title: Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
abstract: 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<1x10(-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 = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-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.
authors: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Ilja M
authors: IM
authors: Nolte
authors: Chris
authors: C
authors: Wallace
authors: Stephen J
authors: SJ
authors: Newhouse
authors: Daryl
authors: D
authors: Waggott
authors: Jingyuan
authors: J
authors: Fu
authors: Nicole
authors: N
authors: Soranzo
authors: Rhian
authors: R
authors: Gwilliam
authors: Panos
authors: P
authors: Deloukas
authors: Irina
authors: I
authors: Savelieva
authors: Dongling
authors: D
authors: Zheng
authors: Chrysoula
authors: C
authors: Dalageorgou
authors: Martin
authors: M
authors: Farrall
authors: Nilesh J
authors: NJ
authors: Samani
authors: John
authors: J
authors: Connell
authors: Morris
authors: M
authors: Brown
authors: Anna
authors: A
authors: Dominiczak
authors: Mark
authors: M
authors: Lathrop
authors: Eleftheria
authors: E
authors: Zeggini
authors: Louise V
authors: LV
authors: Wain
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Mark
authors: M
authors: Eijgelsheim
authors: Kenneth
authors: K
authors: Rice
authors: Paul I W
authors: PI
authors: de Bakker
authors: Arne
authors: A
authors: Pfeufer
authors: Serena
authors: S
authors: Sanna
authors: Dan E
authors: DE
authors: Arking
authors: Folkert W
authors: FW
authors: Asselbergs
authors: Tim D
authors: TD
authors: Spector
authors: Nicholas D
authors: ND
authors: Carter
authors: Steve
authors: S
authors: Jeffery
authors: Martin
authors: M
authors: Tobin
authors: Mark
authors: M
authors: Caulfield
authors: Harold
authors: H
authors: Snieder
authors: Andrew D
authors: AD
authors: Paterson
authors: Patricia B
authors: PB
authors: Munroe
authors: Yalda
authors: Y
authors: Jamshidi
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006321:Heart / Q000502:physiology*; D006801:Humans; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D000099211:Phospholamban