Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Research output: Contribution to journalArticle

Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

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Authors
  • Marcel den Hoed
  • Mark Eijgelsheim
  • Tonu Esko
  • Bianca J. J. M. Brundel
  • David S. Peal
  • David M. Evans
  • Ilja M. Nolte
  • Ayellet V. Segre
  • Hilma Holm
  • Robert E. Handsaker
  • Harm-Jan Westra
  • Toby Johnson
  • Aaron Isaacs
  • Jian Yang
  • Alicia Lundby
  • Jing Hua Zhao
  • Young Jin Kim
  • Min Jin Go
  • Peter Almgren
  • Murielle Bochud
  • Gabrielle Boucher
  • Marilyn C. Cornelis
  • Daniel Gudbjartsson
  • David Hadley
  • Pim van der Harst
  • Caroline Hayward
  • Martin den Heijer
  • Wilmar Igl
  • Anne U. Jackson
  • Zoltan Kutalik
  • Jian'an Luan
  • John P. Kemp
  • Kati Kristiansson
  • Claes Ladenvall
  • Mattias Lorentzon
  • May E. Montasser
  • Omer T. Njajou
  • Paul F. O'Reilly
  • Sandosh Padmanabhan
  • Beate St. Pourcain
  • Tuomo Rankinen
  • Perttu Salo
  • Toshiko Tanaka
  • Nicholas J. Timpson
  • Veronique Vitart
  • Lindsay Waite
  • William Wheeler
  • Weihua Zhang
  • Harmen H. M. Draisma
  • Mary F. Feitosa
  • Kathleen F. Kerr
  • Penelope A. Lind
  • Evelin Mihailov
  • N. Charlotte Onland-Moret
  • Ci Song
  • Michael N. Weedon
  • Weijia Xie
  • Loic Yengo
  • Devin Absher
  • Christine M. Albert
  • Alvaro Alonso
  • Dan E. Arking
  • Paul I. W. de Bakker
  • Beverley Balkau
  • Cristina Barlassina
  • Paola Benaglio
  • Joshua C. Bis
  • Nabila Bouatia-Naji
  • Soren Brage
  • Stephen J. Chanock
  • Peter S. Chines
  • Mina Chung
  • Dawood Darbar
  • Christian Dina
  • Marcus Doerr
  • Paul Elliott
  • Stephan B. Felix
  • Krista Fischer
  • Christian Fuchsberger
  • Eco J. C. de Geus
  • Philippe Goyette
  • Vilmundur Gudnason
  • Tamara B. Harris
  • Anna-Liisa Hartikainen
  • Aki S. Havulinna
  • Susan R. Heckbert
  • Andrew A. Hicks
  • Albert Hofman
  • Suzanne Holewijn
  • Femke Hoogstra-Berends
  • Jouke-Jan Hottenga
  • Majken K. Jensen
  • Asa Johansson
  • Juhani Junttila
  • Stefan Kaeaeb
  • Bart Kanon
  • Shamika Ketkar
  • Kay-Tee Khaw
  • Joshua W. Knowles
  • Angrad S. Kooner
  • Jan A. Kors
  • Meena Kumari
  • Lili Milani
  • Paeivi Laiho
  • Edward G. Lakatta
  • Claudia Langenberg
  • Maarten Leusink
  • Yongmei Liu
  • Robert N. Luben
  • Kathryn L. Lunetta
  • Stacey N. Lynch
  • Marcello R. P. Markus
  • Pedro Marques-Vidal
  • Irene Mateo Leach
  • Wendy L. McArdle
  • Steven A. McCarroll
  • Sarah E. Medland
  • Kathryn A. Miller
  • Grant W. Montgomery
  • Alanna C. Morrison
  • Martina Mueller-Nurasyid
  • Pau Navarro
  • Mari Nelis
  • Jeffrey R. O'Connell
  • Christopher J. O'Donnell
  • Ken K. Ong
  • Anne B. Newman
  • Annette Peters
  • Ozren Polasek
  • Anneli Pouta
  • Peter P. Pramstaller
  • Bruce M. Psaty
  • Dabeeru C. Rao
