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

Summary, in English

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.

• Author: 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; Leif Groop; 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
• Department/s: Translational Muscle Research; EXODIAB: Excellence of Diabetes Research in Sweden
• Publishing year: 2013
• Language: English
• Pages: 621-631
• Publication/Series: Nature Genetics
• Volume: 45
• Issue: 6
• Links: http://dx.doi.org/10.1038/ng.2610
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Translational Muscle Research
• ISBN/ISSN/Other: ISSN: 1546-1718