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 SmithMaristella 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 Jan 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, Nona Sotoodehnia

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9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2904
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Jul 25 2018

Cite this

van Setten, J., Brody, J. A., Jamshidi, Y., Swenson, B. R., Butler, A. M., Campbell, H., Del Greco, F. M., Evans, D. S., Gibson, Q., Gudbjartsson, D. F., Kerr, K. F., Krijthe, B. P., Lyytikäinen, L-P., Müller, C., Müller-Nurasyid, M., Nolte, I. M., Padmanabhan, S., Ritchie, M. D., Robino, A., ... Sotoodehnia, N. (2018). PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. Nature Communications, 9(1), 2904. https://doi.org/10.1038/s41467-018-04766-9