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Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

By Jessica van Setten, Jennifer A Brody, Yalda Jamshidi, Brenton R. Swenson, Anne M. Butler, Harry Campbell, M. Fabiola 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 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 JF 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, 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 Gharib, Paul IW de Bakker, Aaron Isaacs, Dan E Arking, Nona Sotoodehnia

Posted 17 Jan 2018
bioRxiv DOI: 10.1101/241489

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

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