Genome-wide association meta-analysis of PR interval identifies 47 novel 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 , Fabiola Del Greco 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 , 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. , Mateo Leach Irene , 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. , Uitterlinden Andre G. , van Wagoner David R. , Völker Uwe , Völzke Henry , Waldenberger Melanie , Westra Harm Jan , 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 , de Bakker Paul I.W. , Isaacs Aaron , Arking Dan E. , Sotoodehnia Nona 
Published: January 2018

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.