52 genetic loci influencing myocardial mass

van der Harst, P. et al. (2016) 52 genetic loci influencing myocardial mass. Journal of the American College of Cardiology, 68(13), pp. 1435-1448. (doi:10.1016/j.jacc.2016.07.729) (PMID:27659466)

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Abstract

Background: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Macfarlane, Professor Peter and Ford, Professor Ian and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: van der Harst, P., van Setten, J., Verweij, N., Vogler, G., Franke, L., Maurano, M. T., Wang, X., Leach, I. M., Eijgelsheim, M., Sotoodehnia, N., Hayward, C., Sorice, R., Meirelles, O., Lytikäinen, L.-P., Polašek, O., Tanaka, T., Arking, D. E., Ulivi, S., Trompet, S., Müller-Nurasyid, M., Smith, A. V., Dörr, M., Kerr, K. F., Magnani, J. W., Del Greco M., F., Zhang, W., Nolte, I. A., Silva, C. T., Padmanabhan, S., Tragante, V., Esko, T., Abecasis, G. R., Adriaens, M. E., Andersen, K., Barnett, P., Bis, J. C., Bodmer, R., Buckley, B. M., Campbell, H., Cannon, M. V., Chakravarti, A., Chen, L. Y., Delitala, A., Devereux, R. B., Doevendands, P. A., Dominiczak, A. F., Ferrucci, L., Ford, I., Gieger, C., Harris, T. B., Haugen, E., Heinig, M., Hernandez, D. G., Hillege, H. L., Hirschhorn, J. N., Hofman, A., Hubner, N., Hwang, S.-J., Iorio, A., Kähönen, M., Kellis, M., Kolcic, I., Kooner, I. K., Kooner, J. S., Kors, J. A., Lakatta, E. G., Lage, K., Launder, L. J., Levy, D., Lundby, A., Macfarlane, P. W., May, D., Meitinger, T., Metspalu, A., Nappo, S., Naitza, S., Neph, S., Nord, A. S., Nutile, T., Okin, P. M., Olsen, J. V., Oostra, B. A., Penninger, J. M., Pennacchio, L. A., Pers, T. H., Perz, S., Peters, A., Pinto, Y. M., Pfeufer, A., Pilia, M. G., Pramstaller, P. P., Prins, B. P., Raitakari, O. T., Raychaudhuri, S., Rice, K. M., Rossin, E. J., Rotter, J. I., Schafer, S., Schlessinger, D., Schmidt, C. O., Sehmi, J., Silljé, H. H.W., Singara, G., Sinner, M. F., Slowikowski, K., Soliman, E. Z., Spector, T. D., Spiering, W., Stamatoyannopoulos, J. A., Stolk, R. P., Strauch, K., Tan, S.-T., Tarasov, K. V., Trinh, B., Uitterlinden, A. G., van den Boogaard, M., van Duijn, C. M., van Gilst, W. H., Siikari, J. S., Visscher, P. M., Vitart, V., Völker, U., Waldenberger, M., Weichenberger, C. X., Westra, H.-J., Wijmenga, C., Wolffenbutel, B. H., Yang, J., Bezzina, C. R., Munroe, P. B., Snieder, H., Wright, A. F., Rudan, I., Boyer, L. A., Asselbergs, F. W., van Veldhuisen, D. J., Stricker, B. H., Psaty, B. M., Ciullo, M., Sanna, S., Lehtimäki, T., Wilson, J. F., Bandinelli, S., Alonso, A., Gasparini, P., Wouter Jukema, J., Kääb, S., Gudnason, V., Felix, S. B., Heckbert, S. R., de Boer, R. A., Newton-Cheh, C., Hicks, A. A., Chambers, J. C., Jamshidi, Y., Visel, A., Christoffels, V. M., Isaacs, A., Samani, N. J., and de Bakker, P. I.W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier
ISSN:0735-1097
ISSN (Online):1558-3597|
Published Online:19 September 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of the American College of Cardiology 38(13):1435-1448
Publisher Policy:Reproduced under a Creative Commons License

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