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1. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

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. 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 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, and Nona Sotoodehnia

Subjects
Science
Abstract

Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.

Published
2018
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2. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, 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, Gandin, Ilaria, 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, Thoma, Mitchell, Braxton D, Munzel, Thoma, 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, Marcu, 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, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., 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., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018

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