PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
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
(2018) Nature Communications, volume 9, issue 1
(Article)
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
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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.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: Competing interests: The authors declare no competing non-financial interests, but the following competing financial interests: Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb, Bayer HealthCare, Biotronik, and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics, Bristol Myers Squibb.Dr. Ellinor is the PI on a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics for cardiovascular diseases. Dr. Ellinor has served as a consultant to Novartis and Quest Diagnostics.Dr. Butler has received investigator-initiated grant support from Amgen and AstraZeneca for unrelated projects.All authors affiliated with deCODE genetics/Amgen, Inc. are employed by the company. Publisher Copyright: © 2018, The Author(s).
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