Genome-wide association analysis identifies multiple loci related to resting heart rate

被引：108

作者：

Eijgelsheim, Mark ^{[1
]}

Newton-Cheh, Christopher ^{[5
,7
,8
]}

Sotoodehnia, Nona ^{[9
,10
]}

de Bakker, Paul I. W. ^{[7
,13
]}

Mueller, Martina ^{[14
,15
,16
]}

Morrison, Alanna C. ^{[17
]}

Smith, Albert V. ^{[18
]}

Isaacs, Aaron ^{[1
]}

Sanna, Serena ^{[19
]}

Doerr, Marcus ^{[20
]}

Navarro, Pau ^{[23
]}

Fuchsberger, Christian ^{[24
]}

Nolte, Ilja M. ^{[25
]}

de Geus, Eco J. C. ^{[26
]}

Estrada, Karol ^{[2
]}

Hwang, Shih-Jen ^{[8
]}

Bis, Joshua C. ^{[10
]}

Rueckert, Ina-Maria ^{[15
]}

Alonso, Alvaro ^{[27
]}

Launer, Lenore J. ^{[28
]}

Hottenga, Jouke Jan ^{[26
]}

Rivadeneira, Fernando ^{[1
,2
]}

Noseworthy, Peter A. ^{[5
]}

Rice, Kenneth M.

Perz, Siegfried ^{[29
]}

Arking, Dan E. ^{[30
,31
]}

Spector, Tim D. ^{[32
,33
]}

Kors, Jan A. ^{[3
]}

Aulchenko, Yurii S. ^{[1
]}

Tarasov, Kirill V. ^{[34
]}

Homuth, Georg ^{[21
]}

Wild, Sarah H. ^{[35
]}

Marroni, Fabio ^{[24
,36
]}

Gieger, Christian ^{[15
]}

Licht, Carmilla M. ^{[37
]}

Prineas, Ronald J. ^{[38
]}

Hofman, Albert ^{[1
,39
]}

Rotter, Jerome I. ^{[40
]}

Hicks, Andrew A. ^{[24
]}

Ernst, Florian ^{[21
]}

Najjar, Samer S. ^{[34
]}

Wright, Alan F. ^{[23
]}

Peters, Annette ^{[15
]}

Fox, Ervin R. ^{[41
]}

Oostra, Ben A. ^{[4
]}

Kroemer, Heyo K. ^{[42
]}

Couper, David ^{[43
]}

Voelzke, Henry ^{[22
]}

Campbell, Harry ^{[35
]}

Meitinger, Thomas ^{[44
,45
]}

机构：

[1] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[2] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

[3] Erasmus MC, Dept Med Informat, NL-3000 CA Rotterdam, Netherlands

[4] Erasmus MC, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands

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

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

[7] Broad Inst Harvard & MIT, Program Med Populat Genet, Cambridge, MA USA

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

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

[10] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

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

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

[13] Brighams & Womens Hosp, Div Genet, Dept Med, Boston, MA USA

[14] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Epidemiol, Neuherberg, Germany

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

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

[17] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA

[18] Iceland Heart Assoc Res Inst, Kopavogur, Iceland

[19] Cittadella Univ Monserrato, Ist Neurogenet & Neurofarmacol, Consiglio Nazl Ric, Cagliari, Italy

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

[21] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[22] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany

[23] Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

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

[25] Univ Groningen, Univ Med Ctr Groningen, Unit Genet Epidemiol & Bioinformat, Dept Epidemiol, NL-9713 AV Groningen, Netherlands

[26] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

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

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

[29] Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Munich, Germany

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

[31] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[32] St Thomas Hosp, Dept Twin Res, Kings Coll London, London, England

[33] St Thomas Hosp, Genet Epidemiol Unit, Kings Coll London, London, England

[34] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA

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

[36] Inst Appl Genom, Udine, Italy

[37] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands

[38] EPICARE Ctr, Salem, NC USA

[39] Netherlands Genom Initiat Sponsored Netherlands C, Rotterdam, Netherlands

[40] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[41] Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS 39216 USA

