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

Mark Eijgelsheim; C Newton-Cheh; N Sotoodehnia; PIW de Bakker; M (Majon) Muller; AC Morrison; AV Smith; Aaron Isaacs; S Sanna; M Dorr; P Navarro; C Fuchsberger; IM (Ilja) Nolte; EJC de Geus; Karol Estrada Gil; SJ Hwang; JC Bis; IM Ruckert; A Alonso; LJ (Lenore) Launer; JJ (Jouke Jan) Hottenga; Fernando Rivadeneira; PA Noseworthy; KM Rice; S Perz; DE Arking; TD Spector; Jan Kors; YS Aulchenko; KV Tarasov; G Homuth; SH Wild; F Marroni; C Gieger; CM Licht; RJ Prineas; Bert Hofman; JI Rotter; AA Hicks; F Ernst; SS Najjar; AF Wright; A Peters; ER Fox; Ben Oostra; HK Kroemer; D Couper; H Volzke; H Campbell; T Meitinger; M Uda; JCM Witteman; BM Psaty; HE Wichmann; TB Harris; S Kaab; DS Siscovick; Y Jamshidi; André Uitterlinden; AR Folsom; MG Larson; JF Wilson; BW Penninx; H Snieder; PP Pramstaller; Cornelia Duijn; EG Lakatta; SB Felix; V Gudnason; A Pfeufer; SR Heckbert; Bruno Stricker; E Boerwinkle; CJ O'Donnell

doi:10.1093/hmg/ddq303

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

Mark Eijgelsheim, C Newton-Cheh, N Sotoodehnia, PIW de Bakker, M (Majon) Muller, AC Morrison, AV Smith, Aaron Isaacs, S Sanna, M Dorr, P Navarro, C Fuchsberger, IM (Ilja) Nolte, EJC de Geus, Karol Estrada Gil, SJ Hwang, JC Bis, IM Ruckert, A Alonso, LJ (Lenore) LaunerJJ (Jouke Jan) Hottenga, Fernando Rivadeneira, PA Noseworthy, KM Rice, S Perz, DE Arking, TD Spector, Jan Kors, YS Aulchenko, KV Tarasov, G Homuth, SH Wild, F Marroni, C Gieger, CM Licht, RJ Prineas, Bert Hofman, JI Rotter, AA Hicks, F Ernst, SS Najjar, AF Wright, A Peters, ER Fox, Ben Oostra, HK Kroemer, D Couper, H Volzke, H Campbell, T Meitinger, M Uda, JCM Witteman, BM Psaty, HE Wichmann, TB Harris, S Kaab, DS Siscovick, Y Jamshidi, André Uitterlinden, AR Folsom, MG Larson, JF Wilson, BW Penninx, H Snieder, PP Pramstaller, Cornelia Duijn, EG Lakatta, SB Felix, V Gudnason, A Pfeufer, SR Heckbert, Bruno Stricker, E Boerwinkle, CJ O'Donnell

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

116 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 similar to 2.5 million markers. Results with P < 5 x 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 similar to 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	Undefined/Unknown
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 - 2010

Research programs

EMC MM-01-39-02
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-01-64-03
EMC NIHES-03-77-02

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/hmg/ddq303

http://hdl.handle.net/1765/28118

Cite this

Eijgelsheim, M., Newton-Cheh, C., Sotoodehnia, N., de Bakker, PIW., Muller, M., Morrison, AC., Smith, AV., Isaacs, A., Sanna, S., Dorr, M., Navarro, P., Fuchsberger, C., Nolte, IM., de Geus, EJC., Estrada Gil, K., Hwang, SJ., Bis, JC., Ruckert, IM., Alonso, A., ... O'Donnell, CJ. (2010). Genome-wide association analysis identifies multiple loci related to resting heart rate. Human Molecular Genetics, 19(19), 3885-3894. https://doi.org/10.1093/hmg/ddq303

@article{f70d858ef3f94604bddf9cf08d155cb0,

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 similar to 2.5 million markers. Results with P < 5 x 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 similar to 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 C Newton-Cheh and N Sotoodehnia and {de Bakker}, PIW and Muller, {M (Majon)} and AC Morrison and AV Smith and Aaron Isaacs and S Sanna and M Dorr and P Navarro and C Fuchsberger and Nolte, {IM (Ilja)} and {de Geus}, EJC and {Estrada Gil}, Karol and SJ Hwang and JC Bis and IM Ruckert and A Alonso and Launer, {LJ (Lenore)} and Hottenga, {JJ (Jouke Jan)} and Fernando Rivadeneira and PA Noseworthy and KM Rice and S Perz and DE Arking and TD Spector and Jan Kors and YS Aulchenko and KV Tarasov and G Homuth and SH Wild and F Marroni and C Gieger and CM Licht and RJ Prineas and Bert Hofman and JI Rotter and AA Hicks and F Ernst and SS Najjar and AF Wright and A Peters and ER Fox and Ben Oostra and HK Kroemer and D Couper and H Volzke and H Campbell and T Meitinger and M Uda and JCM Witteman and BM Psaty and HE Wichmann and TB Harris and S Kaab and DS Siscovick and Y Jamshidi and Andr{\'e} Uitterlinden and AR Folsom and MG Larson and JF Wilson and BW Penninx and H Snieder and PP Pramstaller and Cornelia Duijn and EG Lakatta and SB Felix and V Gudnason and A Pfeufer and SR Heckbert and Bruno Stricker and E Boerwinkle and CJ O'Donnell",