  • Susan M. Ring
  • Elizabeth J. Rossin
  • Diana Rudan
  • Serena Sanna
  • Robert A. Scott
  • Jaban S. Sehmi
  • Stephen Sharp
  • Jordan T. Shin
  • Andrew B. Singleton
  • Albert V. Smith
  • Nicole Soranzo
  • Tim D. Spector
  • Chip Stewart
  • Heather M. Stringham
  • Kirill V. Tarasov
  • Andre G. Uitterlinden
  • Liesbeth Vandenput
  • Shih-Jen Hwang
  • John B. Whitfield
  • Cisca Wijmenga
  • Sarah H. Wild
  • Gonneke Willemsen
  • James F. Wilson
  • Jacqueline C. M. Witteman
  • Andrew Wong
  • Quenna Wong
  • Yalda Jamshidi
  • Paavo Zitting
  • Jolanda M. A. Boer
  • Dorret I. Boomsma
  • Ingrid B. Borecki
  • Cornelia M. van Duijn
  • Ulf Ekelund
  • Nita G. Forouhi
  • Philippe Froguel
  • Aroon Hingorani
  • Erik Ingelsson
  • Mika Kivimaki
  • Richard A. Kronmal
  • Diana Kuh
  • Lars Lind
  • Nicholas G. Martin
  • Ben A. Oostra
  • Nancy L. Pedersen
  • Thomas Quertermous
  • Jerome I. Rotter
  • Yvonne T. van der Schouw
  • W. M. Monique Verschuren
  • Mark Walker
  • Demetrius Albanes
  • David O. Arnar
  • Themistocles L. Assimes
  • Stefania Bandinelli
  • Michael Boehnke
  • Rudolf A. de Boer
  • Claude Bouchard
  • W. L. Mark Caulfield
  • John C. Chambers
  • Gary Curhan
  • Daniele Cusi
  • Johan Eriksson
  • Luigi Ferrucci
  • Wiek H. van Gilst
  • Nicola Glorioso
  • Jacqueline de Graaf
  • Ulf Gyllensten
  • Wen-Chi Hsueh
  • Frank B. Hu
  • Heikki V. Huikuri
  • David J. Hunter
  • Carlos Iribarren
  • Bo Isomaa
  • Marjo-Riitta Jarvelin
  • Antti Jula
  • Mika Kahonen
  • Lambertus A. Kiemeney
  • Melanie M. van der Klauw
  • Jaspal S. Kooner
  • Peter Kraft
  • Licia Iacoviello
  • Terho Lehtimaki
  • Marja-Liisa L. Lokki
  • Braxton D. Mitchell
  • Gerjan Navis
  • Markku S. Nieminen
  • Claes Ohlsson
  • Neil R. Poulter
  • Lu Qi
  • Olli T. Raitakari
  • Eric B. Rimm
  • John D. Rioux
  • Federica Rizzi
  • Igor Rudan
  • Veikko Salomaa
  • Peter S. Sever
  • Denis C. Shields
  • Alan R. Shuldiner
  • Juha Sinisalo
  • Alice V. Stanton
  • Ronald P. Stolk
  • David P. Strachan
  • Jean-Claude Tardif
  • Unnur Thorsteinsdottir
  • Jaako Tuomilehto
  • Dirk J. van Veldhuisen
  • Jarmo Virtamo
  • Jorma Viikari
  • Peter Vollenweider
  • Gerard Waeber
  • Elisabeth Widen
  • Yoon Shin Cho
  • Jesper V. Olsen
  • Peter M. Visscher
  • Cristen Willer
  • Lude Franke
  • Jeanette Erdmann
  • John R. Thompson
  • Arne Pfeufer
  • Nona Sotoodehnia
  • Christopher Newton-Cheh
  • Patrick T. Ellinor
  • Bruno H. Ch Stricker
  • Andres Metspalu
  • Markus Perola
  • Jacques S. Beckmann
  • George Davey Smith
  • Kari Stefansson
  • Nicholas J. Wareham
  • Patricia B. Munroe
  • Ody C. M. Sibon
  • David J. Milan
  • Harold Snieder
  • Nilesh J. Samani
  • Ruth J. F. Loos
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)621-631
JournalNature Genetics
Volume45
Issue number6
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes