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

Jessica van Setten; Niek Verweij; Hamdi Mbarek; Maartje N. Niemeijer; Stella Trompet; Dan E. Arking; Jennifer A. Brody; Ilaria Gandin; Niels Grarup; Leanne M. Hall; Daiane Hemerich; Leo Pekka Lyytikäinen; Hao Mei; Martina Müller-Nurasyid; Bram P. Prins; Antonietta Robino; Albert V. Smith; Helen R. Warren; Folkert W. Asselbergs; Dorret I. Boomsma; Mark J. Caulfield; Mark Eijgelsheim; Ian Ford; Torben Hansen; Tamara B. Harris; Susan R. Heckbert; Jouke Jan Hottenga; Annamaria Iorio; Jan A. Kors; Allan Linneberg; Peter W. MacFarlane; Thomas Meitinger; Christopher P. Nelson; Olli T. Raitakari; Claudia T. Silva Aldana; Gianfranco Sinagra; Moritz Sinner; Elsayed Z. Soliman; Monika Stoll; Andre Uitterlinden; Cornelia M. van Duijn; Melanie Waldenberger; Alvaro Alonso; Paolo Gasparini; Vilmundur Gudnason; Yalda Jamshidi; Stefan Kääb; Jørgen K. Kanters; Terho Lehtimäki; Patricia B. Munroe; Annette Peters; Nilesh J. Samani; Nona Sotoodehnia; Sheila Ulivi; James G. Wilson; Eco J.C. de Geus; J. Wouter Jukema; Bruno Stricker; Pim van der Harst; Paul I.W. de Bakker; Aaron Isaacs

doi:10.1038/s41431-018-0295-z

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

Jessica van Setten^*
, Niek Verweij
, Hamdi Mbarek
, Maartje N. Niemeijer
, Stella Trompet
, Dan E. Arking
, Jennifer A. Brody
, Ilaria Gandin
, Niels Grarup
, Leanne M. Hall
, Daiane Hemerich
, Leo Pekka Lyytikäinen
, Hao Mei
, Martina Müller-Nurasyid
, Bram P. Prins
, Antonietta Robino
, Albert V. Smith
, Helen R. Warren
, Folkert W. Asselbergs
, Dorret I. Boomsma

Mark J. Caulfield, Mark Eijgelsheim, Ian Ford, Torben Hansen, Tamara B. Harris, Susan R. Heckbert, Jouke Jan Hottenga, Annamaria Iorio, Jan A. Kors, Allan Linneberg, Peter W. MacFarlane, Thomas Meitinger, Christopher P. Nelson, Olli T. Raitakari, Claudia T. Silva Aldana, Gianfranco Sinagra, Moritz Sinner, Elsayed Z. Soliman, Monika Stoll, Andre Uitterlinden, Cornelia M. van Duijn, Melanie Waldenberger, Alvaro Alonso, Paolo Gasparini, Vilmundur Gudnason, Yalda Jamshidi, Stefan Kääb, Jørgen K. Kanters, Terho Lehtimäki, Patricia B. Munroe, Annette Peters, Nilesh J. Samani, Nona Sotoodehnia, Sheila Ulivi, James G. Wilson, Eco J.C. de Geus, J. Wouter Jukema, Bruno Stricker, Pim van der Harst, Paul I.W. de Bakker, Aaron Isaacs

