Discovery of novel heart rate-associated loci using the Exome Chip

Marten E van den Berg, Helen R Warren, Claudia P Cabrera, Niek Verweij, Borbala Mifsud, Jeffrey Haessler, Nathan A Bihlmeyer, Yi-Ping Fu, Stefan Weiss, Henry J Lin, Niels Grarup, Ruifang Li-Gao, Giorgio Pistis, Nabi Shah, Jennifer A Brody, Martina Müller-Nurasyid, Honghuang Lin, Hao Mei, Albert V Smith, Leo-Pekka LyytikäinenLeanne M Hall, Jessica van Setten, Stella Trompet, Bram P Prins, Aaron Isaacs, Farid Radmanesh, Jonathan Marten, Aiman Entwistle, Jan A Kors, Claudia T Silva, Alvaro Alonso, Joshua C Bis, Rudolf de Boer, Hugoline G de Haan, Renée de Mutsert, George Dedoussis, Anna F Dominiczak, Alex S F Doney, Patrick T Ellinor, Ruben N Eppinga, Stephan B Felix, Xiuqing Guo, Yanick Hagemeijer, Torben Hansen, Tamara B Harris, Susan R Heckbert, Paul L Huang, Shih-Jen Hwang, Mika Kähönen, Jørgen K Kanters, Ivana Kolcic, Lenore J Launer, Man Li, Jie Yao, Allan Linneberg, Simin Liu, Peter W Macfarlane, Massimo Mangino, Andrew D Morris, Antonella Mulas, Alison D Murray, Christopher P Nelson, Marco Orrú, Sandosh Padmanabhan, Annette Peters, David J Porteous, Neil Poulter, Bruce M Psaty, Lihong Qi, Olli T Raitakari, Fernando Rivadeneira, Carolina Roselli, Igor Rudan, Naveed Sattar, Peter Sever, Moritz F Sinner, Elsayed Z Soliman, Timothy D Spector, Alice V Stanton, Kathleen E Stirrups, Kent D Taylor, Martin D Tobin, André Uitterlinden, Ilonca Vaartjes, Arno W Hoes, Peter van der Meer, Uwe Völker, Melanie Waldenberger, Zhijun Xie, Magdalena Zoledziewska, Andrew Tinker, Ozren Polasek, Jonathan Rosand, Yalda Jamshidi, Cornelia M van Duijn, Eleftheria Zeggini, J Wouter Jukema, Folkert W Asselbergs, Nilesh J Samani, Terho Lehtimäki, Vilmundur Gudnason, James Wilson, Steven A Lubitz, Stefan Kääb, Nona Sotoodehnia, Mark J Caulfield, Colin N A Palmer, Serena Sanna, Dennis O Mook-Kanamori, Panos Deloukas, Oluf Pedersen, Jerome I Rotter, Marcus Dörr, Chris J O'Donnell, Caroline Hayward, Dan E Arking, Charles Kooperberg, Pim van der Harst, Mark Eijgelsheim, Bruno H Stricker, Patricia B Munroe

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Abstract

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Original languageEnglish
Pages (from-to)2346-2363
Number of pages18
JournalHuman Molecular Genetics
Volume26
Issue number12
Early online date3 Apr 2017
DOIs
Publication statusPublished - 15 Jun 2017

Keywords

  • Journal Article
  • heart rate
  • lung
  • chromatin
  • follow-up
  • genes
  • genetics
  • heart
  • candidate disease gene
  • genome-wide association study
  • exome
  • biobanks
  • datasets

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    van den Berg, M. E., Warren, H. R., Cabrera, C. P., Verweij, N., Mifsud, B., Haessler, J., Bihlmeyer, N. A., Fu, Y-P., Weiss, S., Lin, H. J., Grarup, N., Li-Gao, R., Pistis, G., Shah, N., Brody, J. A., Müller-Nurasyid, M., Lin, H., Mei, H., Smith, A. V., ... Munroe, P. B. (2017). Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics, 26(12), 2346-2363. https://doi.org/10.1093/hmg/ddx113