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 Lyytikainen; Hao Mei; Martina Mueller-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 Kaab; Jorgen K. Kanters; Terho Lehtimaki; 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 Lyytikainen, Hao Mei, Martina Mueller-Nurasyid, Bram P. Prins, Antonietta Robino, Albert V. Smith, Helen R. Warren, Folkert W. Asselbergs, Dorret I. BoomsmaMark 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 Kaab, Jorgen K. Kanters, Terho Lehtimaki, 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

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

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 - Jun 2019

Keywords

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

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Cite this

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., Lyytikainen, L.-P., Mei, H., Mueller-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{76d47cee507e4e47a7354fc975143ab3,

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.",

keywords = "QT INTERVAL DURATION, GLUCOCORTICOID-RECEPTOR, COMMON VARIANTS, HEART-RATE, PROTEIN, PHOSPHOLAMBAN, CONTRACTILITY, POLYMORPHISM, ANNOTATION, MUTATIONS",

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 Leo-Pekka Lyytikainen and Hao Mei and Martina Mueller-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 Jouke-Jan Hottenga 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 Aldana, {Claudia T. Silva} 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 Kaab and Kanters, {Jorgen K.} and Terho Lehtimaki 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 = "Funding Information: Funding Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Funding Information: CAPES Foundation, Ministry of Education of Brazil, Bras{\'i}lia, DF 70040-020, Brazil Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = jun,

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

language = "English",

volume = "27",

pages = "952--962",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

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, Lyytikainen, L-P, Mei, H, Mueller-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, J-J, Iorio, A, Kors, JA, Linneberg, A, MacFarlane, PW, Meitinger, T, Nelson, CP, Raitakari, OT, Aldana, CTS, Sinagra, G, Sinner, M, Soliman, EZ, Stoll, M, Uitterlinden, A, van Duijn, CM, Waldenberger, M, Alonso, A, Gasparini, P, Gudnason, V, Jamshidi, Y, Kaab, S, Kanters, JK, Lehtimaki, 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 - Lyytikainen, Leo-Pekka

AU - Mei, Hao

AU - Mueller-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 - Aldana, Claudia T. Silva

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 - Kaab, Stefan

AU - Kanters, Jorgen K.

AU - Lehtimaki, 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

N1 - Funding Information: Funding Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Funding Information: CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil Publisher Copyright: © 2019, The Author(s).

PY - 2019/6

Y1 - 2019/6

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.

KW - QT INTERVAL DURATION

KW - GLUCOCORTICOID-RECEPTOR

KW - COMMON VARIANTS

KW - HEART-RATE

KW - PROTEIN

KW - PHOSPHOLAMBAN

KW - CONTRACTILITY

KW - POLYMORPHISM

KW - ANNOTATION

KW - MUTATIONS

U2 - 10.1038/s41431-018-0295-z

DO - 10.1038/s41431-018-0295-z

M3 - Article

C2 - 30679814

SN - 1018-4813

VL - 27

SP - 952

EP - 962

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 6

ER -