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Genetic loci associated with heart rate variability and their effects on cardiac disease risk

  • Ilja M Nolte
  • , M Loretto Munoz
  • , Vinicius Tragante
  • , Azmeraw T Amare
  • , Rick Jansen
  • , Ahmad Vaez
  • , Benedikt von der Heyde
  • , Christy L Avery
  • , Joshua C Bis
  • , Bram Dierckx
  • , Jenny van Dongen
  • , Stephanie M Gogarten
  • , Philippe Goyette
  • , Jussi Hernesniemi
  • , Ville Huikari
  • , Shih-Jen Hwang
  • , Deepali Jaju
  • , Kathleen F Kerr
  • , Alexander Kluttig
  • , Bouwe P Krijthe
    • Jitender Kumar, Sander W van der Laan, Leo-Pekka Lyytikäinen, Adam X Maihofer, Arpi Minassian, Peter J van der Most, Martina Müller-Nurasyid, Michel Nivard, Erika Salvi, James D Stewart, Julian F Thayer, Niek Verweij, Andrew Wong, Delilah Zabaneh, Mohammad H Zafarmand, Abdel Abdellaoui, Sulayma Albarwani, Christine Albert, Alvaro Alonso, Foram Ashar, Juha Auvinen, Tomas Axelsson, Dewleen G Baker, Paul I W de Bakker, Matteo Barcella, Riad Bayoumi, Rob J Bieringa, Dorret Boomsma, Gabrielle Boucher, Annie R Britton, Ingrid Christophersen, Andrea Dietrich, George B Ehret, Patrick T Ellinor, Markku Eskola, Janine F Felix, John S Floras, Oscar H Franco, Peter Friberg, Maaike G J Gademan, Mark A Geyer, Vilmantas Giedraitis, Catharina A Hartman, Daiane Hemerich, Albert Hofman, Jouke-Jan Hottenga, Heikki Huikuri, Nina Hutri-Kähönen, Xavier Jouven, Juhani Junttila, Markus Juonala, Antti M Kiviniemi, Jan A. Kors, Meena Kumari, Tatiana Kuznetsova, Cathy C Laurie, Joop D. Lefrandt, Yong Li, Yun Li, Duanping Liao, Marian C Limacher, Henry J Lin, Cecilia M Lindgren, Steven A Lubitz, Anubha Mahajan, Barbara McKnight, Henriette Meyer Zu Schwabedissen, Yuri Milaneschi, Nina Mononen, Andrew P Morris, Mike A Nalls, Gerjan Navis, Melanie Neijts, Kjell Nikus, Kari E North, Daniel T O'Connor, Johan Ormel, Siegfried Perz, Annette Peters, Bruce M Psaty, Olli T Raitakari, Victoria B Risbrough, Moritz F Sinner, David Siscovick, Johannes H Smit, Nicholas L Smith, Elsayed Z Soliman, Nona Sotoodehnia, Jan A Staessen, Phyllis K Stein, Adrienne M Stilp, Katarzyna Stolarz-Skrzypek, Konstantin Strauch, Johan Sundström, Cees A. Swenne, Ann-Christine Syvänen, Jean-Claude Tardif, Kent D Taylor, Alexander Teumer, Timothy A Thornton, Lesley E Tinker, André G Uitterlinden, Jessica van Setten, Andreas Voss, Melanie Waldenberger, Kirk C Wilhelmsen, Gonneke Willemsen, Quenna Wong, Zhu-Ming Zhang, Alan B Zonderman, Daniele Cusi, Michele K Evans, Halina K Greiser, Pim van der Harst, Mohammad Hassan, Erik Ingelsson, Marjo-Riitta Järvelin, Stefan Kääb, Mika Kähönen, Mika Kivimaki, Charles Kooperberg, Diana Kuh, Terho Lehtimäki, Lars Lind, Caroline M Nievergelt, Chris J O'Donnell, Albertine J Oldehinkel, Brenda Penninx, Alexander P Reiner, Harriëtte Riese, Arie M. Van Roon, John D Rioux, Jerome I Rotter, Tamar Sofer, Bruno H Stricker, Henning Tiemeier, Tanja G M Vrijkotte, Folkert W Asselbergs, Bianca J J M Brundel, Susan R Heckbert, Eric A Whitsel, Marcel den Hoed, Harold Snieder, Eco J C de Geus

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

Abstract

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<rg<-0.55) and blood pressure (-0.35<rg<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Original languageEnglish
Article number15805
Pages (from-to)1-17
Number of pages17
JournalNature Communications
Volume8
Early online date14 Jun 2017
DOIs
Publication statusPublished - 2017

