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

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 Lyytikainen; Christian Muller; Martina Muller-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 Kahonen; 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 Volker; Henry Volzke; Melanie Waldenberger; Harm Jan Westra; Philipp S. Wild; Tanja Zeller; Alvaro Alonso; Christy L. Avery; Stefania Bandinelli; Emelia J. Benjamin; Francesco Cucca; Marcus Dorr; Luigi Ferrucci; Paolo Gasparini; Vilmundur Gudnason; Caroline Hayward; Susan R. Heckbert; Andrew A. Hicks; J. Wouter Jukema; Stefan Kaab; Terho Lehtimaki; 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; Nona Sotoodehnia

doi:10.1038/s41467-018-04766-9

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

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 Lyytikainen, Christian Muller, Martina Muller-Nurasyid, Ilja M. Nolte, Sandosh Padmanabhan, Marylyn D. Ritchie, Antonietta Robino, Albert V. SmithMaristella 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 Kahonen, 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 Volker, Henry Volzke, Melanie Waldenberger, Harm Jan Westra, Philipp S. Wild, Tanja Zeller, Alvaro Alonso, Christy L. Avery, Stefania Bandinelli, Emelia J. Benjamin, Francesco Cucca, Marcus Dorr, Luigi Ferrucci, Paolo Gasparini, Vilmundur Gudnason, Caroline Hayward, Susan R. Heckbert, Andrew A. Hicks, J. Wouter Jukema, Stefan Kaab, Terho Lehtimaki, 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, Nona Sotoodehnia

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

44 Citations (Web of Science)

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 genomewide 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 overrepresented 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 similar to 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, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Original language	English
Article number	2904
Number of pages	11
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-04766-9
Publication status	Published - 25 Jul 2018

Keywords

COMMON VARIANTS
HEART-RATE
QRS DURATION
CARDIAC CONDUCTION
FIBRILLATION
EPIDEMIOLOGY
COHORTS
RISK
RARE
SNPS

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10.1038/s41467-018-04766-9

https://www.nature.com/articles/s41467-018-04766-9.pdf

Cite this

van Setten, J., Brody, J. A., Jamshidi, Y., Swenson, B. R., Butler, A. M., Campbell, H., Del Greco, F. M., Evans, D. S., Gibson, Q., Gudbjartsson, D. F., Kerr, K. F., Krijthe, B. P., Lyytikainen, L-P., Muller, C., Muller-Nurasyid, M., Nolte, I. M., Padmanabhan, S., Ritchie, M. D., Robino, A., ... Sotoodehnia, N. (2018). PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. Nature Communications, 9, [2904]. https://doi.org/10.1038/s41467-018-04766-9

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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 genomewide 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 overrepresented 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 similar to 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, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.",

keywords = "COMMON VARIANTS, HEART-RATE, QRS DURATION, CARDIAC CONDUCTION, FIBRILLATION, EPIDEMIOLOGY, COHORTS, RISK, RARE, SNPS",

author = "{van Setten}, Jessica and Brody, {Jennifer A.} and Yalda Jamshidi and Swenson, {Brenton R.} and Butler, {Anne M.} and Harry Campbell and {Del Greco}, {Fabiola M.} and Evans, {Daniel S.} and Quince Gibson and Gudbjartsson, {Daniel F.} and Kerr, {Kathleen F.} and Krijthe, {Bouwe P.} and Leo-Pekka Lyytikainen and Christian Muller and Martina Muller-Nurasyid and Nolte, {Ilja M.} and Sandosh Padmanabhan and Ritchie, {Marylyn D.} and Antonietta Robino and Smith, {Albert V.} and Maristella Steri and Toshiko Tanaka and Alexander Teumer and Stella Trompet and Sheila Ulivi and Niek Verweij and Xiaoyan Yin and Arnar, {David O.} and Asselbergs, {Folkert W.} and Bader, {Joel S.} and John Barnard and Josh Bis and Stefan Blankenberg and Eric Boerwinkle and Yuki Bradford and Buckley, {Brendan M.} and Chung, {Mina K.} and Dana Crawford and {den Hoed}, Marcel and Denny, {Josh C.} and Dominiczak, {Anna F.} and Ehret, {Georg B.} and Mark Eijgelsheim and Ellinor, {Patrick T.} and Felix, {Stephan B.} and Franco, {Oscar H.} and Lude Franke and Harris, {Tamara B.} and Hilma Holm and Gandin Ilaria and Annamaria Iorio and Mika Kahonen and Ivana Kolcic and Kors, {Jan A.} and Lakatta, {Edward G.} and Launer, {Lenore J.} and Honghuang Lin and Lin, {Henry J.} and Loos, {Ruth J. F.} and Lubitz, {Steven A.} and Macfarlane, {Peter W.} and Magnani, {Jared W.} and Leach, {Irene Mateo} and Thomas Meitinger and Mitchell, {Braxton D.} and Thomas Munzel and Papanicolaou, {George J.} and Annette Peters and Arne Pfeufer and Pramstaller, {Peter P.} and Raitakari, {Olli T.} and Rotter, {Jerome I.} and Igor Rudan and Samani, {Nilesh J.} and David Schlessinger and Aldana, {Claudia T. Silva} and Sinner, {Moritz F.} and Smith, {Jonathan D.} and Harold Snieder and Soliman, {Elsayed Z.} and Spector, {Timothy D.} and Stott, {David J.} and Konstantin Strauch and Tarasov, {Kirill V.} and Unnur Thorsteinsdottir and Uitterlinden, {Andre G.} and {Van Wagoner}, {David R.} and Uwe Volker and Henry Volzke and Melanie Waldenberger and Westra, {Harm Jan} and Wild, {Philipp S.} and Tanja Zeller and Alvaro Alonso and Avery, {Christy L.} and Stefania Bandinelli and Benjamin, {Emelia J.} and Francesco Cucca and Marcus Dorr and Luigi Ferrucci and Paolo Gasparini and Vilmundur Gudnason and Caroline Hayward and Heckbert, {Susan R.} and Hicks, {Andrew A.} and Jukema, {J. Wouter} and Stefan Kaab and Terho Lehtimaki and Yongmei Liu and Munroe, {Patricia B.} and Afshin Parsa and Ozren Polasek and Psaty, {Bruce M.} and Roden, {Dan M.} and Schnabel, {Renate B.} and Gianfranco Sinagra and Kari Stefansson and Stricker, {Bruno H.} and {van der Harst}, Pim and {van Duijn}, {Cornelia M.} and Wilson, {James F.} and Gharib, {Sina A.} and {de Bakker}, {Paul I. W.} and Aaron Isaacs and Arking, {Dan E.} and Nona Sotoodehnia",