[42] Ctr Pharmacol & Expt Therapeut, Dept Pharmacol, Greifswald, Germany

[43] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[44] Helmholtz Ctr Munich, Inst Human Genet, Munich, Germany

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

[46] Grp Hlth Res Inst, Seattle, WA USA

[47] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

[48] St Georges Univ London, London, England

[49] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA

[50] Gen Cent Hosp, Dept Neurol, Bolzano, Italy

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 19期

基金：

英国医学研究理事会;

关键词：

RECTIFIER POTASSIUM CHANNEL; CARDIAC-PACEMAKER CELLS; QT INTERVAL DURATION; MYOSIN HEAVY-CHAIN; MIDDLE-AGED MEN; COMMON VARIANTS; FUNCTIONAL EXPRESSION; ADRENERGIC-RECEPTOR; GENETIC-VARIANTS; RISK-FACTOR;

D O I：

10.1093/hmg/ddq303

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and similar to 2.5 million markers. Results with P < 5 x 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain similar to 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

引用

页码：3885 / 3894

页数：10

共 65 条

[1] Genome-wide scan to identify quantitative trait loci for baseline resting heart rate and its response to endurance exercise training: The HERITAGE Family Study [J].

An, P ;

Rice, T ;

Rankinen, T ;

Leon, AS ;

Skinner, JS ;

Wilmore, JH ;

Bouchard, C ;

Rao, DC .

INTERNATIONAL JOURNAL OF SPORTS MEDICINE, 2006, 27 (01) :31-36

[2] Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts [J].

Aulchenko, Yurii S. ;

Ripatti, Samuli ;

Lindqvist, Ida ;

Boomsma, Dorret ;

Heid, Iris M. ;

Pramstaller, Peter P. ;

Penninx, Brenda W. J. H. ;

Janssens, A. Cecile J. W. ;

Wilson, James F. ;

Spector, Tim ;

Martin, Nicholas G. ;

Pedersen, Nancy L. ;

Kyvik, Kirsten Ohm ;

Kaprio, Jaakko ;

Hofman, Albert ;

Freimer, Nelson B. ;

Jarvelin, Marjo-Riitta ;

Gyllensten, Ulf ;

Campbell, Harry ;

Rudan, Igor ;

Johansson, Asa ;

Marroni, Fabio ;

Hayward, Caroline ;

Vitart, Veronique ;

Jonasson, Inger ;

Pattaro, Cristian ;

Wright, Alan ;

Hastie, Nick ;

Pichler, Irene ;

Hicks, Andrew A. ;

Falchi, Mario ;

Willemsen, Gonneke ;

Hottenga, Jouke-Jan ;

de Geus, Eco J. C. ;

Montgomery, Grant W. ;

Whitfield, John ;

Magnusson, Patrik ;

Saharinen, Juha ;

Perola, Markus ;

Silander, Kaisa ;

Isaacs, Aaron ;

Sijbrands, Eric J. G. ;

Uitterlinden, Andre G. ;

Witteman, Jacqueline C. M. ;

Oostra, Ben A. ;

Elliott, Paul ;

Ruokonen, Aimo ;

Sabatti, Chiara ;

Gieger, Christian ;

Meitinger, Thomas .

NATURE GENETICS, 2009, 41 (01) :47-55

[3] Protein kinase D in the cardiovascular system - Emerging roles in health and disease [J].

Avkiran, Metin ;

Rowland, Alexandra J. ;

Cuello, Friederike ;

Haworth, Robert S. .

CIRCULATION RESEARCH, 2008, 102 (02) :157-163

[4] The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system [J].

Bang, ML ;

Centner, T ;

Fornoff, F ;

Geach, AJ ;

Gotthardt, M ;

McNabb, M ;

Witt, CC ;

Labeit, D ;

Gregorio, CC ;

Granzier, H ;

Labeit, S .

