Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

被引：25

作者：

van Setten, Jessica ^{[1
]}

Verweij, Niek ^{[2
,3
]}

Mbarek, Hamdi ^{[4
]}

Niemeijer, Maartje N. ^{[5
]}

Trompet, Stella ^{[6
]}

Arking, Dan E. ^{[7
]}

Brody, Jennifer A. ^{[8
]}

Gandin, Ilaria ^{[9
]}

Grarup, Niels ^{[10
]}

Hall, Leanne M. ^{[11
,12
]}

Hemerich, Daiane ^{[1
,13
]}

Lyytikainen, Leo-Pekka ^{[14
,15
]}

Mei, Hao ^{[16
]}

Mueller-Nurasyid, Martina ^{[17
,18
,19
,20
]}

Prins, Bram P. ^{[21
]}

Robino, Antonietta ^{[22
]}

Smith, Albert V. ^{[23
,24
]}

Warren, Helen R. ^{[25
,26
]}

Asselbergs, Folkert W. ^{[1
,27
,28
,29
,30
]}

Boomsma, Dorret I. ^{[4
]}

Caulfield, Mark J. ^{[25
,26
]}

Eijgelsheim, Mark ^{[5
,31
]}

Ford, Ian ^{[32
]}

Hansen, Torben ^{[10
]}

Harris, Tamara B. ^{[33
]}

Heckbert, Susan R. ^{[34
,35
]}

Hottenga, Jouke-Jan ^{[4
]}

Iorio, Annamaria ^{[36
,37
]}

Kors, Jan A. ^{[38
]}

Linneberg, Allan ^{[39
,40
]}

MacFarlane, Peter W. ^{[41
]}

Meitinger, Thomas ^{[19
,42
,43
]}

Nelson, Christopher P. ^{[11
,12
]}

Raitakari, Olli T. ^{[44
,45
]}

Aldana, Claudia T. Silva ^{[46
,47
,48
]}

Sinagra, Gianfranco ^{[36
,37
]}

Sinner, Moritz ^{[18
,19
]}

Soliman, Elsayed Z. ^{[49
]}

Stoll, Monika ^{[50
,51
,52
]}

Uitterlinden, Andre ^{[5
,53
]}

van Duijn, Cornelia M. ^{[46
]}

Waldenberger, Melanie ^{[19
,54
,55
]}

Alonso, Alvaro ^{[56
]}

Gasparini, Paolo ^{[57
,58
]}

Gudnason, Vilmundur ^{[23
,24
]}

Jamshidi, Yalda ^{[21
]}

Kaab, Stefan ^{[18
,19
]}

Kanters, Jorgen K. ^{[59
]}

Lehtimaki, Terho ^{[14
,15
]}

Munroe, Patricia B. ^{[25
,26
]}

机构：

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

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

[3] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Biol Psychol, Amsterdam, Netherlands

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

[6] Leiden Univ, Med Ctr, Sect Gerontol & Geriatr, Dept Internal Med, Leiden, Netherlands

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

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

[9] AREA Sci Pk, Res Unit, Trieste, Italy

[10] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark

[11] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[12] Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Groby Rd, Leicester, Leics, England

[13] Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil

[14] Univ Tampere, Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland

[15] Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere 33520, Finland

[16] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA

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

[18] Ludwig Maximilians Univ Munchen, Dept Med 1, Munich, Germany

[19] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany

[20] Ludwig Maximilians Univ Munchen, Fac Med, IBE, Chair Genet Epidemiol, Munich, Germany

[21] St Georges Univ London, ICCS, Human Genet Res Ctr, London, England

[22] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy

[23] Iceland Heart Assoc, Kopavogur, Iceland

[24] Univ Iceland, Fac Med, Reykavik, Iceland

[25] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[26] Queen Mary Univ London, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Res Ctr, London, England

[27] Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands

[28] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[29] UCL, Farr Inst Hlth Informat Res, London, England

[30] UCL, Inst Hlth Informat, London, England

[31] Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands

[32] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

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

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

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

[36] Ospedali Riuniti, Cardiovasc Dept, Trieste, Italy

[37] Univ Trieste, Trieste, Italy

[38] Erasmus Univ, Med Ctr, Dept Med Informat, Rotterdam, Netherlands

[39] Bispebjerg & Frederiksberg Hosp Capital Reg, Ctr Clin Res & Prevent, Copenhagen, Denmark

[40] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[41] Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland

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

[43] Tech Univ Munich, Inst Human Genet, Munich, Germany

[44] Univ Turku, Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland

[45] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland

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

[47] Univ Rosario, Doctoral Program Biomed Sci, Bogota, Colombia

[48] Univ Rosario, Sch Med & Hlth Sci, GENIUROS Res Grp,CIGGUR, Inst Translat Med,IMT,Ctr Res Genet & Genom, Rosario, Colombia

[49] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27109 USA

[50] Maastricht Univ, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2019年 / 27卷 / 06期

关键词：

QT INTERVAL DURATION; GLUCOCORTICOID-RECEPTOR; COMMON VARIANTS; HEART-RATE; PROTEIN; PHOSPHOLAMBAN; CONTRACTILITY; POLYMORPHISM; ANNOTATION; MUTATIONS;

D O I：

10.1038/s41431-018-0295-z

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：

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

引用

页码：952 / 962

页数：11

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Rice, Kenneth M.
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Fox, Ervin R.
Oostra, Ben A.
Kroemer, Heyo K.
Couper, David
Voelzke, Henry
Campbell, Harry
Meitinger, Thomas
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van Veldhuisen, Dirk J.
Munroe, Patricia B.
Verweij, Niek
van der Harst, Pim
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Menelaou, Andronild
Pulit, Sara L.
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Rivadeneira, Fernando
Estrada, Karol
Medina-Gomez, Carolina
Isaacs, Aaron
McCarroll, Steven A.
Beekrnan, Marian
De Craen, Anton J. M.
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Hinds, David A.
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Belmont, John W.
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Hardenbol, Paul
Leal, Suzanne M.
Pasternak, Shiran
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Willis, Thomas D.
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Onofrio, Robert C.
Parkin, Melissa
Roy, Jessica
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Okazaki, T
Panhuysen, CIM
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Potter, JJ
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Silverberg, MS
Duerr, RH
Cho, JH
Gregersen, PK
Wu, YQ
Achkar, JP
Dassopoulos, T
Mezey, E
Bayless, TM
Nouvet, FJ
Brant, SR
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