Helmholtz Zentrum München - German Research Centre for Environmental Health)

  • Chaolong Wang

    (Agency for Science Technology and Research
    Huazhong University of Science and Technology)

  • 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
    Duke-NUS Medical School
    National University of Singapore and National University Health System)

  • Qiong Yang

    (Boston University School of Public Health)

  • Masayuki Yasuda

    (Singapore National Eye Centre
    Tohoku University Graduate School of Medicine)

  • Shreeram Akilesh

    (University of Washington
    University of Washington Medical Center)

  • Murielle Bochud

    (University of Lausanne)

  • Carsten A. Böger

    (University Hospital Regensburg
    Kliniken Südostbayern)

  • Olivier Devuyst

    (University of Zurich)

  • Todd L. Edwards

    (Vanderbilt University Medical Centre
    Tennessee Valley Healthcare System (626)/Vanderbilt University)

  • Kevin Ho

    (Kidney Health Research Institute (KHRI), Geisinger
    Geisinger)

  • Andrew P. Morris

    (University of Liverpool
    University of Oxford)

  • Afshin Parsa

    (National Institutes of Health
    University of Maryland School of Medicine)

  • Sarah A. Pendergrass

    (Biomedical and Translational Informatics Institute)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Jerome I. Rotter

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
    Harbor-UCLA Medical Centre
    Harbor-UCLA Medical Centre)

  • 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
    University of Leipzig)

  • Adam S. Butterworth

    (University of Cambridge
    University of Cambridge)

  • Adriana M. Hung

    (Division of Nephrology & Hypertension
    Tennessee Valley Healthcare System (626)/Vanderbilt University)

  • Cristian Pattaro

    (Institute for Biomedicine (affiliated to the University of Lübeck))

  • Anna Köttgen

    (Faculty of Medicine and Medical Center - University of Freiburg
    Johns Hopkins Bloomberg School of Public Health)

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.

Suggested Citation

  • 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 B, 2019. "Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11576-0
    DOI: 10.1038/s41467-019-11576-0
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    Cited by:

    1. Parker C. Wilson & Yoshiharu Muto & Haojia Wu & Anil Karihaloo & Sushrut S. Waikar & Benjamin D. Humphreys, 2022. "Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Pascal Schlosser & Adrienne Tin & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Antoine Weihs & Zhi Yu & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Ade, 2021. "Meta-analyses identify DNA methylation associated with kidney function and damage," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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