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 & 41 others Mark J. Caulfield, Mark Eijgelsheim, Ian Ford, Torben Hansen, Tamara B. Harris, Susan R. Heckbert, Jouke Jan Hottenga, Anita 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

Research output: Contribution to JournalArticleAcademicpeer-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.

LanguageEnglish
Pages952-962
Number of pages11
JournalEuropean Journal of Human Genetics
Volume27
Issue number6
DOIs
Publication statusPublished - Jun 2019

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Quantitative Trait Loci
Genome-Wide Association Study
Single Nucleotide Polymorphism
Meta-Analysis
Genome
Nucleic Acid Regulatory Sequences
Gene Frequency
Netherlands
Exons
Heart Rate
Genotype
Genes

Cite this

van Setten, Jessica ; Verweij, Niek ; Mbarek, Hamdi ; Niemeijer, Maartje N. ; Trompet, Stella ; Arking, Dan E. ; Brody, Jennifer A. ; Gandin, Ilaria ; Grarup, Niels ; Hall, Leanne M. ; Hemerich, Daiane ; Lyytikäinen, Leo Pekka ; Mei, Hao ; Müller-Nurasyid, Martina ; Prins, Bram P. ; Robino, Antonietta ; Smith, Albert V. ; Warren, Helen R. ; Asselbergs, Folkert W. ; Boomsma, Dorret I. ; Caulfield, Mark J. ; Eijgelsheim, Mark ; Ford, Ian ; Hansen, Torben ; Harris, Tamara B. ; Heckbert, Susan R. ; Hottenga, Jouke Jan ; Iorio, Anita ; Kors, Jan A. ; Linneberg, Allan ; MacFarlane, Peter W. ; Meitinger, Thomas ; Nelson, Christopher P. ; Raitakari, Olli T. ; Silva Aldana, Claudia T. ; Sinagra, Gianfranco ; Sinner, Moritz ; Soliman, Elsayed Z. ; Stoll, Monika ; Uitterlinden, Andre ; van Duijn, Cornelia M. ; Waldenberger, Melanie ; Alonso, Alvaro ; Gasparini, Paolo ; Gudnason, Vilmundur ; Jamshidi, Yalda ; Kääb, Stefan ; Kanters, Jørgen K. ; Lehtimäki, Terho ; Munroe, Patricia B. ; Peters, Annette ; Samani, Nilesh J. ; Sotoodehnia, Nona ; Ulivi, Sheila ; Wilson, James G. ; de Geus, Eco J.C. ; Jukema, J. Wouter ; Stricker, Bruno ; van der Harst, Pim ; de Bakker, Paul I.W. ; Isaacs, Aaron. / Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits. In: European Journal of Human Genetics. 2019 ; Vol. 27, No. 6. pp. 952-962.
@article{28706f57bfc4450ab5819338a887dea5,
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 Anita 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",
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month = "6",
doi = "10.1038/s41431-018-0295-z",
language = "English",
volume = "27",
pages = "952--962",
journal = "European Journal of Human Genetics",
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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

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits. / van Setten, Jessica; Verweij, Niek; Mbarek, Hamdi; Niemeijer, Maartje N.; Trompet, Stella; Arking, Dan E.; Brody, Jennifer A.; Gandin, Ilaria; Grarup, Niels; Hall, Leanne M.; Hemerich, Daiane; Lyytikäinen, Leo Pekka; Mei, Hao; Müller-Nurasyid, Martina; Prins, Bram P.; Robino, Antonietta; Smith, Albert V.; Warren, Helen R.; Asselbergs, Folkert W.; Boomsma, Dorret I.; Caulfield, Mark J.; Eijgelsheim, Mark; Ford, Ian; Hansen, Torben; Harris, Tamara B.; Heckbert, Susan R.; Hottenga, Jouke Jan; Iorio, Anita; Kors, Jan A.; Linneberg, Allan; MacFarlane, Peter W.; Meitinger, Thomas; Nelson, Christopher P.; Raitakari, Olli T.; Silva Aldana, Claudia T.; Sinagra, Gianfranco; Sinner, Moritz; Soliman, Elsayed Z.; Stoll, Monika; Uitterlinden, Andre; van Duijn, Cornelia M.; Waldenberger, Melanie; Alonso, Alvaro; Gasparini, Paolo; Gudnason, Vilmundur; Jamshidi, Yalda; Kääb, Stefan; Kanters, Jørgen K.; Lehtimäki, Terho; Munroe, Patricia B.; Peters, Annette; Samani, Nilesh J.; Sotoodehnia, Nona; Ulivi, Sheila; Wilson, James G.; de Geus, Eco J.C.; Jukema, J. Wouter; Stricker, Bruno; van der Harst, Pim; de Bakker, Paul I.W.; Isaacs, Aaron.

In: European Journal of Human Genetics, Vol. 27, No. 6, 06.2019, p. 952-962.

Research output: Contribution to JournalArticleAcademicpeer-review

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, Anita

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

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.

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U2 - 10.1038/s41431-018-0295-z

DO - 10.1038/s41431-018-0295-z

M3 - Article

VL - 27

SP - 952

EP - 962

JO - European Journal of Human Genetics

T2 - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 6

ER -