TY - JOUR
T1 - Common genetic variation near the phospholamban gene is associated with cardiac repolarisation
T2 - Meta-analysis of three genome-wide association studies
AU - Nolte, Ilja M.
AU - Wallace, Chris
AU - Newhouse, Stephen J.
AU - Waggott, Daryl
AU - Fu, Jingyuan
AU - Soranzo, Nicole
AU - Gwilliam, Rhian
AU - Deloukas, Panos
AU - Savelieva, Irina
AU - Zheng, Dongling
AU - Dalageorgou, Chrysoula
AU - Farrall, Martin
AU - Samani, Nilesh J.
AU - Connell, John
AU - Brown, Morris
AU - Dominiczak, Anna
AU - Lathrop, Mark
AU - Zeginni, Eleftheria
AU - Wain, Louise V.
AU - Newton-Cheh, Christopher
AU - Eijgelsheim, Mark
AU - Rice, Kenneth
AU - De Bakker, Paul I.W.
AU - Pfeufer, Arne
AU - Sanna, Serena
AU - Arking, Dan E.
AU - Asselbergs, Folkert W.
AU - Spector, Tim D.
AU - Carter, Nicholas D.
AU - Jeffery, Steve
AU - Tobin, Martin
AU - Caulfield, Mark
AU - Snieder, Harold
AU - Paterson, Andrew D.
AU - Munroe, Patricia B.
AU - Jamshidi, Yalda
N1 - Funding Information:
For Twins UK: Analyses were performed on the Genetic Cluster Computer, which is financed by an NWO Medium Investment grant 480-05-003 and by the Faculty of Psychology and Education of the VU University, Amsterdam, The Netherlands. Genotyping of TwinsUK samples: We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Génotypage, France, led by Mark Lathrop, for genotyping; Duke University, North Carolina, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie.
PY - 2009/7/9
Y1 - 2009/7/9
N2 - To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1×10-6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10-83) and the phospholamban (PLN) gene (P = 1.9×10-29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
AB - To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1×10-6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10-83) and the phospholamban (PLN) gene (P = 1.9×10-29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
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U2 - 10.1371/journal.pone.0006138
DO - 10.1371/journal.pone.0006138
M3 - Article
C2 - 19587794
AN - SCOPUS:67650280679
SN - 1932-6203
VL - 4
JO - PloS one
JF - PloS one
IS - 7
M1 - e6138
ER -