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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.pdf (2.26 MB)

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

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posted on 2019-08-09, 13:25 authored by J van Setten, JA Brody, Y Jamshidi, BR Swenson, AM Butler, H Campbell, FM Del Greco, DS Evans, Q Gibson, DF Gudbjartsson, KF Kerr, BP Krijthe, L-P Lyytikäinen, C Müller, M Müller-Nurasyid, IM Nolte, S Padmanabhan, MD Ritchie, A Robino, AV Smith, M Steri, T Tanaka, A Teumer, S Trompet, S Ulivi, N Verweij, X Yin, DO Arnar, FW Asselbergs, JS Bader, J Barnard, J Bis, S Blankenberg, E Boerwinkle, Y Bradford, BM Buckley, MK Chung, D Crawford, M den Hoed, JC Denny, AF Dominiczak, GB Ehret, M Eijgelsheim, PT Ellinor, SB Felix, OH Franco, L Franke, TB Harris, H Holm, G Ilaria, A Iorio, M Kähönen, I Kolcic, JA Kors, EG Lakatta, LJ Launer, H Lin, HJ Lin, RJF Loos, SA Lubitz, PW Macfarlane, JW Magnani, IM Leach, T Meitinger, BD Mitchell, T Munzel, GJ Papanicolaou, A Peters, A Pfeufer, PP Pramstaller, OT Raitakari, JI Rotter, I Rudan, NJ Samani, D Schlessinger, CT Silva Aldana, MF Sinner, JD Smith, H Snieder, EZ Soliman, TD Spector, DJ Stott, K Strauch, KV Tarasov, U Thorsteinsdottir, AG Uitterlinden, DR Van Wagoner, U Völker, H Völzke, M Waldenberger, H Jan Westra, PS Wild, T Zeller, A Alonso, CL Avery, S Bandinelli, EJ Benjamin, F Cucca, M Dörr, L Ferrucci, P Gasparini, V Gudnason, C Hayward, SR Heckbert, AA Hicks, JW Jukema, S Kääb, T Lehtimäki, Y Liu, PB Munroe, A Parsa, O Polasek, BM Psaty, DM Roden, RB Schnabel, G Sinagra, K Stefansson, BH Stricker, P van der Harst, CM van Duijn, JF Wilson, SA Gharib, PIW de Bakker, A Isaacs, DE Arking, N Sotoodehnia
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.

Funding

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.

History

Citation

Nature Communications, 2018, volume 9, Article number: 2904

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Research (part of Springer Nature)

eissn

2041-1723

Acceptance date

2018-05-21

Copyright date

2018

Available date

2019-08-09

Publisher DOI

Publisher version

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

Notes

The full meta-analysis results are available for download through the CHARGE repository in dbGaP: http://www.chargeconsortium.com/main/results Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-04766-9.

Language

en

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    University of Leicester Publications

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    Keywords

    Atrial fibrillationCardiovascular geneticsGenetic association study

    Licence

    CC BY 4.0

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