Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies

IM Nolte; C Wallace; Stephen Newhouse; D Waggott; J Fu; N Soranzo; R Gwilliam; P Deloukas; I Savelieva; D Zheng; C Dalageorgou; M Farrall; NJ Samani; J Connell; A Dominiczak; M Lathrop; E Zeggini; LV Wain; Wellcome Trust Case Control Consortium; DCCT/EDIC Research Group; C Newton-Cheh; M Eijgelsheim; K Rice; PI de Bakker; QTGEN Consortium; A Pfeufer; S Sanna; DE Arking; QTSCD Consortium; FW Asselbergs; TD Spector; ND Carter; S Jeffery; M Tobin; M Caulfield; H Snieder; AD Paterson; PB Munroe; YM Jamshidi

doi:10.1371/journal.pone.0006138

Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies

IM Nolte, C Wallace, Stephen Newhouse, D Waggott, J Fu, N Soranzo, R Gwilliam, P Deloukas, I Savelieva, D Zheng, C Dalageorgou, M Farrall, NJ Samani, J Connell, A Dominiczak, M Lathrop, E Zeggini, LV Wain, Wellcome Trust Case Control Consortium, DCCT/EDIC Research GroupC Newton-Cheh, M Eijgelsheim, K Rice, PI de Bakker, QTGEN Consortium, A Pfeufer, S Sanna, DE Arking, QTSCD Consortium, FW Asselbergs, TD Spector, ND Carter, S Jeffery, M Tobin, M Caulfield, H Snieder, AD Paterson, PB Munroe, YM Jamshidi

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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<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.

Original language	English
Article number	e6138
Journal	PL o S One
Volume	4
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0006138
Publication status	Published - 9 Jul 2009

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Common Genetic Variation Near_NEWHOUSE_Published 9Jul2009_GOLD VoRFinal published version, 231 KBLicence: CC BY

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Nolte, IM., Wallace, C., Newhouse, S., Waggott, D., Fu, J., Soranzo, N., Gwilliam, R., Deloukas, P., Savelieva, I., Zheng, D., Dalageorgou, C., Farrall, M., Samani, NJ., Connell, J., Dominiczak, A., Lathrop, M., Zeggini, E., Wain, LV., Wellcome Trust Case Control Consortium, ... Jamshidi, YM. (2009). Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PL o S One , 4(7), Article e6138. https://doi.org/10.1371/journal.pone.0006138

@article{9158e0c8a7484433a8e97f89b6edbb3d,

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<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.",

author = "IM Nolte and C Wallace and Stephen Newhouse and D Waggott and J Fu and N Soranzo and R Gwilliam and P Deloukas and I Savelieva and D Zheng and C Dalageorgou and M Farrall and NJ Samani and J Connell and A Dominiczak and M Lathrop and E Zeggini and LV Wain and {Wellcome Trust Case Control Consortium} and {DCCT/EDIC Research Group} and C Newton-Cheh and M Eijgelsheim and K Rice and {de Bakker}, PI and {QTGEN Consortium} and A Pfeufer and S Sanna and DE Arking and {QTSCD Consortium} and FW Asselbergs and TD Spector and ND Carter and S Jeffery and M Tobin and M Caulfield and H Snieder and AD Paterson and PB Munroe and YM Jamshidi",

year = "2009",

month = jul,

day = "9",

doi = "10.1371/journal.pone.0006138",

language = "English",

volume = "4",

journal = "PL o S One ",

issn = "1932-6203",

publisher = "Public Library of Science",

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Nolte, IM, Wallace, C, Newhouse, S, Waggott, D, Fu, J, Soranzo, N, Gwilliam, R, Deloukas, P, Savelieva, I, Zheng, D, Dalageorgou, C, Farrall, M, Samani, NJ, Connell, J, Dominiczak, A, Lathrop, M, Zeggini, E, Wain, LV, Wellcome Trust Case Control Consortium, DCCT/EDIC Research Group, Newton-Cheh, C, Eijgelsheim, M, Rice, K, de Bakker, PI, QTGEN Consortium, Pfeufer, A, Sanna, S, Arking, DE, QTSCD Consortium, Asselbergs, FW, Spector, TD, Carter, ND, Jeffery, S, Tobin, M, Caulfield, M, Snieder, H, Paterson, AD, Munroe, PB & Jamshidi, YM 2009, 'Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies', PL o S One , vol. 4, no. 7, e6138. https://doi.org/10.1371/journal.pone.0006138

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, IM

AU - Wallace, C

AU - Newhouse, Stephen

AU - Waggott, D

AU - Fu, J

AU - Soranzo, N

AU - Gwilliam, R

AU - Deloukas, P

AU - Savelieva, I

AU - Zheng, D

AU - Dalageorgou, C

AU - Farrall, M

AU - Samani, NJ

AU - Connell, J

AU - Dominiczak, A

AU - Lathrop, M

AU - Zeggini, E

AU - Wain, LV

AU - Wellcome Trust Case Control Consortium

AU - DCCT/EDIC Research Group

AU - Newton-Cheh, C

AU - Eijgelsheim, M

AU - Rice, K

AU - de Bakker, PI

AU - QTGEN Consortium

AU - Pfeufer, A

AU - Sanna, S

AU - Arking, DE

AU - QTSCD Consortium

AU - Asselbergs, FW

AU - Spector, TD

AU - Carter, ND

AU - Jeffery, S

AU - Tobin, M

AU - Caulfield, M

AU - Snieder, H

AU - Paterson, AD

AU - Munroe, PB

AU - Jamshidi, YM

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.

U2 - 10.1371/journal.pone.0006138

DO - 10.1371/journal.pone.0006138

M3 - Article

SN - 1932-6203

VL - 4

JO - PL o S One

JF - PL o S One

IS - 7

M1 - e6138

ER -

Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies

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