Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

被引：270

作者：

Sotoodehnia, Nona ^{[1
,2
]}

Isaacs, Aaron ^{[3
,4
]}

de Bakker, Paul I. W. ^{[5
,6
,7
,8
]}

Doerr, Marcus ^{[9
]}

Newton-Cheh, Christopher ^{[10
,11
,12
]}

Nolte, Ilja M. ^{[13
]}

van der Harst, Pim ^{[14
]}

Mueller, Martina ^{[15
,16
,17
]}

Eijgelsheim, Mark ^{[18
]}

Alonso, Alvaro ^{[19
]}

Hicks, Andrew A. ^{[20
,21
]}

Padmanabhan, Sandosh ^{[22
]}

Hayward, Caroline ^{[23
]}

Smith, Albert Vernon ^{[24
,25
]}

Polasek, Ozren ^{[26
]}

Giovannone, Steven ^{[27
]}

Fu, Jingyuan ^{[13
,28
]}

Magnani, Jared W. ^{[12
,29
]}

Marciante, Kristin D. ^{[2
]}

Pfeufer, Arne ^{[21
,30
,31
]}

Gharib, Sina A. ^{[32
]}

Teumer, Alexander ^{[33
]}

Li, Man ^{[34
,35
]}

Bis, Joshua C. ^{[2
]}

Rivadeneira, Fernando ^{[18
,36
]}

Aspelund, Thor ^{[24
,25
]}

Koettgen, Anna ^{[34
]}

Johnson, Toby ^{[37
,38
]}

Rice, Kenneth ^{[39
]}

Sie, Mark P. S. ^{[3
]}

Wang, Ying A. ^{[12
,40
]}

Klopp, Norman ^{[17
]}

Fuchsberger, Christian ^{[20
,21
]}

Wild, Sarah H. ^{[41
]}

Leach, Irene Mateo ^{[14
]}

Estrada, Karol ^{[36
]}

Voelker, Uwe ^{[33
]}

Wright, Alan F. ^{[23
]}

Asselbergs, Folkert W. ^{[13
,14
,42
]}

Qu, Jiaxiang ^{[27
]}

Chakravarti, Aravinda ^{[43
]}

Sinner, Moritz F. ^{[16
]}

Kors, Jan A. ^{[44
]}

Petersmann, Astrid ^{[45
]}

Harris, Tamara B. ^{[46
]}

Soliman, Elsayed Z. ^{[47
]}

Munroe, Patricia B. ^{[37
,38
]}

Psaty, Bruce M. ^{[2
,48
,49
,50
]}

Oostra, Ben A. ^{[4
,51
]}

Cupples, L. Adrienne ^{[12
,40
]}

机构：

[1] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA

[2] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[3] Erasmus Med Ctr MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands

[4] Ctr Med Syst Biol, Leiden, Netherlands

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA

[6] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[7] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands

[8] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[9] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany

[10] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[11] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[12] NHLBI, Framingham Heart Study, Framingham, MA USA

[13] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[15] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[16] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany

[17] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[18] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[19] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[20] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy

[21] Univ Lubeck, Affiliated Inst, Lubeck, Germany

[22] Univ Glasgow, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland

[23] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[24] Iceland Heart Assoc, Kopavogur, Iceland

[25] Univ Iceland, Reykjavik, Iceland

[26] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia

[27] NYU, Sch Med, Leon H Charney Div Cardiol, New York, NY USA

[28] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 AB Groningen, Netherlands

[29] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA

[30] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[31] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany

[32] Univ Washington, Dept Med, Ctr Lung Biol, Seattle, WA USA

[33] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany

[34] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[35] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA

[36] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[37] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Clin Pharmacol & Barts & London Genome Ctr, London, England

[38] Barts & London Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England

[39] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[40] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[41] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[42] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[43] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[44] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands

[45] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[46] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA

[47] Wake Forest Univ, Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27109 USA

[48] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[49] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[50] Grp Hlth Cooperat Puget Sound, Gup Hlth Res Inst, Seattle, WA 98121 USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; QT INTERVAL DURATION; RICH REPEAT PROTEIN; HEART-RATE; TRANSCRIPTION FACTOR; GENE-EXPRESSION; PR INTERVAL; SYSTEM; DISEASE; ELECTROCARDIOGRAM;

D O I：

10.1038/ng.716

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

引用

页码：1068 / U62

页数：11

共 66 条

[11] QT interval is linked to 2 long-QT syndrome loci in normal subjects [J].

Busjahn, A ;

Knoblauch, H ;

Faulhaber, HD ;

Boeckel, T ;

Rosenthal, M ;

Uhlmann, R ;

Hoehe, M ;

Schuster, H ;

Luft, FC .

CIRCULATION, 1999, 99 (24) :3161-3164

[12] A network-based analysis of systemic inflammation in humans [J].

