52 genetic loci influencing myocardial mass

Item Type:	Article
Title:	52 genetic loci influencing myocardial mass
Creators Name:	van der Harst, P. and van Setten, J. and Verweij, N. and Vogler, G. and Franke, L. and Maurano, M.T. and Wang, X. and Mateo Leach, I. and Eijgelsheim, M. and Sotoodehnia, N. and Hayward, C. and Sorice, R. and Meirelles, O. and Lyytikaeinen, L.P. and Polašek, O. and Tanaka, T. and Arking, D.E. and Ulivi, S. and Trompet, S. and Mueller-Nurasyid, M. and Smith, A.V. and Dörr, M. and Kerr, K.F. and Magnani, J.W. and Del Greco, M.F. and Zhang, W. and Nolte, I.M. and Silva, C.T. and Padmanabhan, S. and Tragante, V. and Esko, T. and Abecasis, G.R. and Adriaens, M.E. and Andersen, K. and Barnett, P. and Bis, J.C. and Bodmer, R. and Buckley, B.M. and Campbell, H. and Cannon, M.V. and Chakravarti, A. and Chen, L.Y. and Delitala, A. and Devereux, R.B. and Doevendans, P.A. and Dominiczak, A.F. and Ferrucci, L. and Ford, I. and Gieger, C. and Harris, T.B. and Haugen, E. and Heinig, M. and Hernandez, D.G. and Hillege, H.L. and Hirschhorn, J.N. and Hofman, A. and Hubner, N. and Hwang, S.J. and Iorio, A. and Kaehoenen, M. and Kellis, M. and Kolcic, I. and Kooner, Is.K. and Kooner, J.S. and Kors, J.A. and Lakatta, E.G. and Lage, K. and Launer, L.J. and Levy, D. and Lundby, A. and Macfarlane, P.W. and May, D. and Meitinger, T. and Metspalu, A. and Nappo, S. and Naitza, S. and Neph, S. and Nord, A.S. and Nutile, T. and Okin, P.M. and Olsen, J.V. and Oostra, B.A. and Penninger, J.M. and Pennacchio, L.A. and Pers, T.H. and Perz, S. and Peters, A. and Pinto, Y.M. and Pfeufer, A. and Pilia, M.G. and Pramstaller, P.P. and Prins, B.P. and Raitakari, O.T. and Raychaudhuri, S. and Rice, K.M. and Rossin, E.J. and Rotter, J.I. and Schaefer, S. and Schlessinger, D. and Schmidt, C.O. and Sehmi, J. and Sillje, H.H.W. and Sinagra, G. and Sinner, M.F. and Slowikowski, K. and Soliman, E.Z. and Spector, T.D. and Spiering, W. and Stamatoyannopoulos, J.A. and Stolk, R.P. and Strauch, K. and Tan, S.T. and Tarasov, K.V. and Trinh, B. and Uitterlinden, A.G. and van den Boogaard, M. and van Duijn, C.M. and van Gilst, W.H. and Viikari, J.S. and Visscher, P.M. and Vitart, V. and Völker, U. and Waldenberger, M. and Weichenberger, C.X. and Westra, H.J. and Wijmenga, C. and Wolffenbuttel, B.H. and Yang, J. and Bezzina, C.R. and Munroe, P.B. and Snieder, H. and Wright, A.F. and Rudan, I. and Boyer, L.A. and Asselbergs, F.W. and van Veldhuisen, D.J. and Stricker, B.H. and Psaty, B.M. and Ciullo, M. and Sanna, S. and Lehtimäki, T. and Wilson, J.F. and Bandinelli, S. and Alonso, A. and Gasparini, P. and Jukema, J.W. and Kääb, S. and Gudnason, V. and Felix, S.B. and Heckbert, S.R. and de Boer, R.A. and Newton-Cheh, C. and Hicks, A.A. and Chambers, J.C. and Jamshidi, Y. and Visel, A. and Christoffels, V.M. and Isaacs, A. and Samani, N.J. and de Bakker, P.I.W.
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.
Keywords:	Electrocardiogram, Genetic Association Study, Heart Failure, Left Ventricular Hypertrophy, QRS, Animals
Source:	Journal of the American College of Cardiology
ISSN:	0735-1097
Publisher:	Elsevier
Volume:	68
Number:	13
Page Range:	1435-1448
Date:	27 September 2016
Official Publication:	https://doi.org/10.1016/j.jacc.2016.07.729
PubMed:	View item in PubMed

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