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 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.
Original language | English (US) |
---|---|
Article number | 2904 |
Journal | Nature communications |
Volume | 9 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2018 |
All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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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.
In: Nature communications, Vol. 9, No. 1, 2904, 01.12.2018.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
AU - van Setten, Jessica
AU - Brody, Jennifer A.
AU - Jamshidi, Yalda
AU - Swenson, Brenton R.
AU - Butler, Anne M.
AU - Campbell, Harry
AU - Del Greco, Fabiola M.
AU - Evans, Daniel S.
AU - Gibson, Quince
AU - Gudbjartsson, Daniel F.
AU - Kerr, Kathleen F.
AU - Krijthe, Bouwe P.
AU - Lyytikäinen, Leo Pekka
AU - Müller, Christian
AU - Müller-Nurasyid, Martina
AU - Nolte, Ilja M.
AU - Padmanabhan, Sandosh
AU - Ritchie, Marylyn D.
AU - Robino, Antonietta
AU - Smith, Albert V.
AU - Steri, Maristella
AU - Tanaka, Toshiko
AU - Teumer, Alexander
AU - Trompet, Stella
AU - Ulivi, Sheila
AU - Verweij, Niek
AU - Yin, Xiaoyan
AU - Arnar, David O.
AU - Asselbergs, Folkert W.
AU - Bader, Joel S.
AU - Barnard, John
AU - Bis, Josh
AU - Blankenberg, Stefan
AU - Boerwinkle, Eric
AU - Bradford, Yuki
AU - Buckley, Brendan M.
AU - Chung, Mina K.
AU - Crawford, Dana
AU - den Hoed, Marcel
AU - Denny, Josh C.
AU - Dominiczak, Anna F.
AU - Ehret, Georg B.
AU - Eijgelsheim, Mark
AU - Ellinor, Patrick T.
AU - Felix, Stephan B.
AU - Franco, Oscar H.
AU - Franke, Lude
AU - Harris, Tamara B.
AU - Holm, Hilma
AU - Ilaria, Gandin
AU - Iorio, Annamaria
AU - Kähönen, Mika
AU - Kolcic, Ivana
AU - Kors, Jan A.
AU - Lakatta, Edward G.
AU - Launer, Lenore J.
AU - Lin, Honghuang
AU - Lin, Henry J.
AU - Loos, Ruth J.F.
AU - Lubitz, Steven A.
AU - Macfarlane, Peter W.
AU - Magnani, Jared W.
AU - Leach, Irene Mateo
AU - Meitinger, Thomas
AU - Mitchell, Braxton D.
AU - Munzel, Thomas
AU - Papanicolaou, George J.
AU - Peters, Annette
AU - Pfeufer, Arne
AU - Pramstaller, Peter P.
AU - Raitakari, Olli T.
AU - Rotter, Jerome I.
AU - Rudan, Igor
AU - Samani, Nilesh J.
AU - Schlessinger, David
AU - Silva Aldana, Claudia T.
AU - Sinner, Moritz F.
AU - Smith, Jonathan D.
AU - Snieder, Harold
AU - Soliman, Elsayed Z.
AU - Spector, Timothy D.
AU - Stott, David J.
AU - Strauch, Konstantin
AU - Tarasov, Kirill V.
AU - Thorsteinsdottir, Unnur
AU - Uitterlinden, Andre G.
AU - Van Wagoner, David R.
AU - Völker, Uwe
AU - Völzke, Henry
AU - Waldenberger, Melanie
AU - Jan Westra, Harm
AU - Wild, Philipp S.
AU - Zeller, Tanja
AU - Alonso, Alvaro
AU - Avery, Christy L.
AU - Bandinelli, Stefania
AU - Benjamin, Emelia J.
AU - Cucca, Francesco
AU - Dörr, Marcus
AU - Ferrucci, Luigi
AU - Gasparini, Paolo
AU - Gudnason, Vilmundur
AU - Hayward, Caroline
AU - Heckbert, Susan R.
AU - Hicks, Andrew A.
AU - Jukema, J. Wouter
AU - Kääb, Stefan
AU - Lehtimäki, Terho
AU - Liu, Yongmei
AU - Munroe, Patricia B.
AU - Parsa, Afshin
AU - Polasek, Ozren
AU - Psaty, Bruce M.
AU - Roden, Dan M.
AU - Schnabel, Renate B.
AU - Sinagra, Gianfranco
AU - Stefansson, Kari
AU - Stricker, Bruno H.
AU - van der Harst, Pim
AU - van Duijn, Cornelia M.
AU - Wilson, James F.
AU - Gharib, Sina A.
AU - de Bakker, Paul I.W.
AU - Isaacs, Aaron
AU - Arking, Dan E.
AU - Sotoodehnia, Nona
N1 - 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).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85050692238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050692238&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04766-9
DO - 10.1038/s41467-018-04766-9
M3 - Article
C2 - 30046033
AN - SCOPUS:85050692238
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2904
ER -