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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Listed:
  • Jessica van Setten

    (University of Utrecht)

  • Jennifer A. Brody

    (University of Washington)

  • Yalda Jamshidi

    (St George’s University of London)

  • Brenton R. Swenson

    (University of Washington
    University of Washington)

  • Anne M. Butler

    (Washington University School of Medicine)

  • Harry Campbell

    (University of Edinburgh)

  • Fabiola M. Del Greco

    (Affiliated Institute of the University of Lübeck)

  • Daniel S. Evans

    (California Pacific Medical Center Research Institute)

  • Quince Gibson

    (University of Alabama Birmingham Hospital)

  • Daniel F. Gudbjartsson

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Kathleen F. Kerr

    (University of Washington)

  • Bouwe P. Krijthe

    (Erasmus Medical Center)

  • Leo-Pekka Lyytikäinen

    (Fimlab Laboratories
    University of Tampere)

  • Christian Müller

    (University Heart Center Hamburg-Eppendorf
    DZHK (German Center for Cardiovascular Research) Partner Site)

  • Martina Müller-Nurasyid

    (Helmholtz Zentrum München-German Research Center for Environmental Health
    Hospital of the Ludwig-Maximilians-University (LMU) Munich
    Partner Site Munich Heart Alliance
    University Medical Center Groningen)

  • Ilja M. Nolte

    (University Medical Center Groningen)

  • Sandosh Padmanabhan

    (University of Glasgow)

  • Marylyn D. Ritchie

    (University of Pennsylvania)

  • Antonietta Robino

    (Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”)

  • Albert V. Smith

    (Icelandic Heart Association
    University of Iceland
    University of Michigan)

  • Maristella Steri

    (Consiglio Nazionale delle Ricerche (CNR))

  • Toshiko Tanaka

    (Translational Gerontology Branch, NIA)

  • Alexander Teumer

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Stella Trompet

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Sheila Ulivi

    (Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”)

  • Niek Verweij

    (University of Groningen)

  • Xiaoyan Yin

    (Boston University School of Medicine)

  • David O. Arnar

    (deCODE genetics/Amgen, Inc.
    University of Iceland
    Landspitali University Hospital)

  • Folkert W. Asselbergs

    (University of Utrecht
    Netherlands Heart Institute
    University College London
    University College London)

  • Joel S. Bader

    (Johns Hopkins University)

  • John Barnard

    (Cleveland Clinic)

  • Josh Bis

    (University Heart Center Hamburg-Eppendorf
    DZHK (German Center for Cardiovascular Research) Partner Site)

  • Stefan Blankenberg

    (DZHK (German Center for Cardiovascular Research) Partner Site
    Helmholtz Zentrum München-German Research Center for Environmental Health)

  • Eric Boerwinkle

    (University of Texas Health Science Center at Houston)

  • Yuki Bradford

    (University of Pennsylvania)

  • Brendan M. Buckley

    (University College Cork)

  • Mina K. Chung

    (Cleveland Clinic
    Cleveland Clinic)

  • Dana Crawford

    (Case Western Reserve University)

  • Marcel den Hoed

    (Uppsala University
    Uppsala University)

  • Josh C. Denny

    (Vanderbilt University)

  • Anna F. Dominiczak

    (University of Glasgow)

  • Georg B. Ehret

    (Johns Hopkins University School of Medicine)

  • Mark Eijgelsheim

    (Erasmus Medical Center
    University Medical Center Groningen)

  • Patrick T. Ellinor

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Stephan B. Felix

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Oscar H. Franco

    (Erasmus Medical Center)

  • Lude Franke

    (University Medical Center Groningen)

  • Tamara B. Harris

    (National Institutes of Health)

  • Hilma Holm

    (deCODE genetics/Amgen, Inc.)

  • Gandin Ilaria

    (University of Trieste)

  • Annamaria Iorio

    (“Ospedali Riuniti and University of Trieste”)

  • Mika Kähönen

    (Tampere University Hospital
    University of Tampere)

  • Ivana Kolcic

    (University of Split)

  • Jan A. Kors

    (Erasmus University Medical Center)

  • Edward G. Lakatta

    (National Institutes of Health)

  • Lenore J. Launer

    (National Institutes of Health)

  • Honghuang Lin

    (Boston University School of Medicine)

  • Henry J. Lin

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

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Steven A. Lubitz

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Peter W. Macfarlane

    (University of Glasgow)

  • Jared W. Magnani

    (University of Pittsburgh)

  • Irene Mateo Leach

    (University of Groningen)

  • Thomas Meitinger

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

  • Braxton D. Mitchell

    (Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center)

  • Thomas Munzel

    (University Medical Center of the Johannes Gutenberg-University Mainz
    Partner Site Rhine-Main
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • George J. Papanicolaou

    (National Heart, Lung, and Blood Institute, NIH)

  • Annette Peters

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

  • Arne Pfeufer

    (MVZ für Molekulardiagnostik)

  • Peter P. Pramstaller

    (Affiliated Institute of the University of Lübeck
    Central Hospital)

  • Olli T. Raitakari

    (Turku University Hospital
    University of Turku)

  • Jerome I. Rotter

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

  • Igor Rudan

    (University of Edinburgh)

  • Nilesh J. Samani

    (University of Leicester
    NIHR Leicester Biomedical Research Centre)

  • David Schlessinger

    (National Institute of Health)