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doi = "10.1038/s41467-018-04766-9",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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van Setten, J, Brody, JA, Jamshidi, Y, Swenson, BR, Butler, AM, Campbell, H, Del Greco, FM, Evans, DS, Gibson, Q, Gudbjartsson, DF, Kerr, KF, Krijthe, BP, Lyytikainen, L-P, Muller, C, Muller-Nurasyid, M, Nolte, IM, Padmanabhan, S, Ritchie, MD, Robino, A, Smith, AV, Steri, M, Tanaka, T, Teumer, A, Trompet, S, Ulivi, S, Verweij, N, Yin, X, Arnar, DO, Asselbergs, FW, Bader, JS, Barnard, J, Bis, J, Blankenberg, S, Boerwinkle, E, Bradford, Y, Buckley, BM, Chung, MK, Crawford, D, den Hoed, M, Denny, JC, Dominiczak, AF, Ehret, GB, Eijgelsheim, M, Ellinor, PT, Felix, SB, Franco, OH, Franke, L, Harris, TB, Holm, H, Ilaria, G, Iorio, A, Kahonen, M, Kolcic, I, Kors, JA, Lakatta, EG, Launer, LJ, Lin, H, Lin, HJ, Loos, RJF, Lubitz, SA, Macfarlane, PW, Magnani, JW, Leach, IM, Meitinger, T, Mitchell, BD, Munzel, T, Papanicolaou, GJ, Peters, A, Pfeufer, A, Pramstaller, PP, Raitakari, OT, Rotter, JI, Rudan, I, Samani, NJ, Schlessinger, D, Aldana, CTS, Sinner, MF, Smith, JD, Snieder, H, Soliman, EZ, Spector, TD, Stott, DJ, Strauch, K, Tarasov, KV, Thorsteinsdottir, U, Uitterlinden, AG, Van Wagoner, DR, Volker, U, Volzke, H, Waldenberger, M, Westra, HJ, Wild, PS, Zeller, T, Alonso, A, Avery, CL, Bandinelli, S, Benjamin, EJ, Cucca, F, Dorr, M, Ferrucci, L, Gasparini, P, Gudnason, V, Hayward, C, Heckbert, SR, Hicks, AA, Jukema, JW, Kaab, S, Lehtimaki, T, Liu, Y, Munroe, PB, Parsa, A, Polasek, O, Psaty, BM, Roden, DM, Schnabel, RB, Sinagra, G, Stefansson, K, Stricker, BH, van der Harst, P, van Duijn, CM, Wilson, JF, Gharib, SA, de Bakker, PIW, Isaacs, A, Arking, DE & Sotoodehnia, N 2018, 'PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity', Nature Communications, vol. 9, 2904. https://doi.org/10.1038/s41467-018-04766-9

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 - Lyytikainen, Leo-Pekka

AU - Muller, Christian

AU - Muller-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 - Kahonen, 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 - Aldana, Claudia T. Silva

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 - Volker, Uwe

AU - Volzke, Henry

AU - Waldenberger, Melanie

AU - Westra, Harm Jan

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 - Dorr, 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 - Kaab, Stefan

AU - Lehtimaki, 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

PY - 2018/7/25

Y1 - 2018/7/25

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 genomewide 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 overrepresented 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 similar to 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, ionchannel 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 genomewide 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 overrepresented 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 similar to 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, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

KW - COMMON VARIANTS

KW - HEART-RATE

KW - QRS DURATION

KW - CARDIAC CONDUCTION

KW - FIBRILLATION

KW - EPIDEMIOLOGY

KW - COHORTS

KW - RISK

KW - RARE

KW - SNPS

U2 - 10.1038/s41467-018-04766-9

DO - 10.1038/s41467-018-04766-9

M3 - Article

C2 - 30046033

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 2904

ER -