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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
  • 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
  • Anna Köttgen
Externa organisationer
  • University Medicine Greifswald
  • German Centre for Cardiovascular Research
  • Albert-Ludwigs University Freiburg
  • University of Cambridge
  • Vanderbilt University
  • GlaxoSmithKline
  • University of Pennsylvania
  • Leipzig University
  • Johns Hopkins Bloomberg School of Public Health
  • Merck Sharp and Dohme (MSD)
  • University of Washington
  • Washington University in St. Louis
  • National University Health System
  • Burlo Garofolo Pediatric Institute
  • EURAC Research, Institute for Biomedicine
  • University Clinics of Regensburg
  • University of Regensburg
  • University of Utah
  • University of Edinburgh
  • CNR
  • Erasmus University Medical Center
  • deCODE Genetics/Amgen, Inc.
  • Loyola University Chicago
  • University Medical Center Groningen
  • Karolinska Institute
  • Dalarna University
  • Geneva University Hospital
  • University of Texas
  • German Cancer Research Centre
  • Heidelberg University
  • Singapore Eye Research Institute
  • Duke–NUS Medical School
  • National University of Singapore
  • University of Liverpool
  • Lausanne University Hospital
  • Swiss Institute of Bioinformatics
  • Leiden University Medical Centre
  • University of Kiel
  • Wake Forest University
  • Charité Universitätsmedizin Berlin
  • Friedrich-Alexander University Erlangen-Nürnberg
  • University of Bern
  • Uppsala universitet, Historiska institutionen
  • Icelandic Heart Association
  • University of Iceland
  • Centre hospitalier de l'Université de Montréal
  • National Institute on Aging, United States
  • Framingham Heart Study
  • Stanford University
  • Geisinger, Danville, PA
  • Tampere University Hospital
  • University of Tampere
  • Genome Institute of Singapore
  • German Heart Centre, Munich
  • University of Ulm
  • Medical University of Innsbruck
  • University of Colorado-Denver
  • Fimlab Laboratories
  • Khoo Teck Puat Hospital
  • University of Oxford
  • Broad Institute
  • Wellcome Trust Centre for Human Genetics
  • Celgene Corporation
  • Vanderbilt University School of Medicine
  • Helmholtz Zentrum München
  • World Orthopaedic Concern
  • Technical University of Munich
  • University of Virginia
  • Boston University
  • University of Maryland School of Medicine
  • National University Hospital of Iceland
  • German Center for Diabetes Research
  • University of North Carolina
  • University of California, Los Angeles
  • University of Leipzig Heart Center
  • Interuniversity Cardiology Institute of the Netherlands
  • Huazhong University of Science and Technology
  • Tohoku University
  • University of Washington, Seattle
  • Kliniken Südostbayern - Klinikum Traunstein
  • University Hospital of Zurich
  • Kaiser Permanente Research Institute
  • University of Mississippi
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Antal sidor1
TidskriftNature Communications
Volym10
Utgåva nummer1
StatusPublished - 2019 sep 11
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa