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

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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 languageEnglish
Pages (from-to)952-962
Number of pages11
JournalEuropean Journal of Human Genetics
Volume27
Issue number6
DOIs
Publication statusPublished - Jun-2019

Keywords

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

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