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.
| Original language | English |
|---|---|
| Pages (from-to) | 621-631 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 45 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2013 |
ASJC Scopus subject areas
- Genetics
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. / Den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S.; Evans, David M.; Nolte, Ilja M.; Segrè, Ayellet V.; Holm, Hilma; Handsaker, Robert E.; Westra, Harm Jan; Johnson, Toby; Isaacs, Aaron; Yang, Jian; Lundby, Alicia; Zhao, Jing Hua; Kim, Young Jin; Go, Min Jin; Almgren, Peter; Bochud, Murielle; Boucher, Gabrielle; Cornalis, Marilyn C.; Gudbjartsson, Daniel; Hadley, David; Van Der Harst, Pim; Hayward, Caroline; Den Heijer, Martin; Igl, Wilmar; Jackson, Anne U.; Kutalik, Zoltán; Luan, Jian'An; Kemp, John P.; Kristiansson, Kati; Ladenvall, Claes; Lorentzon, Mattias; Montasser, May E.; Njajou, Omer T.; O'Reilly, Paul F.; Padmanabhan, Sandosh; St. Pourcain, Beate; Rankinen, Tuomo; Salo, Perttu; Tanaka, Toshiko; Timpson, Nicholas J.; Vitart, Veronique; Waite, Lindsay; Wheeler, William; Zhang, Weihua; Draisma, Harmen H M; Feitosa, Mary F.; Kerr, Kathleen F.; Lind, Penelope A.; Mihailov, Evelin; Onland-Moret, N. Charlotte; Song, Ci; Weedon, Michael N.; Xie, Weijia; Yengo, Loic; Absher, Devin; Albert, Christine M.; Alonso, Alvaro; Arking, Dan E.; De Bakker, Paul I W; Balkau, Beverley; Barlassina, Cristina; Benaglio, Paola; Bis, Joshua C.; Bouatia-Naji, Nabila; Brage, Søren; Chanock, Stephen J.; Chines, Peter S.; Chung, Mina; Darbar, Dawood; Dina, Christian; Dörr, Marcus; Elliott, Paul; Felix, Stephan B.; Fischer, Krista; Fuchsberger, Christian; De Geus, Eco J C; Goyette, Philippe; Gudnason, Vilmundur; Harris, Tamara B.; Hartikainen, Anna Liisa; Havulinna, Aki S.; Heckbert, Susan R.; Hicks, Andrew A.; Hofman, Albert; Holewijn, Suzanne; Hoogstra-Berends, Femke; Hottenga, Jouke Jan; Jensen, Majken K.; Johansson, Åsa; Junttila, Juhani; Kääb, Stefan; Kanon, Bart; Ketkar, Shamika; Khaw, Kay Tee; Knowles, Joshua W.; Kooner, Angrad S.; Kors, Jan A.; Kumari, Meena; Milani, Lili; Laiho, Päivi; Lakatta, Edward G.; Langenberg, Claudia; Leusink, Maarten; Liu, Yongmei; Luben, Robert N.; Lunetta, Kathryn L.; Lynch, Stacey N.; Markus, Marcello R P; Marques-Vidal, Pedro; Leach, Irene Mateo; McArdle, Wendy L.; McCarroll, Steven A.; Medland, Sarah E.; Miller, Kathryn A.; Montgomery, Grant W.; Morrison, Alanna C.; Müller-Nurasyid, Martina; Navarro, Pau; Nelis, Mari; O'Connell, Jeffrey R.; O'Donnell, Christopher J.; Ong, Ken K.; Newman, Anne B.; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Psaty, Bruce M.; Rao, Dabeeru C.; Ring, Susan M.; Rossin, Elizabeth J.; Rudan, Diana; Sanna, Serena; Scott, Robert A.; Sehmi, Jaban S.; Sharp, Stephen; Shin, Jordan T.; Singleton, Andrew B.; Smith, Albert V.; Soranzo, Nicole; Spector, Tim D.; Stewart, Chip; Stringham, Heather M.; Tarasov, Kirill V.; Uitterlinden, André G.; Vandenput, Liesbeth; Hwang, Shih Jen; Whitfield, John B.; Wijmenga, Cisca; Wild, Sarah H.; Willemsen, Gonneke; Wilson, James F.; Witteman, Jacqueline C M; Wong, Andrew; Wong, Quenna; Jamshidi, Yalda; Zitting, Paavo; Boer, Jolanda M A; Boomsma, Dorret I.; Borecki, Ingrid B.; Van Duijn, Cornelia M.; Ekelund, Ulf; Forouhi, Nita G.; Froguel, Philippe; Hingorani, Aroon; Ingelsson, Erik; Kivimaki, Mika; Kronmal, Richard A.; Kuh, Diana; Lind, Lars; Martin, Nicholas G.; Oostra, Ben A.; Pedersen, Nancy L.; Quertermous, Thomas; Rotter, Jerome I.; Van Der Schouw, Yvonne T.; Verschuren, W. M Monique; Walker, Mark; Albanes, Demetrius; Arnar, David O.; Assimes, Themistocles L.; Bandinelli, Stefania; Boehnke, Michael; De Boer, Rudolf A.; Bouchard, Claude; W L Mark Caulfield, L Mark Caulfield; Chambers, John C.; Curhan, Gary; Cusi, Daniele; Eriksson, Johan; Ferrucci, Luigi; Van Gilst, Wiek H.; Glorioso, Nicola; De Graaf, Jacqueline; Groop, Leif; Gyllensten, Ulf; Hsueh, Wen Chi; Hu, Frank B.; Huikuri, Heikki V.; Hunter, David J.; Iribarren, Carlos; Isomaa, Bo; Jarvelin, Marjo Riitta; Jula, Antti; Kähönen, Mika; Kiemeney, Lambertus A.; Van Der Klauw, Melanie M.; Kooner, Jaspal S.; Kraft, Peter; Iacoviello, Licia; Lehtimäki, Terho; Lokki, Marja Liisa L; Mitchell, Braxton D.; Navis, Gerjan; Nieminen, Markku S.; Ohlsson, Claes; Poulter, Neil R.; Qi, Lu; Raitakari, Olli T.; Rimm, Eric B.; Rioux, John D.; Rizzi, Federica; Rudan, Igor; Salomaa, Veikko; Sever, Peter S.; Shields, Denis C.; Shuldiner, Alan R.; Sinisalo, Juha; Stanton, Alice V.; Stolk, Ronald P.; Strachan, David P.; Tardif, Jean Claude; Thorsteinsdottir, Unnur; Tuomilehto, Jaako; Van Veldhuisen, Dirk J.; Virtamo, Jarmo; Viikari, Jorma; Vollenweider, Peter; Waeber, Gérard; Widen, Elisabeth; Cho, Yoon Shin; Olsen, Jesper V.; Visscher, Peter M.; Willer, Cristen; Franke, Lude; Erdmann, Jeanette; Thompson, John R.; Pfeufer, Arne; Sotoodehnia, Nona; Newton-Cheh, Christopher; Ellinor, Patrick T.; Stricker, Bruno H Ch; Metspalu, Andres; Perola, Markus; Beckmann, Jacques S.; Smith, George Davey; Stefansson, Kari; Wareham, Nicholas J.; Munroe, Patricia B.; Sibon, Ody C M; Milan, David J.; Snieder, Harold; Samani, Nilesh J.; Loos, Ruth J F.
In: Nature Genetics, Vol. 45, No. 6, 06.2013, p. 621-631.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
AU - Den Hoed, Marcel
AU - Eijgelsheim, Mark
AU - Esko, Tõnu
AU - Brundel, Bianca J J M
AU - Peal, David S.
AU - Evans, David M.
AU - Nolte, Ilja M.
AU - Segrè, Ayellet V.
AU - Holm, Hilma
AU - Handsaker, Robert E.
AU - Westra, Harm Jan
AU - Johnson, Toby
AU - Isaacs, Aaron
AU - Yang, Jian
AU - Lundby, Alicia
AU - Zhao, Jing Hua
AU - Kim, Young Jin
AU - Go, Min Jin
AU - Almgren, Peter
AU - Bochud, Murielle
AU - Boucher, Gabrielle
AU - Cornalis, Marilyn C.
AU - Gudbjartsson, Daniel
AU - Hadley, David
AU - Van Der Harst, Pim
AU - Hayward, Caroline
AU - Den Heijer, Martin
AU - Igl, Wilmar
AU - Jackson, Anne U.
AU - Kutalik, Zoltán
AU - Luan, Jian'An
AU - Kemp, John P.