Calvano, SE ;

Xiao, WZ ;

Richards, DR ;

Felciano, RM ;

Baker, HV ;

Cho, RJ ;

Chen, RO ;

Brownstein, BH ;

Cobb, JP ;

Tschoeke, SK ;

Miller-Graziano, C ;

Moldawer, LL ;

Mindrinos, MN ;

Davis, RW ;

Tompkins, RG ;

Lowry, SF .

NATURE, 2005, 437 (7061) :1032-1037

[13] Genetic variation in SCN10A influences cardiac conduction [J].

Chambers, John C. ;

Zhao, Jing ;

Terracciano, Cesare M. N. ;

Bezzina, Connie R. ;

Zhang, Weihua ;

Kaba, Riyaz ;

Navaratnarajah, Manoraj ;

Lotlikar, Amol ;

Sehmi, Joban S. ;

Kooner, Manraj K. ;

Deng, Guohong ;

Siedlecka, Urszula ;

Parasramka, Saurabh ;

El-Hamamsy, Ismail ;

Wass, Mark N. ;

Dekker, Lukas R. C. ;

de Jong, Jonas S. S. G. ;

Sternberg, Michael J. E. ;

McKenna, William ;

Severs, Nicholas J. ;

de Silva, Ranil ;

Wilde, Arthur A. M. ;

Anand, Praveen ;

Yacoub, Magdi ;

Scott, James ;

Elliott, Paul ;

Wood, John N. ;

Kooner, Jaspal S. .

NATURE GENETICS, 2010, 42 (02) :149-U80

[14] Family-based association tests for genomewide association scans [J].

Chen, Wei-Min ;

Abecasis, Goncalo R. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (05) :913-926

[15] Practical aspects of imputation-driven meta-analysis of genome-wide association studies [J].

de Bakker, Paul I. W. ;

Ferreira, Manuel A. R. ;

Jia, Xiaoming ;

Neale, Benjamin M. ;

Raychaudhuri, Soumya ;

Voight, Benjamin F. .

HUMAN MOLECULAR GENETICS, 2008, 17 :R122-R128

[16] Prognostic significance of quantitative QRS duration [J].

Desai, Aseem D. ;

Yaw, Tan Swee ;

Yamazaki, Takuya ;

Kaykha, Amir ;

Chun, Sung ;

Froelicher, Victor F. .

AMERICAN JOURNAL OF MEDICINE, 2006, 119 (07) :600-606

[17] Gap junction channels and cardiac impulse propagation [J].

Desplantez, Thomas ;

Dupont, Emmanuel ;

Severs, Nicholas J. ;

Weingart, Robert .

JOURNAL OF MEMBRANE BIOLOGY, 2007, 218 (1-3) :13-28

[18] Genomic control, a new approach to genetic-based association studies [J].

Devlin, B ;

Roeder, K ;

Wasserman, L .

THEORETICAL POPULATION BIOLOGY, 2001, 60 (03) :155-166

[19] Electrocardiographic QRS duration and the risk of congestive heart failure - The Framingham heart study [J].

Dhingra, R ;

Pencina, MJ ;

Wang, TJ ;

Nam, BH ;

Benjamin, EJ ;

Levy, D ;

Larson, MG ;

Kannel, WB ;

D'Agostino, RB ;

Vasan, RS .

HYPERTENSION, 2006, 47 (05) :861-867

[20] Multiple common variants for celiac disease influencing immune gene expression [J].

Dubois, Patrick C. A. ;

Trynka, Gosia ;

Franke, Lude ;

Hunt, Karen A. ;

Romanos, Jihane ;

Curtotti, Alessandra ;

Zhernakova, Alexandra ;

Heap, Graham A. R. ;

Adany, Roza ;

Aromaa, Arpo ;

Bardella, Maria Teresa ;

van den Berg, Leonard H. ;

Bockett, Nicholas A. ;

de la Concha, Emilio G. ;

Dema, Barbara ;

Fehrmann, Rudolf S. N. ;

Fernandez-Arquero, Miguel ;

Fiatal, Szilvia ;

Grandone, Elvira ;

Green, Peter M. ;

Groen, Harry J. M. ;

Gwilliam, Rhian ;

Houwen, Roderick H. J. ;

Hunt, Sarah E. ;

Kaukinen, Katri ;

Kelleher, Dermot ;

Korponay-Szabo, Ilma ;

Kurppa, Kalle ;

MacMathuna, Padraic ;

Maki, Markku ;

Mazzilli, Maria Cristina ;

McCann, Owen T. ;

Mearin, M. Luisa ;

Mein, Charles A. ;

Mirza, Muddassar M. ;

Mistry, Vanisha ;

Mora, Barbara ;

Morley, Katherine I. ;

Mulder, Chris J. ;

Murray, Joseph A. ;

Nunez, Concepcion ;

Oosterom, Elvira ;

Ophoff, Roel A. ;

Polanco, Isabel ;

Peltonen, Leena ;

Platteel, Mathieu ;

Rybak, Anna ;

Salomaa, Veikko ;

Schweizer, Joachim J. ;

Sperandeo, Maria Pia .

NATURE GENETICS, 2010, 42 (04) :295-U42

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