PubMed ID:
24952745
Public Release Type:
Journal
Publication Year: 2014
Affiliation: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. [4] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [5].
DOI:
https://doi.org/10.1038/ng.3014
Authors:
Brown M,
Wang X,
Alonso A,
Arking DE,
Sundström J,
Abecasis GR,
Ackerman MJ,
Adamkova V,
Arnar DO,
Ärnlöv J,
Asselbergs FW,
Bader JS,
Barc J,
Bardai A,
Beckmann BM,
Behr ER,
Bezzina CR,
Bis JC,
Bobbo M,
Boyer LA,
Bradford Y,
Brandimarto J,
Brion M,
Campbell H,
Cappola TP,
CARe Consortium,
Carella M,
Carracedo A,
Caulfield MJ,
Chakravarti A,
Chatel S,
COGENT Consortium,
Crotti L,
Cummings SR,
D'Adamo AP,
Dalageorgou C,
Daly MJ,
DCCT/EDIC,
de Bakker PI,
de Boer RA,
del Greco M F,
den Hoed M,
Denny JC,
Dominiczak AF,
Dörr M,
Ehret G,
Eijgelsheim M,
Eisele L,
Ellinghaus D,
El Mokhtari NE,
eMERGE Consortium,
Emilsson V,
Erbel R,
Evans DS,
Felix SB,
Ferrucci L,
Franco OH,
Franke A,
Franke L,
Frey N,
Fuchsberger C,
Gasparini P,
Ghidoni A,
Gieger C,
Giudicessi JR,
Greiser KH,
Griffin M,
Gudbjartsson DF,
Gudnason V,
Gustafsson S,
Haerting J,
Hamilton RM,
Harris TB,
Hayward C,
Heckbert SR,
Hicks AA,
Hingorani AD,
Hoffmann P,
Hofman A,
Hofman N,
Hólm H,
HRGEN Consortium,
Huang H,
Hubacek JA,
Ingelsson E,
Insolia R,
Iorio A,
Isaacs A,
Jamshidi Y,
Jöckel KH,
Johnson AD,
Jula A,
Kääb S,
Kähönen M,
Kälsch H,
Kao WH,
Kedenko L,
Kellis M,
Kiechl S,
Kivimaki M,
Kluttig A,
Knoflach M,
Kolcic I,
Kontula KK,
Koopmann TT,
Kors JA,
Krijthe BP,
Kronenberg F,
Kumari M,
Kumar RD,
Kyndt F,
Lage K,
Lahtinen AM,
Lakatta EG,
Lamina C,
Larson MG,
Launer LJ,
Lee WK,
Lehtimäki TJ,
Lind L,
Liu Y,
Loos RJ,
Lundby A,
Lyytikäinen LP,
Macfarlane PW,
Margulies K,
Marjamaa A,
Markus MR,
Martens E,
Mateo Leach I,
Medeiros-Domingo A,
Meitinger T,
Meyer Zu Schwabedissen H,
Mononen N,
Moravec CE,
Morley M,
Morris RW,
Mühleisen TW,
Mulas A,
Müller-Nurasyid M,
Munroe PB,
Nalls MA,
Naluai ÅT,
Navarro P,
Navis G,
Newhouse SJ,
Newton-Cheh C,
Nicolaides AN,
Nolte IM,
Noseworthy PA,
Nöthen MM,
Nyberg F,
O'Connell JR,
O'Donnell CJ,
Oikarinen L,
Olsen JV,
Oostra BA,
Orrú M,
Padmanabhan S,
Panayiotou AG,
Parsa A,
Paterson AD,
Paulweber B,
Perola M,
Perz S,
Peters A,
Pfeufer A,
Plump AS,
Polašek O,
Porthan K,
Post WS,
Pramstaller PP,
Probst V,
Prucha H,
Psaty BM,
Pulit SL,
Raitakari OT,
Raychaudhuri S,
Ritchie MD,
Roden DM,
Rossin EJ,
Rotter JI,
Rudan I,
Salomaa V,
Samani NJ,
Sanna S,
Scherer SW,
Schlessinger D,
Schott JJ,
Schwartz PJ,
Shuldiner AR,
Sinagra G,
Sinner MF,
Siscovick DS,
Slowikowski K,
Smith AV,
Smith JG,
Snieder H,
Sotoodehnia N,
Spector TD,
Stefansson K,
Strait JB,
Stricker BH,
Strohmer B,
Syvänen AC,
Tanaka T,
Tarasov KV,
Tester DJ,
Thelle DS,
Thorsteinsdottir U,
Torres M,
Uda M,
Uitterlinden AG,
Ulivi S,
van den Berg MP,
van der Harst P,
van der Vleuten PA,
van Duijn CM,
van Veldhuisen DJ,
Viikari JS,
Völker U,
Waggott D,
Waldenberger M,
Watt GC,
Werdan K,
Whincup PH,
Wilde AA,
Wild SH,
Willeit J,
Wilson JF,
Witteman JC,
Wright AF,
Yin X,
Zelante L,
Zuvich RL
Studies:
Diabetes Control and Complications Trial
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.