AU - Kristiansson, Kati
AU - Ladenvall, Claes
AU - Lorentzon, Mattias
AU - Montasser, May E.
AU - Njajou, Omer T.
AU - O'Reilly, Paul F.
AU - Padmanabhan, Sandosh
AU - St. Pourcain, Beate
AU - Rankinen, Tuomo
AU - Salo, Perttu
AU - Tanaka, Toshiko
AU - Timpson, Nicholas J.
AU - Vitart, Veronique
AU - Waite, Lindsay
AU - Wheeler, William
AU - Zhang, Weihua
AU - Draisma, Harmen H M
AU - Feitosa, Mary F.
AU - Kerr, Kathleen F.
AU - Lind, Penelope A.
AU - Mihailov, Evelin
AU - Onland-Moret, N. Charlotte
AU - Song, Ci
AU - Weedon, Michael N.
AU - Xie, Weijia
AU - Yengo, Loic
AU - Absher, Devin
AU - Albert, Christine M.
AU - Alonso, Alvaro
AU - Arking, Dan E.
AU - De Bakker, Paul I W
AU - Balkau, Beverley
AU - Barlassina, Cristina
AU - Benaglio, Paola
AU - Bis, Joshua C.
AU - Bouatia-Naji, Nabila
AU - Brage, Søren
AU - Chanock, Stephen J.
AU - Chines, Peter S.
AU - Chung, Mina
AU - Darbar, Dawood
AU - Dina, Christian
AU - Dörr, Marcus
AU - Elliott, Paul
AU - Felix, Stephan B.
AU - Fischer, Krista
AU - Fuchsberger, Christian
AU - De Geus, Eco J C
AU - Goyette, Philippe
AU - Gudnason, Vilmundur
AU - Harris, Tamara B.
AU - Hartikainen, Anna Liisa
AU - Havulinna, Aki S.
AU - Heckbert, Susan R.
AU - Hicks, Andrew A.
AU - Hofman, Albert
AU - Holewijn, Suzanne
AU - Hoogstra-Berends, Femke
AU - Hottenga, Jouke Jan
AU - Jensen, Majken K.
AU - Johansson, Åsa
AU - Junttila, Juhani
AU - Kääb, Stefan
AU - Kanon, Bart
AU - Ketkar, Shamika
AU - Khaw, Kay Tee
AU - Knowles, Joshua W.
AU - Kooner, Angrad S.
AU - Kors, Jan A.
AU - Kumari, Meena
AU - Milani, Lili
AU - Laiho, Päivi
AU - Lakatta, Edward G.
AU - Langenberg, Claudia
AU - Leusink, Maarten
AU - Liu, Yongmei
AU - Luben, Robert N.
AU - Lunetta, Kathryn L.
AU - Lynch, Stacey N.
AU - Markus, Marcello R P
AU - Marques-Vidal, Pedro
AU - Leach, Irene Mateo
AU - McArdle, Wendy L.
AU - McCarroll, Steven A.
AU - Medland, Sarah E.
AU - Miller, Kathryn A.
AU - Montgomery, Grant W.
AU - Morrison, Alanna C.
AU - Müller-Nurasyid, Martina
AU - Navarro, Pau
AU - Nelis, Mari
AU - O'Connell, Jeffrey R.
AU - O'Donnell, Christopher J.
AU - Ong, Ken K.
AU - Newman, Anne B.
AU - Peters, Annette
AU - Polasek, Ozren
AU - Pouta, Anneli
AU - Pramstaller, Peter P.
AU - Psaty, Bruce M.
AU - Rao, Dabeeru C.
AU - Ring, Susan M.
AU - Rossin, Elizabeth J.
AU - Rudan, Diana
AU - Sanna, Serena
AU - Scott, Robert A.
AU - Sehmi, Jaban S.
AU - Sharp, Stephen
AU - Shin, Jordan T.
AU - Singleton, Andrew B.
AU - Smith, Albert V.
AU - Soranzo, Nicole
AU - Spector, Tim D.
AU - Stewart, Chip
AU - Stringham, Heather M.
AU - Tarasov, Kirill V.
AU - Uitterlinden, André G.
AU - Vandenput, Liesbeth
AU - Hwang, Shih Jen
AU - Whitfield, John B.
AU - Wijmenga, Cisca
AU - Wild, Sarah H.
AU - Willemsen, Gonneke
AU - Wilson, James F.