Funding

FundersFunder number
Eunice Kennedy Shriver National Institute of Child Health and Human Development
European Commission
U.S. Department of Veterans AffairsI01BX002558
National Center for Advancing Translational SciencesUL1TR000124
National Heart, Lung, and Blood InstituteR01HL105756, K23HL114724, R01HL120393, R01HL116747, U01HL130114
Seventh Framework Programme201550
Medical Research CouncilMR/K013351/1, MC_UU_12019/1
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK063491
National Institute of Child Health and Human DevelopmentP2CHD050924
NIH Office of the DirectorS10OD020069
Horizon 2020 Framework Programme633595
National Institute of General Medical SciencesP01GM099568

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    1. SDG 3 - Good Health and Well-being
      SDG 3 Good Health and Well-being

    Keywords

    • Journal Article

    Cohort Studies

    • Netherlands Twin Register (NTR)

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    • 107 Citations
    • 1 Erratum / Corrigendum

    • Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

      Nolte, I. M., Munoz, M. L., Tragante, V., Amare, A. T., Jansen, R., Vaez, A., von der Heyde, B., Avery, C. L., Bis, J. C., Dierckx, B., van Dongen, J., Gogarten, S. M., Goyette, P., Hernesniemi, J., Huikari, V., Hwang, S.-J., Jaju, D., Kerr, K. F., Kluttig, A. & Krijthe, B. P. & 144 others, Kumar, J., van der Laan, S. W., Lyytikainen, L.-P., Maihofer, A. X., Minassian, A., van der Most, P. J., Mueller-Nurasyid, M., Nivard, M., Salvi, E., Stewart, J. D., Thayer, J. F., Verweij, N., Wong, A., Zabaneh, D., Zafarmand, M. H., Abdellaoui, A., Albarwani, S., Albert, C., Alonso, A., Ashar, F., Auvinen, J., Axelsson, T., Baker, D. G., de Bakker, P. I. W., Barcella, M., Bayoumi, R., Bieringa, R. J., Boomsma, D., Boucher, G., Britton, A. R., Christophersen, I., Dietrich, A., Ehret, G. B., Ellinor, P. T., Eskola, M., Felix, J. F., Floras, J. S., Franco, O. H., Friberg, P., Gademan, M. G. J., Geyer, M. A., Giedraitis, V., Hartman, C. A., Hemerich, D., Hofman, A., Hottenga, J.-J., Huikuri, H., Hutri-Kahonen, N., Jouven, X., Junttila, J., Juonala, M., Kiviniemi, A. M., Kors, J. A., Kumari, M., Kuznetsova, T., Laurie, C. C., Lefrandt, J. D., Li, Y., Li, Y., Liao, D., Limacher, M. C., Lin, H. J., Lindgren, C. M., Lubitz, S. A., Mahajan, A., McKnight, B., zu Schwabedissen, H. M., Milaneschi, Y., Mononen, N., Morris, A. P., Nalls, M. A., Navis, G., Neijts, M., Nikus, K., North, K. E., O'Connor, D. T., Ormel, J., Perz, S., Peters, A., Psaty, B. M., Raitakari, O. T., Risbrough, V. B., Sinner, M. F., Siscovick, D., Smit, J. H., Smith, N. L., Soliman, E. Z., Sotoodehnia, N., Staessen, J. A., Stein, P. K., Stilp, A. M., Stolarz-Skrzypek, K., Strauch, K., Sundstrom, J., Swenne, C. A., Syvanen, A.-C., Tardif, J.-C., Taylor, K. D., Teumer, A., Thornton, T. A., Tinker, L. E., Uitterlinden, A. G., van Setten, J., Voss, A., Waldenberger, M., Wilhelmsen, K. C., Willemsen, G., Wong, Q., Zhang, Z.-M., Zonderman, A. B., Cusi, D., Evans, M. K., Greiser, H. K., van der Harst, P., Hassan, M., Ingelsson, E., Jarvelin, M.-R., Kaab, S., Kahonen, M., Kivimaki, M., Kooperberg, C., Kuh, D., Lehtimaki, T., Lind, L., Nievergelt, C. M., O'Donnell, C. J., Oldehinkel, A. J., Penninx, B., Reiner, A. P., Riese, H., van Roon, A. M., Rioux, J. D., Rotter, J. I., Sofer, T., Stricker, B. H., Tiemeier, H., Vrijkotte, T. G. M., Asselbergs, F. W., Brundel, B. J. J. M., Heckbert, S. R., Whitsel, E. A., den Hoed, M., Snieder, H. & de Geus, E. J. C., 2017, In: Nature Communications. 8, 2 p.

      Research output: Contribution to Journal › Erratum / Corrigendum › Academic

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