Genome-wide association analysis identifies multiple loci related to resting heart rate

Mark Eijgelsheim, Christopher Newton-Cheh, Nona Sotoodehnia, Paul I.W. de bakker, Martina Müller, Alanna C. Morrison, Albert V. Smith, Aaron Isaacs, Serena Sanna, Marcus Dörr, Pau Navarro, Christian Fuchsberger, Ilja M. Nolte, Eco J.C. de Geus, Karol Estrada, Shih Jen Hwang, Joshua C. Bis, Ina Maria Rückert, Alvaro Alonso, Lenore J. LaunerJouke Jan Hottenga, Fernando Rivadeneira, Peter A. Noseworthy, Kenneth M. Rice, Siegfried Perz, Dan E. Arking, Tim D. Spector, Jan A. Kors, Yurii S. Aulchenko, Kirill V. Tarasov, Georg Homuth, Sarah H. Wild, Fabio Marroni, Christian Gieger, Carmilla M. Licht, Ronald J. Prineas, Albert Hofman, Jerome I. Rotter, Andrew A. Hicks, Florian Ernst, Samer S. Najjar, Alan F. Wright, Annette Peters, Ervin R. Fox, Ben A. Oostra, Heyo K. Kroemer, David Couper, Henry Völzke, Harry Campbell, Thomas Meitinger, Manuela Uda, Jacqueline C.M. Witteman, Bruce M. Psaty, H. Erich Wichmann, Tamara B. Harris, Stefan Kääb, David S. Siscovick, Yalda Jamshidi, André G. Uitterlinden, Aaron R. Folsom, Martin G. Larson, James F. Wilson, Brenda W. Penninx, Harold Snieder, Peter P. Pramstaller, Cornelia M. van Duijn, Edward G. Lakatta, Stephan B. Felix, Vilmundur Gudnason, Arne Pfeufer, Susan R. Heckbert, Bruno H.Ch Stricker, Eric Boerwinkle, Christopher J. O'Donnell

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Original languageEnglish (US)
Article numberddq303
Pages (from-to)3885-3894
Number of pages10
JournalHuman molecular genetics
Issue number19
StatePublished - Jul 16 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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