Genome-wide association analysis identifies multiple loci related to resting heart rate

Mark Eijgelsheim; Christopher Newton-Cheh; Nona Sotoodehnia; Paul I.W. de bakker; Martina Müller; Alanna C. Morrison; Albert V. Smith; Aaron Isaacs; Serena Sanna; Marcus Dörr; Pau Navarro; Christian Fuchsberger; Ilja M. Nolte; Eco J.C. de Geus; Karol Estrada; Shih Jen Hwang; Joshua C. Bis; Ina Maria Rückert; Alvaro Alonso; Lenore J. Launer; Jouke Jan Hottenga; Fernando Rivadeneira; Peter A. Noseworthy; Kenneth M. Rice; Siegfried Perz; Dan E. Arking; Tim D. Spector; Jan A. Kors; Yurii S. Aulchenko; Kirill V. Tarasov; Georg Homuth; Sarah H. Wild; Fabio Marroni; Christian Gieger; Carmilla M. Licht; Ronald J. Prineas; Albert Hofman; Jerome I. Rotter; Andrew A. Hicks; Florian Ernst; Samer S. Najjar; Alan F. Wright; Annette Peters; Ervin R. Fox; Ben A. Oostra; Heyo K. Kroemer; David Couper; Henry Völzke; Harry Campbell; Thomas Meitinger; Manuela Uda; Jacqueline C.M. Witteman; Bruce M. Psaty; H. Erich Wichmann; Tamara B. Harris; Stefan Kääb; David S. Siscovick; Yalda Jamshidi; André G. Uitterlinden; Aaron R. Folsom; Martin G. Larson; James F. Wilson; Brenda W. Penninx; Harold Snieder; Peter P. Pramstaller; Cornelia M. van Duijn; Edward G. Lakatta; Stephan B. Felix; Vilmundur Gudnason; Arne Pfeufer; Susan R. Heckbert; Bruno H.Ch Stricker; Eric Boerwinkle; Christopher J. O'Donnell

doi:10.1093/hmg/ddq303

Genome-wide association analysis identifies multiple loci related to resting heart rate

Mark Eijgelsheim
, Christopher Newton-Cheh
, Nona Sotoodehnia
, Paul I.W. de bakker
, Martina Müller
, Alanna C. Morrison
, Albert V. Smith
, Aaron Isaacs
, Serena Sanna
, Marcus Dörr
, Pau Navarro
, Christian Fuchsberger
, Ilja M. Nolte
, Eco J.C. de Geus
, Karol Estrada
, Shih Jen Hwang
, Joshua C. Bis
, Ina Maria Rückert
, Alvaro Alonso
, Lenore J. Launer

Jouke Jan Hottenga, Fernando Rivadeneira, Peter A. Noseworthy, Kenneth M. Rice, Siegfried Perz, Dan E. Arking, Tim D. Spector, Jan A. Kors, Yurii S. Aulchenko, Kirill V. Tarasov, Georg Homuth, Sarah H. Wild, Fabio Marroni, Christian Gieger, Carmilla M. Licht, Ronald J. Prineas, Albert Hofman, Jerome I. Rotter, Andrew A. Hicks, Florian Ernst, Samer S. Najjar, Alan F. Wright, Annette Peters, Ervin R. Fox, Ben A. Oostra, Heyo K. Kroemer, David Couper, Henry Völzke, Harry Campbell, Thomas Meitinger, Manuela Uda, Jacqueline C.M. Witteman, Bruce M. Psaty, H. Erich Wichmann, Tamara B. Harris, Stefan Kääb, David S. Siscovick, Yalda Jamshidi, André G. Uitterlinden, Aaron R. Folsom, Martin G. Larson, James F. Wilson, Brenda W. Penninx, Harold Snieder, Peter P. Pramstaller, Cornelia M. van Duijn, Edward G. Lakatta, Stephan B. Felix, Vilmundur Gudnason, Arne Pfeufer, Susan R. Heckbert, Bruno H.Ch Stricker^*, Eric Boerwinkle, Christopher J. O'Donnell

^*Corresponding author for this work

Department of Epidemiology
Erasmus University Rotterdam
Center for Human Genetics Research
Massachusetts General Hospital
Program in Medical and Population Genetics
Broad Institute
National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Cardiovascular Health Research Unit
University of Washington
Division of Genetics, Department of Medicine
Brigham and Women’s Hospital
Institute of Epidemiology
Helmholtz Zentrum München - German Research Center for Environmental Health
Ludwig Maximilian University of Munich
Ludwig-Maximilians-Universität
University of Texas Health Science Center at Houston
Icelandic Heart Association
Istituto di Neurogeneticae Neurofarmacologia
National Research Council of Italy
Department of Internal Medicine B
University of Greifswald
NHS Lothian
Institute of Genetic Medicine
EURAC Research
Department of Epidemiology
University of Groningen
Department of Biological Psychology
Vrije Universiteit Amsterdam
Department of Internal Medicine
Cardiovascular Health Research Unit
Department of Medicine
Division of Epidemiology and Community Health
University of Minnesota Twin Cities
National Institute of Aging's Laboratory for Epidemiology, Demography, and Biometry
Institute of Biological and Medical Imaging
Johns Hopkins University
Division of Cardiology, Department of Medicine
Department of Twin Research and Genetic Epidemiology
King's College London
Department of Medical Informatics
Laboratory of Cardiovascular Science, Intramural Research Program
National Institutes of Health
Interfaculty Institute for Genetics and Functional Genomics
Centre for Population Health Sciences
University of Edinburgh
Institute of Applied Genomics
Psychiatry
VU University Medical Center
EPICARE Center
Netherlands Genomics Initiative
Medical Genetics Institute
Cedars-Sinai Medical Center
University of Mississippi
Department of Clinical Genetics
Department of Pharmacology
Center for Pharmacology and Experimental Therapeutics
University of North Carolina at Chapel Hill
Institute for Community Medicine
Institute of Human Genetics
Technical University of Munich
Group Health Cooperative
St. George's University of London
Boston University
Department of Neurology
General Central Hospital
University of Lübeck
University of Iceland
Inspectorate for Health Care
Cardiology Division
Institute of Human Genetics
Department of Neurology

Research output: Contribution to journal › Article › peer-review

121 Citations (Scopus)

Abstract

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10^-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10^-5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Original language	English
Article number	ddq303
Pages (from-to)	3885-3894
Number of pages	10
Journal	Human Molecular Genetics
Volume	19
Issue number	19
DOIs	https://doi.org/10.1093/hmg/ddq303
Publication status	Published - 16 Jul 2010
Externally published	Yes

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10.1093/hmg/ddq303

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Eijgelsheim, M., Newton-Cheh, C., Sotoodehnia, N., de bakker, P. I. W., Müller, M., Morrison, A. C., Smith, A. V., Isaacs, A., Sanna, S., Dörr, M., Navarro, P., Fuchsberger, C., Nolte, I. M., de Geus, E. J. C., Estrada, K., Hwang, S. J., Bis, J. C., Rückert, I. M., Alonso, A., ... O'Donnell, C. J. (2010). Genome-wide association analysis identifies multiple loci related to resting heart rate. Human Molecular Genetics, 19(19), 3885-3894. Article ddq303. https://doi.org/10.1093/hmg/ddq303

@article{53fd2e23534e4bcd847d44a91774195f,

title = "Genome-wide association analysis identifies multiple loci related to resting heart rate",

abstract = "Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and \textasciitilde{}2.5 million markers. Results with P < 5 {\texttimes} 10-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain \textasciitilde{}0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5 increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.",

author = "Mark Eijgelsheim and Christopher Newton-Cheh and Nona Sotoodehnia and \{de bakker\}, \{Paul I.W.\} and Martina M{\"u}ller and Morrison, \{Alanna C.\} and Smith, \{Albert V.\} and Aaron Isaacs and Serena Sanna and Marcus D{\"o}rr and Pau Navarro and Christian Fuchsberger and Nolte, \{Ilja M.\} and \{de Geus\}, \{Eco J.C.\} and Karol Estrada and Hwang, \{Shih Jen\} and Bis, \{Joshua C.\} and R{\"u}ckert, \{Ina Maria\} and Alvaro Alonso and Launer, \{Lenore J.\} and Hottenga, \{Jouke Jan\} and Fernando Rivadeneira and Noseworthy, \{Peter A.\} and Rice, \{Kenneth M.\} and Siegfried Perz and Arking, \{Dan E.\} and Spector, \{Tim D.\} and Kors, \{Jan A.\} and Aulchenko, \{Yurii S.\} and Tarasov, \{Kirill V.\} and Georg Homuth and Wild, \{Sarah H.\} and Fabio Marroni and Christian Gieger and Licht, \{Carmilla M.\} and Prineas, \{Ronald J.\} and Albert Hofman and Rotter, \{Jerome I.\} and Hicks, \{Andrew A.\} and Florian Ernst and Najjar, \{Samer S.\} and Wright, \{Alan F.\} and Annette Peters and Fox, \{Ervin R.\} and Oostra, \{Ben A.\} and Kroemer, \{Heyo K.\} and David Couper and Henry V{\"o}lzke and Harry Campbell and Thomas Meitinger and Manuela Uda and Witteman, \{Jacqueline C.M.\} and Psaty, \{Bruce M.\} and Wichmann, \{H. Erich\} and Harris, \{Tamara B.\} and Stefan K{\"a}{\"a}b and Siscovick, \{David S.\} and Yalda Jamshidi and Uitterlinden, \{Andr{\'e} G.\} and Folsom, \{Aaron R.\} and Larson, \{Martin G.\} and Wilson, \{James F.\} and Penninx, \{Brenda W.\} and Harold Snieder and Pramstaller, \{Peter P.\} and \{van Duijn\}, \{Cornelia M.\} and Lakatta, \{Edward G.\} and Felix, \{Stephan B.\} and Vilmundur Gudnason and Arne Pfeufer and Heckbert, \{Susan R.\} and Stricker, \{Bruno H.Ch\} and Eric Boerwinkle and O'Donnell, \{Christopher J.\}",

