PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
Authors: van Setten Jessica , Brody Jennifer A. , Jamshidi Yalda , Swenson Brenton R. , Butler Anne M. , Campbell Harry , Del Greco Fabiola M. , Evans Daniel S. , Gibson Quince , Gudbjartsson Daniel F. , Kerr Kathleen F. , Krijthe Bouwe P. , Lyytikäinen Leo-Pekka , Müller Christian , Müller-Nurasyid Martina , Nolte Ilja M. , Padmanabhan Sandosh , Ritchie Marylyn D. , Robino Antonietta , Smith Albert V. , Steri Maristella , Tanaka Toshiko , Teumer Alexander , Trompet Stella , Ulivi Sheila , Verweij Niek , Yin Xiaoyan , Arnar David O. , Asselbergs Folkert W. , Bader Joel S. , Barnard John , Bis Josh , Blankenberg Stefan , Boerwinkle Eric , Bradford Yuki , Buckley Brendan M. , Chung Mina K. , Crawford Dana , den Hoed Marcel , Denny Josh C. , Dominiczak Anna F. , Ehret Georg B. , Eijgelsheim Mark , Ellinor Patrick T. , Felix Stephan B. , Franco Oscar H. , Franke Lude , Harris Tamara B. , Holm Hilma , Ilaria Gandin , Iorio Annamaria , Kähönen Mika , Kolcic Ivana , Kors Jan A. , Lakatta Edward G. , Launer Lenore J. , Lin Honghuang , Lin Henry J. , Loos Ruth J. F. , Lubitz Steven A. , Macfarlane Peter W. , Magnani Jared W. , Leach Irene Mateo , Meitinger Thomas , Mitchell Braxton D. , Munzel Thomas , Papanicolaou George J. , Peters Annette , Pfeufer Arne , Pramstaller Peter P. , Raitakari Olli T. , Rotter Jerome I. , Rudan Igor , Samani Nilesh J. , Schlessinger David , Silva Aldana Claudia T. , Sinner Moritz F. , Smith Jonathan D. , Snieder Harold , Soliman Elsayed Z. , Spector Timothy D. , Stott David J. , Strauch Konstantin , Tarasov Kirill V. , Thorsteinsdottir Unnur , Uitterlinden Andre G. , Van Wagoner David R. , Völker Uwe , Völzke Henry , Waldenberger Melanie , Jan Westra Harm , Wild Philipp S. , Zeller Tanja , Alonso Alvaro , Avery Christy L. , Bandinelli Stefania , Benjamin Emelia J. , Cucca Francesco , Dörr Marcus , Ferrucci Luigi , Gasparini Paolo , Gudnason Vilmundur , Hayward Caroline , Heckbert Susan R. , Hicks Andrew A. , Jukema J. Wouter , Kääb Stefan , Lehtimäki Terho , Liu Yongmei , Munroe Patricia B. , Parsa Afshin , Polasek Ozren , Psaty Bruce M. , Roden Dan M. , Schnabel Renate B. , Sinagra Gianfranco , Stefansson Kari , Stricker Bruno H. , van der Harst Pim , van Duijn Cornelia M. , Wilson James F. , Gharib Sina A. , de Bakker Paul I. W. , Isaacs Aaron , Arking Dan E. , Sotoodehnia Nona 
Published: July 2018

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.