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

Authors:
Dr Zoltán Kutalik, PhD
Dr Zoltán Kutalik, PhD
Institute of Social and Preventive Medicine, CHUV
Assistant Professor
Biostatistics
Lausanne, Vaud | Switzerland
Marcel den Hoed Mark Eijgelsheim Tõnu Esko Bianca J J M Brundel David S Peal David M Evans Ilja M Nolte Ayellet V Segrè 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 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 Søren Brage Stephen J Chanock Peter S Chines Mina Chung Dawood Darbar Christian Dina Marcus Dörr 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 Kääb Bart Kanon Shamika Ketkar Kay-Tee Khaw Joshua W Knowles Angrad S Kooner Jan A Kors Meena Kumari Lili Milani Päivi 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 Müller-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 André 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 Kähönen Lambertus A Kiemeney Melanie M van der Klauw Jaspal S Kooner Peter Kraft Licia Iacoviello Terho Lehtimäki 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 Gérard 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

Nat Genet 2013 Jun 14;45(6):621-31. Epub 2013 Apr 14.

Medical Research Council MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

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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