year = "2010",

month = jul,

day = "16",

doi = "10.1093/hmg/ddq303",

language = "English",

volume = "19",

pages = "3885--3894",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

}

Eijgelsheim, M, Newton-Cheh, C, Sotoodehnia, N, de bakker, PIW, Müller, M, Morrison, AC, Smith, AV, Isaacs, A, Sanna, S, Dörr, M, Navarro, P, Fuchsberger, C, Nolte, IM, de Geus, EJC, Estrada, K, Hwang, SJ, Bis, JC, Rückert, IM, Alonso, A, Launer, LJ, Hottenga, JJ, Rivadeneira, F, Noseworthy, PA, Rice, KM, Perz, S, Arking, DE, Spector, TD, Kors, JA, Aulchenko, YS, Tarasov, KV, Homuth, G, Wild, SH, Marroni, F, Gieger, C, Licht, CM, Prineas, RJ, Hofman, A, Rotter, JI, Hicks, AA, Ernst, F, Najjar, SS, Wright, AF, Peters, A, Fox, ER, Oostra, BA, Kroemer, HK, Couper, D, Völzke, H, Campbell, H, Meitinger, T, Uda, M, Witteman, JCM, Psaty, BM, Wichmann, HE, Harris, TB, Kääb, S, Siscovick, DS, Jamshidi, Y, Uitterlinden, AG, Folsom, AR, Larson, MG, Wilson, JF, Penninx, BW, Snieder, H, Pramstaller, PP, van Duijn, CM, Lakatta, EG, Felix, SB, Gudnason, V, Pfeufer, A, Heckbert, SR, Stricker, BHC, Boerwinkle, E & O'Donnell, CJ 2010, 'Genome-wide association analysis identifies multiple loci related to resting heart rate', Human Molecular Genetics, vol. 19, no. 19, ddq303, pp. 3885-3894. https://doi.org/10.1093/hmg/ddq303

TY - JOUR

T1 - Genome-wide association analysis identifies multiple loci related to resting heart rate

AU - Eijgelsheim, Mark

AU - Newton-Cheh, Christopher

AU - Sotoodehnia, Nona

AU - de bakker, Paul I.W.

AU - Müller, Martina

AU - Morrison, Alanna C.

AU - Smith, Albert V.

AU - Isaacs, Aaron

AU - Sanna, Serena

AU - Dörr, Marcus

AU - Navarro, Pau

AU - Fuchsberger, Christian

AU - Nolte, Ilja M.

AU - de Geus, Eco J.C.

AU - Estrada, Karol

AU - Hwang, Shih Jen

AU - Bis, Joshua C.

AU - Rückert, Ina Maria

AU - Alonso, Alvaro

AU - Launer, Lenore J.

AU - Hottenga, Jouke Jan

AU - Rivadeneira, Fernando

AU - Noseworthy, Peter A.

AU - Rice, Kenneth M.

AU - Perz, Siegfried

AU - Arking, Dan E.

AU - Spector, Tim D.

AU - Kors, Jan A.

AU - Aulchenko, Yurii S.

AU - Tarasov, Kirill V.

AU - Homuth, Georg

AU - Wild, Sarah H.

AU - Marroni, Fabio

AU - Gieger, Christian

AU - Licht, Carmilla M.

AU - Prineas, Ronald J.

AU - Hofman, Albert

AU - Rotter, Jerome I.

AU - Hicks, Andrew A.

AU - Ernst, Florian

AU - Najjar, Samer S.

AU - Wright, Alan F.

AU - Peters, Annette

AU - Fox, Ervin R.

AU - Oostra, Ben A.

AU - Kroemer, Heyo K.

AU - Couper, David

AU - Völzke, Henry

AU - Campbell, Harry

AU - Meitinger, Thomas

AU - Uda, Manuela

AU - Witteman, Jacqueline C.M.

AU - Psaty, Bruce M.

AU - Wichmann, H. Erich

AU - Harris, Tamara B.

AU - Kääb, Stefan

AU - Siscovick, David S.

AU - Jamshidi, Yalda

AU - Uitterlinden, André G.

AU - Folsom, Aaron R.

AU - Larson, Martin G.

AU - Wilson, James F.

AU - Penninx, Brenda W.

AU - Snieder, Harold

AU - Pramstaller, Peter P.

AU - van Duijn, Cornelia M.

AU - Lakatta, Edward G.

AU - Felix, Stephan B.

AU - Gudnason, Vilmundur

AU - Pfeufer, Arne

AU - Heckbert, Susan R.

AU - Stricker, Bruno H.Ch

AU - Boerwinkle, Eric

AU - O'Donnell, Christopher J.

PY - 2010/7/16

Y1 - 2010/7/16

N2 - Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

AB - Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

UR - https://www.scopus.com/pages/publications/77956512209

U2 - 10.1093/hmg/ddq303

DO - 10.1093/hmg/ddq303

M3 - Article

C2 - 20639392

AN - SCOPUS:77956512209

SN - 0964-6906

VL - 19

SP - 3885

EP - 3894

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

M1 - ddq303

ER -

Genome-wide association analysis identifies multiple loci related to resting heart rate

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