Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Arking, D. E. et al. (2014) Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature Genetics, 46(8), pp. 826-836. (doi: 10.1038/ng.3014) (PMID:24952745) (PMCID:PMC4124521)

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ~8–10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval–associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Macfarlane, Professor Peter and Watt, Professor Graham and Lee, Dr Wai Kwong and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
• Authors: Arking, D. E., Pulit, S. L., Crotti, L., van der Harst, P., Munroe, P. B., Koopmann, T. T., Sotoodehnia, N., Rossin, E. J., Morley, M., Wang, X., Johnson, A. D., Lundby, A., Gudbjartsson, D. F., Noseworthy, P. A., Eijgelsheim, M., Bradford, Y., Tarasov, K. V., Dörr, M., Müller-Nurasyid, M., Lahtinen, A. M., Nolte, I. M., Smith, A. V., Bis, J. C., Isaacs, A., Newhouse, S. J., Evans, D. S., Post, W. S., Waggott, D., Lyytikäinen, L.-P., Hicks, A. A., Eisele, L., Ellinghaus, D., Hayward, C., Navarro, P., Ulivi, S., Tanaka, T., Tester, D. J., Chatel, S., Gustafsson, S., Kumari, M., Morris, R. W., Naluai, Å. T., Padmanabhan, S., Kluttig, A., Strohmer, B., Panayiotou, A. G., Torres, M., Knoflach, M., Hubacek, J. A., Slowikowski, K., Raychaudhuri, S., Kumar, R. D., Harris, T. B., Launer, L. J., Shuldiner, A. R., Alonso, A., Bader, J. S., Ehret, G., Huang, H., Kao, W. H. L., Strait, J. B., Macfarlane, P. W., Brown, M., Caulfield, M. J., Samani, N. J., Kronenberg, F., Willeit, J., Smith, J. G., Greiser, K. H., Meyer zu Schwabedissen, H., Werdan, K., Carella, M., Zelante, L., Heckbert, S. R., Psaty, B. M., Rotter, J. I., Kolcic, I., Polašek, O., Wright, A. F., Griffin, M., Daly, M. J., Arnar, D. O., Hólm, H., Thorsteinsdottir, U., Denny, J. C., Roden, D. M., Zuvich, R. L., Emilsson, V., Plump, A. S., Larson, M. G., O'Donnell, C. J., Yin, X., Bobbo, M., D'Adamo, A. P., Iorio, A., Sinagra, G., Carracedo, A., Cummings, S. R., Nalls, M. A., Jula, A., Kontula, K. K., Marjamaa, A., Oikarinen, L., Perola, M., Porthan, K., Erbel, R., Hoffmann, P., Jöckel, K.-H., Kälsch, H., Nöthen, M. M., den Hoed, M., Loos, R. J. F., Thelle, D. S., Gieger, C., Meitinger, T., Perz, S., Peters, A., Prucha, H., Sinner, M. F., Waldenberger, M., de Boer, R. A., Franke, L., van der Vleuten, P. A., Beckmann, B. M., Martens, E., Bardai, A., Hofman, N., Wilde, A. A. M., Behr, E. R., Dalageorgou, C., Giudicessi, J. R., Medeiros-Domingo, A., Barc, J., Kyndt, F., Probst, V., Ghidoni, A., Insolia, R., Hamilton, R. M., Scherer, S. W., Brandimarto, J., Margulies, K., Moravec, C. E., Greco M, F. d., Fuchsberger, C., O'Connell, J. R., Lee, W. K., Watt, G. C. M., Campbell, H., Wild, S. H., El Mokhtari, N. E., Frey, N., Asselbergs, F. W., Leach, I. M., Navis, G., van den Berg, M. P., van Veldhuisen, D. J., Kellis, M., Krijthe, B. P., Franco, O. H., Hofman, A., Kors, J. A., Uitterlinden, A. G., Witteman, J. C. M., Kedenko, L., Lamina, C., Oostra, B. A., Abecasis, G. R., Lakatta, E. G., Mulas, A., Orrú, M., Schlessinger, D., Uda, M., Markus, M. R. P., Völker, U., Snieder, H., Spector, T. D., Ärnlöv, J., Lind, L., Sundström, J., Syvänen, A.-C., Kivimaki, M., Kähönen, M., Mononen, N., Raitakari, O. T., Viikari, J. S., Adamkova, V., Kiechl, S., Brion, M., Nicolaides, A. N., Paulweber, B., Haerting, J., Dominiczak, A. F., Nyberg, F., Whincup, P. H., Hingorani, A. D., Schott, J.-J., Bezzina, C. R., Ingelsson, E., Ferrucci, L., Gasparini, P., Wilson, J. F., Rudan, I., Franke, A., Mühleisen, T. W., Pramstaller, P. P., Lehtimäki, T. J., Paterson, A. D., Parsa, A., Liu, Y., van Duijn, C. M., Siscovick, D. S., Gudnason, V., Jamshidi, Y., Salomaa, V., Felix, S. B., Sanna, S., Ritchie, M. D., Stricker, B. H., Stefansson, K., Boyer, L. A., Cappola, T. P., Olsen, J. V., Lage, K., Schwartz, P. J., Kääb, S., Chakravarti, A., Ackerman, M. J., Pfeufer, A., de Bakker, P. I. W., and Newton-Cheh, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Genetics
• Publisher: Nature Publishing Group
• ISSN: 1061-4036
• ISSN (Online): 1546-1718