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

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, Kathleen F. Kerr, Bouwe P. Krijthe, Leo-Pekka Lyytikäinen, Christian Müller, Martina Müller-Nurasyid, Ilja M. Nolte, Sandosh Padmanabhan, Marylyn D. Ritchie, Antonietta Robino, Albert V. Smith, Maristella Steri, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sheila Ulivi, Niek Verweij, Xiaoyan Yin, David O. Arnar, Folkert W. Asselbergs, Joel S. Bader, John Barnard, Josh Bis, Stefan Blankenberg, Eric Boerwinkle, Yuki Bradford, Brendan M. Buckley, Mina K. Chung, Dana Crawford, Marcel den Hoed, Josh C. Denny, Anna F. Dominiczak, Georg B. Ehret, Mark Eijgelsheim, Patrick T. Ellinor, Stephan B. Felix, Oscar H. Franco, Lude Franke, Tamara B. Harris, Hilma Holm, Gandin Ilaria, Annamaria Iorio, Mika Kähönen, Ivana Kolcic, Jan A. Kors, Edward G. Lakatta, Lenore J. Launer, Honghuang Lin, Henry J. Lin, Ruth J. F. Loos, Steven A. Lubitz, Peter W. Macfarlane, Jared W. Magnani, Irene Mateo Leach, Thomas Meitinger, Braxton D. Mitchell, Thomas Munzel, George J. Papanicolaou, Annette Peters, Arne Pfeufer, Peter P. Pramstaller, Olli T. Raitakari, Jerome I. Rotter, Igor Rudan, Nilesh J. Samani, David Schlessinger, Claudia T. Silva Aldana, Moritz F. Sinner, Jonathan D. Smith, Harold Snieder, Elsayed Z. Soliman, Timothy D. Spector, David J. Stott, Konstantin Strauch, Kirill V. Tarasov, Unnur Thorsteinsdottir, Andre G. Uitterlinden, David R. Van Wagoner, Uwe Völker, Henry Völzke, Melanie Waldenberger, Harm Westra, Philipp S. Wild, Tanja Zeller, Alvaro Alonso, Christy L. Avery, Stefania Bandinelli, Emelia J. Benjamin, Francesco Cucca, Marcus Dörr, Luigi Ferrucci, Paolo Gasparini, Vilmundur Gudnason, Caroline Hayward, Susan R. Heckbert, Andrew A. Hicks, J. Wouter Jukema, Stefan Kääb, Terho Lehtimäki, Yongmei Liu, Patricia B. Munroe, Afshin Parsa, Ozren Polasek, Bruce M. Psaty, Dan M. Roden, Renate B. Schnabel, Gianfranco Sinagra, Kari Stefansson, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, James F. Wilson, Sina A. Gharib, Paul I. W. de Bakker, Aaron Isaacs, Dan E. Arking and Nona Sotoodehnia ()
Additional contact information
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
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.
Kathleen F. Kerr: University of Washington
Bouwe P. Krijthe: Erasmus Medical Center
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Christian Müller: University Heart Center Hamburg-Eppendorf
Martina Müller-Nurasyid: Helmholtz Zentrum München-German Research Center for Environmental Health
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
Maristella Steri: Consiglio Nazionale delle Ricerche (CNR)
Toshiko Tanaka: Translational Gerontology Branch, NIA
Alexander Teumer: University Medicine Greifswald
Stella Trompet: 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.
Folkert W. Asselbergs: University of Utrecht
Joel S. Bader: Johns Hopkins University
John Barnard: Cleveland Clinic
Josh Bis: University Heart Center Hamburg-Eppendorf
Stefan Blankenberg: DZHK (German Center for Cardiovascular Research) Partner Site
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
Dana Crawford: Case Western Reserve University
Marcel den Hoed: 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
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Stephan B. Felix: Partner Site 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
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
Steven A. Lubitz: The Broad Institute of MIT and Harvard
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
Braxton D. Mitchell: Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center
Thomas Munzel: 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
Arne Pfeufer: MVZ für Molekulardiagnostik
Peter P. Pramstaller: Affiliated Institute of the University of Lübeck
Olli T. Raitakari: Turku University Hospital
Jerome I. Rotter: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Igor Rudan: University of Edinburgh
Nilesh J. Samani: University of Leicester
David Schlessinger: National Institute of Health
Claudia T. Silva Aldana: Erasmus University Medical Center
Moritz F. Sinner: Hospital of the Ludwig-Maximilians-University (LMU) Munich
Jonathan D. Smith: 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
Kirill V. Tarasov: National Institutes of Health
Unnur Thorsteinsdottir: deCODE genetics/Amgen, Inc.
Andre G. Uitterlinden: Erasmus Medical Center
David R. Van Wagoner: Cleveland Clinic
Uwe Völker: Partner Site Greifswald
Henry Völzke: University Medicine Greifswald
Melanie Waldenberger: Partner Site Munich Heart Alliance
Harm Westra: University Medical Center Groningen
Philipp S. Wild: Partner Site Rhine-Main
Tanja Zeller: University Heart Center Hamburg-Eppendorf
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
Luigi Ferrucci: Translational Gerontology Branch, NIA
Paolo Gasparini: Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”
Vilmundur Gudnason: Icelandic Heart Association
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
Stefan Kääb: Hospital of the Ludwig-Maximilians-University (LMU) Munich
Terho Lehtimäki: Fimlab Laboratories
Yongmei Liu: Wake Forest University
Patricia B. Munroe: Queen Mary University of London
Afshin Parsa: University of Maryland School of Medicine and Baltimore VA Medical Center
Ozren Polasek: University of Split
Bruce M. Psaty: University of Washington
Dan M. Roden: Vanderbilt University
Renate B. Schnabel: University Heart Center Hamburg-Eppendorf
Gianfranco Sinagra: “Ospedali Riuniti and University of Trieste”
Kari Stefansson: deCODE genetics/Amgen, Inc.
Bruno H. Stricker: Erasmus Medical Center
Pim van der Harst: University of Groningen
Cornelia M. van Duijn: Erasmus University Medical Center
James F. Wilson: University of Edinburgh
Sina A. Gharib: University of Washington
Paul I. W. de Bakker: University Medical Center Utrecht
Aaron Isaacs: CARIM School for Cardiovascular Diseases
Dan E. Arking: Johns Hopkins University School of Medicine
Nona Sotoodehnia: University of Washington

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04766-9

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