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52 Genetic Loci Influencing Myocardial Mass.

journal contribution
posted on 11.11.2016, 09:45 by P. van der Harst, J. van Setten, N. Verweij, G. Vogler, L. Franke, M. T. Maurano, X. Wang, I. Mateo Leach, M. Eijgelsheim, N. Sotoodehnia, C. Hayward, R. Sorice, O. Meirelles, L. P. Lyytikäinen, O. Polašek, T. Tanaka, D. E. Arking, S. Ulivi, S. Trompet, M. Müller-Nurasyid, A. V. Smith, M. Dörr, K. F. Kerr, J. W. Magnani, F. Del Greco M, W. Zhang, I. M. Nolte, C. T. Silva, S. Padmanabhan, V. Tragante, T. Esko, G. R. Abecasis, M. E. Adriaens, K. Andersen, P. Barnett, J. C. Bis, R. Bodmer, B. M. Buckley, H. Campbell, M. V. Cannon, A. Chakravarti, L. Y. Chen, A. Delitala, R. B. Devereux, P. A. Doevendans, A. F. Dominiczak, L. Ferrucci, I. Ford, C. Gieger, T. B. Harris, E. Haugen, M. Heinig, D. G. Hernandez, H. L. Hillege, J. N. Hirschhorn, A. Hofman, N. Hubner, S. J. Hwang, A. Iorio, M. Kähönen, M. Kellis, I. Kolcic, I. K. Kooner, J. S. Kooner, J. A. Kors, E. G. Lakatta, K. Lage, L. J. Launer, D. Levy, A. Lundby, P. W. Macfarlane, D. May, T. Meitinger, A. Metspalu, S. Nappo, S. Naitza, S. Neph, A. S. Nord, T. Nutile, P. M. Okin, J. V. Olsen, B. A. Oostra, J. M. Penninger, L. A. Pennacchio, T. H. Pers, S. Perz, A. Peters, Y. M. Pinto, A. Pfeufer, M. G. Pilia, P. P. Pramstaller, B. P. Prins, O. T. Raitakari, S. Raychaudhuri, K. M. Rice, E. J. Rossin, J. I. Rotter, S. Schafer, D. Schlessinger, C. O. Schmidt, J. Sehmi, H. H. Silljé, G. Sinagra, M. F. Sinner, K. Slowikowski, E. Z. Soliman, Timothy D. Spector, Wilko Spiering, J. A. Stamatoyannopoulos, R. P. Stolk, K. Strauch, S. T. Tan, K. V. Tarasov, B. Trinh, A. G. Uitterlinden, M. van den Boogaard, C. M. van Duijn, W. H. van Gilst, J. S. Viikari, P. M. Visscher, V. Vitart, U. Völker, M. Waldenberger, C. X. Weichenberger, H. J. Westra, C. Wijmenga, B. H. Wolffenbuttel, J. Yang, C. R. Bezzina, P. B. Munroe, H. Snieder, A. F. Wright, I. Rudan, L. A. Boyer, F. W. Asselbergs, D. J. van Veldhuisen, B. H. Stricker, B. M. Psaty, M. Ciullo, S. Sanna, T. Lehtimäki, J. F. Wilson, S. Bandinelli, A. Alonso, P. Gasparini, J. W. Jukema, S. Kääb, V. Gudnason, S. B. Felix, S. R. Heckbert, R. A. de Boer, C. Newton-Cheh, A. A. Hicks, J. C. Chambers, Y. Jamshidi, A. Visel, V. M. Christoffels, A. Isaacs, Nilesh J. Samani, P. I. de Bakker
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.

History

Citation

Journal of the American College of Cardiology, 2016, 68 (13), pp. 1435-1448

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Journal of the American College of Cardiology

Publisher

Elsevie for American College of Cardiology

issn

0735-1097

eissn

1558-3597

Acceptance date

14/07/2016

Publisher version

http://www.sciencedirect.com/science/article/pii/S0735109716346642

Notes

Awaiting copyright permissions.

Language

en