Model Organisms Genetics and Genomics

scientificprotocols authored over 3 years ago

Authors: Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, David S Peal, Ayellet V Segrè,  Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Jian Yang, Alicia Lundby, Peter M Visscher, Cristen Willer, Lude Franke, Ody CM Sibon, David J Milan, Harold Snieder, Nilesh J Samani & Ruth JF Loos

Abstract

Elevated resting heart rate is associated with increased risk of cardiovascular disease and mortality. In a two-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 seven previously established loci. Experimental down-regulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes from 11 loci as 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 decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into mechanisms regulating heart rate and identify novel targets that may be modifiable for therapeutic benefit.

Introduction

We designed a multistage study comprising a meta-analysis of genome wide association studies (GWAS) (stage 1) with data from up to 92,355 individuals from 36 studies and selected lead SNPs from 42 loci – the 12 loci that reached genome wide significance (p<5×10e−8) after stage 1 and 30 additional loci with the lowest p-values for association that did not reach genome wide significance (p<3×10e−5) - for follow up in stage 2 (Supplementary Figure 1). Stage 2 comprised data from up to 88,823 additional individuals from 37 studies. Meta-analysis of summary statistics from stage 1 and stage 2 identified variants in 21 loci that reached genome wide significance. For these loci we subsequently performed additional association analyses to examine their relevance for cardiovacular intermediates and disease, as well as functional follow-up experiments in animal models to identify potentially causal genes.

Figures

Figure 1: Study design

Download Figure 1

Online Protocols: Online Protocols

Download Online Protocols

All (Supplementary) Figures and Tables that we refer to in the Online Protocols can be found in the original article and accompanying Supplementary Information.

Associated Publications

Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders. 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, Zoltán 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, 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, Åsa 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 M[vuml]ller-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, and Ruth J F Loos. Nature Genetics doi:10.1038/ng.2610

Author information

Marcel den Hoed, HRGen consortium and Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Mark Eijgelsheim, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands

Tonu Esko, Estonian Genome Center, University of Tartu, Tartu, Estonia

David S Peal & David J Milan, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

Ayellet V Segrè & Robert E Handsaker, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

Harm-Jan Westra & Lude Franke, University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands

Toby Johnson, Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Jian Yang, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

Alicia Lundby, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Peter M Visscher, Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

Cristen Willer, University of Michigan, Department of Internal Medicine, Ann Arbor, MI, USA

Ody CM Sibon, University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, The Netherlands

Harold Snieder, University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands

Nilesh J Samani, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK

Ruth JF Loos, The Genetics of Obesity and Related Metabolic Traits Program, The Ichan School of Medicine at Mount Sinai, New York, NY, USA

Correspondence to: Ruth JF Loos ([email protected])

Source: Protocol Exchange (2013) doi:10.1038/protex.2013.041. Originally published online 15 April 2013

Average rating 0 ratings