  • Claudia T. Silva Aldana

    (Erasmus University Medical Center
    Universidad del Rosario)

  • Moritz F. Sinner

    (Hospital of the Ludwig-Maximilians-University (LMU) Munich
    Partner Site Munich Heart Alliance)

  • Jonathan D. Smith

    (Cleveland Clinic
    Cleveland Clinic)

  • Harold Snieder

    (University Medical Center Groningen)

  • Elsayed Z. Soliman

    (Wake Forest School of Medicine)

  • Timothy D. Spector

    (King’s College London)

  • David J. Stott

    (University of Glasgow)

  • Konstantin Strauch

    (Helmholtz Zentrum München-German Research Center for Environmental Health
    LMU Munich)

  • Kirill V. Tarasov

    (National Institutes of Health)

  • Unnur Thorsteinsdottir

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Andre G. Uitterlinden

    (Erasmus Medical Center)

  • David R. Van Wagoner

    (Cleveland Clinic
    Cleveland Clinic)

  • Uwe Völker

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Henry Völzke

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Melanie Waldenberger

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

  • Harm Westra

    (University Medical Center Groningen)

  • Philipp S. Wild

    (Partner Site Rhine-Main
    University Medical Center of the Johannes Gutenberg-University Mainz
    University Medical Center of the Johannes Gutenberg-University Mainz
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • Tanja Zeller

    (University Heart Center Hamburg-Eppendorf
    DZHK (German Center for Cardiovascular Research) Partner Site)

  • Alvaro Alonso

    (Emory University)

  • Christy L. Avery

    (University of North Carolina at Chapel Hill)

  • Stefania Bandinelli

    (Azienda Sanitaria Firenze (ASF))

  • Emelia J. Benjamin

    (Netherlands Heart Institute)

  • Francesco Cucca

    (Consiglio Nazionale delle Ricerche (CNR))

  • Marcus Dörr

    (Partner Site Greifswald
    University Medicine Greifswald)

  • Luigi Ferrucci

    (Translational Gerontology Branch, NIA)

  • Paolo Gasparini

    (Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”
    University of Trieste)

  • Vilmundur Gudnason

    (Icelandic Heart Association
    University of Iceland)

  • Caroline Hayward

    (University of Edinburgh)

  • Susan R. Heckbert

    (University of Washington)

  • Andrew A. Hicks

    (Affiliated Institute of the University of Lübeck)

  • J. Wouter Jukema

    (Leiden University Medical Center
    Leiden University Medical Center
    Interuniversity Cardiology Institute of the Netherlands)

  • Stefan Kääb

    (Hospital of the Ludwig-Maximilians-University (LMU) Munich
    Partner Site Munich Heart Alliance)

  • Terho Lehtimäki

    (Fimlab Laboratories
    University of Tampere)

  • Yongmei Liu

    (Wake Forest University)

  • Patricia B. Munroe

    (Queen Mary University of London
    Barts Health NHS Trust and Queen Mary University of London)

  • Afshin Parsa

    (University of Maryland School of Medicine and Baltimore VA Medical Center)

  • Ozren Polasek

    (University of Split
    Psychiatric hospital “Sveti Ivan”
    Gen-info Ltd.)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Dan M. Roden

    (Vanderbilt University)

  • Renate B. Schnabel

    (University Heart Center Hamburg-Eppendorf
    DZHK (German Center for Cardiovascular Research) Partner Site)

  • Gianfranco Sinagra

    (“Ospedali Riuniti and University of Trieste”)

  • Kari Stefansson

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Bruno H. Stricker

    (Erasmus Medical Center
    Erasmus Medical Center
    Inspectorate for Health Care)

  • Pim van der Harst

    (University of Groningen
    University of Groningen, University Medical Center Groningen, Department of Genetics
    ICIN-Netherlands Heart Institute)

  • Cornelia M. van Duijn

    (Erasmus University Medical Center)

  • James F. Wilson

    (University of Edinburgh
    University of Edinburgh)

  • Sina A. Gharib

    (University of Washington)

  • Paul I. W. de Bakker

    (University Medical Center Utrecht
    University Medical Center Utrecht)

  • Aaron Isaacs

    (CARIM School for Cardiovascular Diseases
    Maastricht University
    Maastricht University)

  • Dan E. Arking

    (Johns Hopkins University School of Medicine)

  • Nona Sotoodehnia

    (University of Washington)

Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Suggested Citation

  • Jessica van Setten & Jennifer A. Brody & Yalda Jamshidi & Brenton R. Swenson & Anne M. Butler & Harry Campbell & Fabiola M. Del Greco & Daniel S. Evans & Quince Gibson & Daniel F. Gudbjartsson & Kathl, 2018. "PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04766-9
    DOI: 10.1038/s41467-018-04766-9
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    Cited by:

    1. Matteo D’Antonio & Jennifer P. Nguyen & Timothy D. Arthur & Hiroko Matsui & Agnieszka D’Antonio-Chronowska & Kelly A. Frazer, 2023. "Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Yordi J. Vegte & Ruben N. Eppinga & M. Yldau Ende & Yanick P. Hagemeijer & Yuvaraj Mahendran & Elias Salfati & Albert V. Smith & Vanessa Y. Tan & Dan E. Arking & Ioanna Ntalla & Emil V. Appel & Claudi, 2023. "Genetic insights into resting heart rate and its role in cardiovascular disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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