CIRCULATION RESEARCH, 2001, 89 (11) :1065-1072

[5] MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice [J].

Callis, Thomas E. ;

Pandya, Kumar ;

Seok, Hee Young ;

Tang, Ru-Hang ;

Tatsuguchi, Mariko ;

Huang, Zhan-Peng ;

Chen, Jian-Fu ;

Deng, Zhongliang ;

Gunn, Bronwyn ;

Shumate, Janelle ;

Willis, Monte S. ;

Selzman, Craig H. ;

Wang, Da-Zhi .

JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (09) :2772-2786

[6] α-Myosin heavy chain -: A sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy [J].

Carniel, E ;

Taylor, MRG ;

Sinagra, G ;

Di Lenarda, A ;

Ku, L ;

Fain, PR ;

Boucek, MM ;

Cavanaugh, J ;

Miocic, S ;

Slavov, D ;

Graw, SL ;

Feiger, J ;

Zhu, XZ ;

Dao, D ;

Ferguson, DA ;

Bristow, MR ;

Mestroni, L .

CIRCULATION, 2005, 112 (01) :54-59

[7] Molecular Architecture of the Human Sinus Node Insights Into the Function of the Cardiac Pacemaker [J].

Chandler, Natalie J. ;

Greener, Ian D. ;

Tellez, James O. ;

Inada, Shin ;

Musa, Hanny ;

Molenaar, Peter ;

DiFrancesco, Dario ;

Baruscotti, Mirko ;

Longhi, Renato ;

Anderson, Robert H. ;

Billeter, Rudolf ;

Sharma, Vinod ;

Sigg, Daniel C. ;

Boyett, Mark R. ;

Dobrzynski, Halina .

CIRCULATION, 2009, 119 (12) :1562-1575

[8] Relation of heart rate at rest and mortality in the women's health and aging study [J].

Chang, M ;

Havlik, RJ ;

Corti, MC ;

Chaves, PHM ;

Fried, LP ;

Guralnik, JM .

AMERICAN JOURNAL OF CARDIOLOGY, 2003, 92 (11) :1294-1299

[9] Mutation in myosin heavy chain 6 causes atrial septal defect [J].

Ching, YH ;

Ghosh, TK ;

Cross, SJ ;

Packham, EA ;

Honeyman, L ;

Loughna, S ;

Robinson, TE ;

Dearlove, AM ;

Ribas, G ;

Bonser, AJ ;

Thomas, NR ;

Scotter, AJ ;

Caves, LSD ;

Tyrrell, GP ;

Newbury-Ecob, RA ;

Munnich, A ;

Bonnet, D ;

Brook, JD .

NATURE GENETICS, 2005, 37 (04) :423-428

[10] A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits [J].

Cho, Yoon Shin ;

Go, Min Jin ;

Kim, Young Jin ;

Heo, Jee Yeon ;

Oh, Ji Hee ;

Ban, Hyo-Jeong ;

Yoon, Dankyu ;

Lee, Mi Hee ;

Kim, Dong-Joon ;

Park, Miey ;

Cha, Seung-Hun ;

Kim, Jun-Woo ;

Han, Bok-Ghee ;

Min, Haesook ;

Ahn, Younjhin ;

Park, Man Suk ;

Han, Hye Ree ;

Jang, Hye-Yoon ;

Cho, Eun Young ;

Lee, Jong-Eun ;

Cho, Nam H. ;

Shin, Chol ;

Park, Taesung ;

Park, Ji Wan ;

Lee, Jong-Keuk ;

Cardon, Lon ;

Clarke, Geraldine ;

McCarthy, Mark I. ;

Lee, Jong-Young ;

Lee, Jong-Koo ;

Oh, Bermseok ;

Kim, Hyung-Lae .

NATURE GENETICS, 2009, 41 (05) :527-534

← 1 2 3 4 5 6 7 →