year = "2010",

doi = "10.1093/hmg/ddq303",

language = "Undefined/Unknown",

volume = "19",

pages = "3885--3894",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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Eijgelsheim, M, Newton-Cheh, C, Sotoodehnia, N, de Bakker, PIW, Muller, M, Morrison, AC, Smith, AV, Isaacs, A, Sanna, S, Dorr, M, Navarro, P, Fuchsberger, C, Nolte, IM, de Geus, EJC, Estrada Gil, K, Hwang, SJ, Bis, JC, Ruckert, IM, Alonso, A, Launer, LJ, Hottenga, JJ, Rivadeneira, F, Noseworthy, PA, Rice, KM, Perz, S, Arking, DE, Spector, TD, Kors, J, Aulchenko, YS, Tarasov, KV, Homuth, G, Wild, SH, Marroni, F, Gieger, C, Licht, CM, Prineas, RJ, Hofman, B, Rotter, JI, Hicks, AA, Ernst, F, Najjar, SS, Wright, AF, Peters, A, Fox, ER, Oostra, B, Kroemer, HK, Couper, D, Volzke, H, Campbell, H, Meitinger, T, Uda, M, Witteman, JCM, Psaty, BM, Wichmann, HE, Harris, TB, Kaab, S, Siscovick, DS, Jamshidi, Y, Uitterlinden, A, Folsom, AR, Larson, MG, Wilson, JF, Penninx, BW, Snieder, H, Pramstaller, PP, Duijn, C, Lakatta, EG, Felix, SB, Gudnason, V, Pfeufer, A, Heckbert, SR, Stricker, B, 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, 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, C

AU - Sotoodehnia, N

AU - de Bakker, PIW

AU - Muller, M (Majon)

AU - Morrison, AC

AU - Smith, AV

AU - Isaacs, Aaron

AU - Sanna, S

AU - Dorr, M

AU - Navarro, P

AU - Fuchsberger, C

AU - Nolte, IM (Ilja)

AU - de Geus, EJC

AU - Estrada Gil, Karol

AU - Hwang, SJ

AU - Bis, JC

AU - Ruckert, IM

AU - Alonso, A

AU - Launer, LJ (Lenore)

AU - Hottenga, JJ (Jouke Jan)

AU - Rivadeneira, Fernando

AU - Noseworthy, PA

AU - Rice, KM

AU - Perz, S

AU - Arking, DE

AU - Spector, TD

AU - Kors, Jan

AU - Aulchenko, YS

AU - Tarasov, KV

AU - Homuth, G

AU - Wild, SH

AU - Marroni, F

AU - Gieger, C

AU - Licht, CM

AU - Prineas, RJ

AU - Hofman, Bert

AU - Rotter, JI

AU - Hicks, AA

AU - Ernst, F

AU - Najjar, SS

AU - Wright, AF

AU - Peters, A

AU - Fox, ER

AU - Oostra, Ben

AU - Kroemer, HK

AU - Couper, D

AU - Volzke, H

AU - Campbell, H

AU - Meitinger, T

AU - Uda, M

AU - Witteman, JCM

AU - Psaty, BM

AU - Wichmann, HE

AU - Harris, TB

AU - Kaab, S

AU - Siscovick, DS

AU - Jamshidi, Y

AU - Uitterlinden, André

AU - Folsom, AR

AU - Larson, MG

AU - Wilson, JF

AU - Penninx, BW

AU - Snieder, H

AU - Pramstaller, PP

AU - Duijn, Cornelia

AU - Lakatta, EG

AU - Felix, SB

AU - Gudnason, V

AU - Pfeufer, A

AU - Heckbert, SR

AU - Stricker, Bruno

AU - Boerwinkle, E

AU - O'Donnell, CJ

PY - 2010

Y1 - 2010

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 similar to 2.5 million markers. Results with P < 5 x 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 similar to 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 similar to 2.5 million markers. Results with P < 5 x 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 similar to 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.

U2 - 10.1093/hmg/ddq303

DO - 10.1093/hmg/ddq303

M3 - Article

C2 - 20639392

SN - 0964-6906

VL - 19

SP - 3885

EP - 3894

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

ER -