^*Corresponding author for this work

Department of Cardiology
Utrecht University
Department of Cardiology
University of Groningen
Program in Medical and Population Genetics
Broad Institute
Department of Biological Psychology
University of Amsterdam
Department of Epidemiology
Erasmus University Rotterdam
Department of Internal Medicine
Leiden University
Johns Hopkins University
Cardiovascular Health Research Unit
University of Washington
Research Unit
University of Copenhagen
Department of Cardiovascular Sciences
University of Leicester
University Hospitals of Leicester NHS Trust
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Department of Clinical Chemistry
Tampere University
Center of Biostatistics and Bioinformatics
University of Mississippi
Institute of Genetic Epidemiology
Helmholtz Zentrum München - German Research Center for Environmental Health
Department of Medicine I
Ludwig Maximilian University of Munich
German Centre for Cardiovascular Research
Institute of Medical Informatics, Biometry and Epidemiology
Human Genetics Research Centre
St. George's University of London
Institute for Maternal and Child Health
IRCCS Ospedale Infantile Burlo Garofolo - Trieste
Icelandic Heart Association
University of Iceland
Queen Mary University of London
NIHR Barts Cardiovascular Biomedical Research Unit
Durrer Center for Cardiovascular Research
Interuniversity Cardiology Institute of the Netherlands
Institute of Cardiovascular Science
University College London
Department of Nephrology
University of Glasgow
Laboratory of Epidemiology
National Institutes of Health
Cardiovascular Department
University of Trieste
Department of Medical Informatics
Center for Clinical Research and Prevention
Department of Clinical Medicine
Institute of Health and Wellbeing
Institute of Human Genetics
Technical University of Munich
Department of Clinical Physiology and Nuclear Medicine
University of Turku
Doctoral Program in Biomedical Sciences
Universidad del Rosario
GENIUROS Group
Department of Epidemiology and Prevention
Wake Forest University
Maastricht University
Maastricht Centre for Systems Biology (MaCSBio)
Department of Biochemistry
Department of Internal Medicine
Research Unit Molecular Epidemiology
Institute of Epidemiology II
Department of Epidemiology
Emory University
Laboratory of Experimental Cardiology
German Center for Diabetes Research
Cardiovascular Health Research Unit
Department of Cardiology
Department of Genetics
Durrer Center for Cardiogenetic Research
Department of Genetics
Department of Epidemiology
Institute of Human Genetics

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	952-962
Number of pages	11
Journal	European Journal of Human Genetics
Volume	27
Issue number	6
DOIs	https://doi.org/10.1038/s41431-018-0295-z
Publication status	Published - 1 Jun 2019
Externally published	Yes

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van Setten, J., Verweij, N., Mbarek, H., Niemeijer, M. N., Trompet, S., Arking, D. E., Brody, J. A., Gandin, I., Grarup, N., Hall, L. M., Hemerich, D., Lyytikäinen, L. P., Mei, H., Müller-Nurasyid, M., Prins, B. P., Robino, A., Smith, A. V., Warren, H. R., Asselbergs, F. W., ... Isaacs, A. (2019). Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits. European Journal of Human Genetics, 27(6), 952-962. https://doi.org/10.1038/s41431-018-0295-z

@article{050566c99a0842749a087a43d81fe3bf,

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

abstract = "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.",

author = "\{van Setten\}, Jessica and Niek Verweij and Hamdi Mbarek and Niemeijer, \{Maartje N.\} and Stella Trompet and Arking, \{Dan E.\} and Brody, \{Jennifer A.\} and Ilaria Gandin and Niels Grarup and Hall, \{Leanne M.\} and Daiane Hemerich and Lyytik{\"a}inen, \{Leo Pekka\} and Hao Mei and Martina M{\"u}ller-Nurasyid and Prins, \{Bram P.\} and Antonietta Robino and Smith, \{Albert V.\} and Warren, \{Helen R.\} and Asselbergs, \{Folkert W.\} and Boomsma, \{Dorret I.\} and Caulfield, \{Mark J.\} and Mark Eijgelsheim and Ian Ford and Torben Hansen and Harris, \{Tamara B.\} and Heckbert, \{Susan R.\} and Hottenga, \{Jouke Jan\} and Annamaria Iorio and Kors, \{Jan A.\} and Allan Linneberg and MacFarlane, \{Peter W.\} and Thomas Meitinger and Nelson, \{Christopher P.\} and Raitakari, \{Olli T.\} and \{Silva Aldana\}, \{Claudia T.\} and Gianfranco Sinagra and Moritz Sinner and Soliman, \{Elsayed Z.\} and Monika Stoll and Andre Uitterlinden and \{van Duijn\}, \{Cornelia M.\} and Melanie Waldenberger and Alvaro Alonso and Paolo Gasparini and Vilmundur Gudnason and Yalda Jamshidi and Stefan K{\"a}{\"a}b and Kanters, \{J{\o}rgen K.\} and Terho Lehtim{\"a}ki and Munroe, \{Patricia B.\} and Annette Peters and Samani, \{Nilesh J.\} and Nona Sotoodehnia and Sheila Ulivi and Wilson, \{James G.\} and \{de Geus\}, \{Eco J.C.\} and Jukema, \{J. Wouter\} and Bruno Stricker and \{van der Harst\}, Pim and \{de Bakker\}, \{Paul I.W.\} and Aaron Isaacs",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = jun,