AU - Witteman, Jacqueline C M
AU - Wong, Andrew
AU - Wong, Quenna
AU - Jamshidi, Yalda
AU - Zitting, Paavo
AU - Boer, Jolanda M A
AU - Boomsma, Dorret I.
AU - Borecki, Ingrid B.
AU - Van Duijn, Cornelia M.
AU - Ekelund, Ulf
AU - Forouhi, Nita G.
AU - Froguel, Philippe
AU - Hingorani, Aroon
AU - Ingelsson, Erik
AU - Kivimaki, Mika
AU - Kronmal, Richard A.
AU - Kuh, Diana
AU - Lind, Lars
AU - Martin, Nicholas G.
AU - Oostra, Ben A.
AU - Pedersen, Nancy L.
AU - Quertermous, Thomas
AU - Rotter, Jerome I.
AU - Van Der Schouw, Yvonne T.
AU - Verschuren, W. M Monique
AU - Walker, Mark
AU - Albanes, Demetrius
AU - Arnar, David O.
AU - Assimes, Themistocles L.
AU - Bandinelli, Stefania
AU - Boehnke, Michael
AU - De Boer, Rudolf A.
AU - Bouchard, Claude
AU - W L Mark Caulfield, L Mark Caulfield
AU - Chambers, John C.
AU - Curhan, Gary
AU - Cusi, Daniele
AU - Eriksson, Johan
AU - Ferrucci, Luigi
AU - Van Gilst, Wiek H.
AU - Glorioso, Nicola
AU - De Graaf, Jacqueline
AU - Groop, Leif
AU - Gyllensten, Ulf
AU - Hsueh, Wen Chi
AU - Hu, Frank B.
AU - Huikuri, Heikki V.
AU - Hunter, David J.
AU - Iribarren, Carlos
AU - Isomaa, Bo
AU - Jarvelin, Marjo Riitta
AU - Jula, Antti
AU - Kähönen, Mika
AU - Kiemeney, Lambertus A.
AU - Van Der Klauw, Melanie M.
AU - Kooner, Jaspal S.
AU - Kraft, Peter
AU - Iacoviello, Licia
AU - Lehtimäki, Terho
AU - Lokki, Marja Liisa L
AU - Mitchell, Braxton D.
AU - Navis, Gerjan
AU - Nieminen, Markku S.
AU - Ohlsson, Claes
AU - Poulter, Neil R.
AU - Qi, Lu
AU - Raitakari, Olli T.
AU - Rimm, Eric B.
AU - Rioux, John D.
AU - Rizzi, Federica
AU - Rudan, Igor
AU - Salomaa, Veikko
AU - Sever, Peter S.
AU - Shields, Denis C.
AU - Shuldiner, Alan R.
AU - Sinisalo, Juha
AU - Stanton, Alice V.
AU - Stolk, Ronald P.
AU - Strachan, David P.
AU - Tardif, Jean Claude
AU - Thorsteinsdottir, Unnur
AU - Tuomilehto, Jaako
AU - Van Veldhuisen, Dirk J.
AU - Virtamo, Jarmo
AU - Viikari, Jorma
AU - Vollenweider, Peter
AU - Waeber, Gérard
AU - Widen, Elisabeth
AU - Cho, Yoon Shin
AU - Olsen, Jesper V.
AU - Visscher, Peter M.
AU - Willer, Cristen
AU - Franke, Lude
AU - Erdmann, Jeanette
AU - Thompson, John R.
AU - Pfeufer, Arne
AU - Sotoodehnia, Nona
AU - Newton-Cheh, Christopher
AU - Ellinor, Patrick T.
AU - Stricker, Bruno H Ch
AU - Metspalu, Andres
AU - Perola, Markus
AU - Beckmann, Jacques S.
AU - Smith, George Davey
AU - Stefansson, Kari
AU - Wareham, Nicholas J.
AU - Munroe, Patricia B.
AU - Sibon, Ody C M
AU - Milan, David J.
AU - Snieder, Harold
AU - Samani, Nilesh J.
AU - Loos, Ruth J F
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878726099&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878726099&partnerID=8YFLogxK
U2 - 10.1038/ng.2610
DO - 10.1038/ng.2610
M3 - Article
C2 - 23583979
AN - SCOPUS:84878726099
VL - 45
SP - 621
EP - 631
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 6
ER -