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

Arking, DE; Pulit, SL; Crotti, L; van der Harst, P; Munroe, PB; Koopmann, TT; Sotoodehnia, N; Rossin, EJ; Morley, M; Wang, X; et al. Arking, 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; Dörr, M; Müller-Nurasyid, M; Lahtinen, AM; Nolte, IM; Smith, AV; Bis, JC; Isaacs, A; Newhouse, SJ; Evans, DS; Post, WS; Waggott, D; Lyytikäinen, LP; 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, WH; Strait, JB; Macfarlane, PW; Brown, M; Caulfield, MJ; Samani, NJ; Kronenberg, F; Willeit, J; CARe Consortium; COGENT Consortium; Smith, JG; Greiser, KH; Meyer Zu Schwabedissen, H; Werdan, K; Carella, M; Zelante, L; Heckbert, SR; Psaty, BM; Rotter, JI; Kolcic, I; Polašek, O; Wright, AF; Griffin, M; Daly, MJ; DCCT/EDIC; Arnar, DO; Hólm, H; Thorsteinsdottir, U; eMERGE Consortium; 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, A; Cummings, SR; Nalls, MA; Jula, A; Kontula, KK; Marjamaa, A; Oikarinen, L; Perola, M; Porthan, K; Erbel, R; Hoffmann, P; Jöckel, KH; Kälsch, H; Nöthen, MM; HRGEN Consortium; den Hoed, M; Loos, RJ; 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, BM; Martens, E; Bardai, A; Hofman, N; Wilde, AA; 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; del Greco M, F; Fuchsberger, C; O'Connell, JR; Lee, WK; Watt, GC; Campbell, H; Wild, SH; El Mokhtari, NE; Frey, N; Asselbergs, FW; Mateo Leach, I; Navis, G; van den Berg, MP; van Veldhuisen, DJ; Kellis, M; Krijthe, BP; Franco, OH; Hofman, A; Kors, JA; Uitterlinden, AG; Witteman, JC; Kedenko, L; Lamina, C; Oostra, BA; Abecasis, GR; Lakatta, EG; Mulas, A; Orrú, M; Schlessinger, D; Uda, M; Markus, MR; Völker, U; Snieder, H; Spector, TD; Ärnlöv, J; Lind, L; Sundström, J; Syvänen, AC; 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, JJ; 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, PI; Newton-Cheh, C (2014) Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature Genetics, 46 (8). pp. 826-836. ISSN 1546-1718 https://doi.org/10.1038/ng.3014
SGUL Authors: Behr, Elijah Raphael Jamshidi, Yalda Whincup, Peter Hynes

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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: Article
Additional Information: Author’s manuscript is made available for academic research only, and cannot be used for commercial purposes without prior permission of the copyright holders. Made available here with permission from the publisher.
Keywords: Adult, 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, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, CHRONIC HEART-FAILURE, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, CARDIAC REPOLARIZATION, SARCOPLASMIC-RETICULUM, QRS DURATION, PR INTERVAL, LOCI, TRPM7, MODEL, Developmental Biology, 11 Medical And Health Sciences, 06 Biological Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: Nature Genetics
ISSN: 1546-1718
Language: eng
Dates:
DateEvent
August 2014Published
Projects:
Project IDFunderFunder ID
CZB/4/710Chief Scientist OfficeUNSPECIFIED
G0701863Medical Research CouncilUNSPECIFIED
G9521010Medical Research CouncilUNSPECIFIED
K23 HL080025NHLBI NIH HHSUNSPECIFIED
MC_U106179471Medical Research CouncilUNSPECIFIED
MC_UU_12015/1Medical Research CouncilUNSPECIFIED
MR/K006584/1Medical Research CouncilUNSPECIFIED
MR/K013351/1Medical Research CouncilUNSPECIFIED
NF-SI-0512-10113Department of HealthUNSPECIFIED
NF-SI-0512-10135Department of HealthUNSPECIFIED
NF-SI-0611-10170Department of HealthUNSPECIFIED
P30 DK063491NIDDK NIH HHSUNSPECIFIED
P30 DK072488NIDDK NIH HHSUNSPECIFIED
PG/12/38/29615British Heart FoundationUNSPECIFIED
R01 HL098283NHLBI NIH HHSUNSPECIFIED
R01 HL105756NHLBI NIH HHSUNSPECIFIED
R01 HL111267NHLBI NIH HHSUNSPECIFIED
R01 HL113933NHLBI NIH HHSUNSPECIFIED
R01 HL120393NHLBI NIH HHSUNSPECIFIED
RG/10/12/28456British Heart FoundationUNSPECIFIED
T32 GM007753NIGMS NIH HHSUNSPECIFIED
U01 DK094157NIDDK NIH HHSUNSPECIFIED
U01 DK094176NIDDK NIH HHSUNSPECIFIED
UL1 TR000114NCATS NIH HHSUNSPECIFIED
UL1 TR000124NCATS NIH HHSUNSPECIFIED
PubMed ID: 24952745
Web of Science ID: WOS:000339704400010
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107365
Publisher's version: https://doi.org/10.1038/ng.3014

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