day = "1",

doi = "10.1038/s41431-018-0295-z",

language = "English",

volume = "27",

pages = "952--962",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "6",

}

van Setten, J, Verweij, N, Mbarek, H, Niemeijer, MN, Trompet, S, Arking, DE, Brody, JA, Gandin, I, Grarup, N, Hall, LM, Hemerich, D, Lyytikäinen, LP, Mei, H, Müller-Nurasyid, M, Prins, BP, Robino, A, Smith, AV, Warren, HR, Asselbergs, FW, Boomsma, DI, Caulfield, MJ, Eijgelsheim, M, Ford, I, Hansen, T, Harris, TB, Heckbert, SR, Hottenga, JJ, Iorio, A, Kors, JA, Linneberg, A, MacFarlane, PW, Meitinger, T, Nelson, CP, Raitakari, OT, Silva Aldana, CT, Sinagra, G, Sinner, M, Soliman, EZ, Stoll, M, Uitterlinden, A, van Duijn, CM, Waldenberger, M, Alonso, A, Gasparini, P, Gudnason, V, Jamshidi, Y, Kääb, S, Kanters, JK, Lehtimäki, T, Munroe, PB, Peters, A, Samani, NJ, Sotoodehnia, N, Ulivi, S, Wilson, JG, de Geus, EJC, Jukema, JW, Stricker, B, van der Harst, P, de Bakker, PIW & Isaacs, A 2019, 'Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits', European Journal of Human Genetics, vol. 27, no. 6, pp. 952-962. https://doi.org/10.1038/s41431-018-0295-z

TY - JOUR

T1 - Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

AU - van Setten, Jessica

AU - Verweij, Niek

AU - Mbarek, Hamdi

AU - Niemeijer, Maartje N.

AU - Trompet, Stella

AU - Arking, Dan E.

AU - Brody, Jennifer A.

AU - Gandin, Ilaria

AU - Grarup, Niels

AU - Hall, Leanne M.

AU - Hemerich, Daiane

AU - Lyytikäinen, Leo Pekka

AU - Mei, Hao

AU - Müller-Nurasyid, Martina

AU - Prins, Bram P.

AU - Robino, Antonietta

AU - Smith, Albert V.

AU - Warren, Helen R.

AU - Asselbergs, Folkert W.

AU - Boomsma, Dorret I.

AU - Caulfield, Mark J.

AU - Eijgelsheim, Mark

AU - Ford, Ian

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Heckbert, Susan R.

AU - Hottenga, Jouke Jan

AU - Iorio, Annamaria

AU - Kors, Jan A.

AU - Linneberg, Allan

AU - MacFarlane, Peter W.

AU - Meitinger, Thomas

AU - Nelson, Christopher P.

AU - Raitakari, Olli T.

AU - Silva Aldana, Claudia T.

AU - Sinagra, Gianfranco

AU - Sinner, Moritz

AU - Soliman, Elsayed Z.

AU - Stoll, Monika

AU - Uitterlinden, Andre

AU - van Duijn, Cornelia M.

AU - Waldenberger, Melanie

AU - Alonso, Alvaro

AU - Gasparini, Paolo

AU - Gudnason, Vilmundur

AU - Jamshidi, Yalda

AU - Kääb, Stefan

AU - Kanters, Jørgen K.

AU - Lehtimäki, Terho

AU - Munroe, Patricia B.

AU - Peters, Annette

AU - Samani, Nilesh J.

AU - Sotoodehnia, Nona

AU - Ulivi, Sheila

AU - Wilson, James G.

AU - de Geus, Eco J.C.

AU - Jukema, J. Wouter

AU - Stricker, Bruno

AU - van der Harst, Pim

AU - de Bakker, Paul I.W.

AU - Isaacs, Aaron

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85060589966

U2 - 10.1038/s41431-018-0295-z

DO - 10.1038/s41431-018-0295-z

M3 - Article

C2 - 30679814

AN - SCOPUS:85060589966

SN - 1018-4813

VL - 27

SP - 952

EP - 962

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 6

ER -

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

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