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Nat Genet DOI:10.1038/ng.3014

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

Publication TypeJournal Article
Year of Publication2014
AuthorsArking, DE, Pulit, SL, Crotti, L, van der Harst, P, Munroe, PB, Koopmann, TT, Sotoodehnia, N, Rossin, EJ, Morley, M, Wang, X, Johnson, AD, Lundby, A, Gudbjartsson, DF, Noseworthy, PA, Eijgelsheim, M, Bradford, Y, Tarasov, KV, Dorr, M, Müller-Nurasyid, M, Lahtinen, AM, Nolte, IM, Smith, AVernon, Bis, JC, Isaacs, A, Newhouse, SJ, Evans, DS, Post, WS, Waggott, D, Lyytikäinen, L-P, Hicks, AA, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, DJ, Chatel, S, Gustafsson, S, Kumari, M, Morris, RW, Naluai, ÅT, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, AG, Torres, M, Knoflach, M, Hubacek, JA, Slowikowski, K, Raychaudhuri, S, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Alonso, A, Bader, JS, Ehret, G, Huang, H, Kao, WHLinda, Strait, JB, Macfarlane, PW, Brown, M, Caulfield, MJ, Samani, NJ, Kronenberg, F, Willeit, J, J Smith, G, Greiser, KH, Schwabedissen, HMeyer Zu, Werdan, K, Carella, M, Zelante, L, Heckbert, SR, Psaty, BM, Rotter, JI, Kolcic, I, Polasek, O, Wright, AF, Griffin, M, Daly, MJ, Arnar, DO, Holm, H, Thorsteinsdottir, U, Denny, JC, Roden, DM, Zuvich, RL, Emilsson, V, Plump, AS, Larson, MG, O'Donnell, CJ, Yin, X, Bobbo, M, D'Adamo, AP, Iorio, A, Sinagra, G, Carracedo, Á, Cummings, SR, Nalls, MA, Jula, A, Kontula, KK, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K-H, Kälsch, H, Nöthen, MM, Hoed, Mden, Loos, RJF, Thelle, DS, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, MF, Waldenberger, M, de Boer, RA, Franke, L, van der Vleuten, PA, Beckmann, BMaria, Martens, E, Bardai, A, Hofman, N, Wilde, AAM, Behr, ER, Dalageorgou, C, Giudicessi, JR, Medeiros-Domingo, A, Barc, J, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, RM, Scherer, SW, Brandimarto, J, Margulies, K, Moravec, CE, M, FDel Greco, Fuchsberger, C, O'Connell, JR, Lee, WK, Watt, GCM, Campbell, H, Wild, SH, Mokhtari, NEEl, Frey, N, Asselbergs, FW, Leach, IMateo, Navis, G, van den Berg, MP, van Veldhuisen, DJ, Kellis, M, Krijthe, BP, Franco, OH, Hofman, A, Kors, JA, Uitterlinden, AG, Witteman, JCM, Kedenko, L, Lamina, C, Oostra, BA, Abecasis, GR, Lakatta, EG, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, MRP, Volker, U, Snieder, H, Spector, TD, Ärnlöv, J, Lind, L, Sundstrom, J, Syvänen, A-C, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, OT, Viikari, JS, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, AN, Paulweber, B, Haerting, J, Dominiczak, AF, Nyberg, F, Whincup, PH, Hingorani, AD, Schott, J-J, Bezzina, CR, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, JF, Rudan, I, Franke, A, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, Parsa, A, Liu, Y, van Duijn, CM, Siscovick, DS, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, SB, Sanna, S, Ritchie, MD, Stricker, BH, Stefansson, K, Boyer, LA, Cappola, TP, Olsen, JV, Lage, K, Schwartz, PJ, Kääb, S, Chakravarti, A, Ackerman, MJ, Pfeufer, A, de Bakker, PIW, Newton-Cheh, C
Corporate AuthorsCARe Consortium, COGENT Consortium, DCCT/EDIC, eMERGE Consortium, HRGEN Consortium
JournalNat Genet
Volume46
Issue8
Pages826-36
Date Published2014 Aug
ISSN1546-1718
KeywordsAdult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide
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.

URLhttp://dx.doi.org/10.1038/ng.3014
DOI10.1038/ng.3014
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24952745
PubMed Central IDPMC4124521
Grant ListCZB/4/710 / / Chief Scientist Office / United Kingdom
G9521010 / / Medical Research Council / United Kingdom
U01 DK094176 / DK / NIDDK NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HG004037 / HG / NHGRI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 HL098283 / HL / NHLBI NIH HHS / United States
UL1 TR000114 / TR / NCATS NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_U106179471 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
MC_PC_U127592696 / / Medical Research Council / United Kingdom
G0701863 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
UL1 TR000142 / TR / NCATS NIH HHS / United States
MR/K006584/1 / / Medical Research Council / United Kingdom
MR/K013351/1 / / Medical Research Council / United Kingdom
RG/13/16/30528 / / British Heart Foundation / United Kingdom
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL113933 / HL / NHLBI NIH HHS / United States
K23 HL080025 / HL / NHLBI NIH HHS / United States
PG/12/38/29615 / / British Heart Foundation / United Kingdom
R01 HL111267 / HL / NHLBI NIH HHS / United States
RG/10/12/28456 / / British Heart Foundation / United Kingdom