Discovery of novel heart rate-associated loci using the Exome Chip

Marten E. Van Den Berg; Helen R. Warren; Claudia P. Cabrera; Niek Verweij; Borbala Mifsud; Jeffrey Haessler; Nathan A. Bihlmeyer; Yi Ping Fu; Stefan Weiss; Henry J. Lin; Niels Grarup; Ruifang Li-Gao; Giorgio Pistis; Nabi Shah; Jennifer A. Brody; Martina Müller-Nurasyid; Honghuang Lin; Hao Mei; Albert V. Smith; Leo Pekka Lyytikäinen; Leanne M. Hall; Jessica Van Setten; Stella Trompet; Bram P. Prins; Aaron Isaacs; Farid Radmanesh; Jonathan Marten; Aiman Entwistle; Jan A. Kors; Claudia T. Silva; Alvaro Alonso; Joshua C. Bis; Rudolf De Boer; Hugoline G. De Haan; Renée De Mutsert; George Dedoussis; Anna F. Dominiczak; Alex S.F. Doney; Patrick T. Ellinor; Ruben N. Eppinga; Stephan B. Felix; Xiuqing Guo; Yanick Hagemeijer; Torben Hansen; Tamara B. Harris; Susan R. Heckbert; Paul L. Huang; Shih Jen Hwang; Mika Kähönen; Jørgen K. Kanters

doi:10.1093/hmg/ddx113

Discovery of novel heart rate-associated loci using the Exome Chip

Marten E. Van Den Berg
, Helen R. Warren
, Claudia P. Cabrera
, Niek Verweij
, Borbala Mifsud
, Jeffrey Haessler
, Nathan A. Bihlmeyer
, Yi Ping Fu
, Stefan Weiss
, Henry J. Lin
, Niels Grarup
, Ruifang Li-Gao
, Giorgio Pistis
, Nabi Shah
, Jennifer A. Brody
, Martina Müller-Nurasyid
, Honghuang Lin
, Hao Mei
, Albert V. Smith
, Leo Pekka Lyytikäinen

Leanne M. Hall, Jessica Van Setten, Stella Trompet, Bram P. Prins, Aaron Isaacs, Farid Radmanesh, Jonathan Marten, Aiman Entwistle, Jan A. Kors, Claudia T. Silva, Alvaro Alonso, Joshua C. Bis, Rudolf De Boer, Hugoline G. De Haan, Renée De Mutsert, George Dedoussis, Anna F. Dominiczak, Alex S.F. Doney, Patrick T. Ellinor, Ruben N. Eppinga, Stephan B. Felix, Xiuqing Guo, Yanick Hagemeijer, Torben Hansen, Tamara B. Harris, Susan R. Heckbert, Paul L. Huang, Shih Jen Hwang, Mika Kähönen, Jørgen K. Kanters

Producción científica: Contribución a revista › Artículo de Investigación › revisión exhaustiva

28 Citas (Scopus)

Resumen

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.

Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.

Idioma original	Inglés estadounidense
Páginas (desde-hasta)	2346-2363
Número de páginas	18
Publicación	Human Molecular Genetics
Volumen	26
N.º	12
DOI	https://doi.org/10.1093/hmg/ddx113
Estado	Publicada - jun. 15 2017

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

ODS 3: Salud y bienestar

Áreas temáticas de ASJC Scopus

Biología molecular
Genética
Genética (clínica)

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10.1093/hmg/ddx113

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Van Den Berg, M. E., Warren, H. R., Cabrera, C. P., Verweij, N., Mifsud, B., Haessler, J., Bihlmeyer, N. A., Fu, Y. P., Weiss, S., Lin, H. J., Grarup, N., Li-Gao, R., Pistis, G., Shah, N., Brody, J. A., Müller-Nurasyid, M., Lin, H., Mei, H., Smith, A. V., ... Kanters, J. K. (2017). Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics, 26(12), 2346-2363. https://doi.org/10.1093/hmg/ddx113

@article{e59259e4d36f4c8f9621a63b169b0d5a,

title = "Discovery of novel heart rate-associated loci using the Exome Chip",

abstract = "Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9\% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.",

author = "\{Van Den Berg\}, \{Marten E.\} and Warren, \{Helen R.\} and Cabrera, \{Claudia P.\} and Niek Verweij and Borbala Mifsud and Jeffrey Haessler and Bihlmeyer, \{Nathan A.\} and Fu, \{Yi Ping\} and Stefan Weiss and Lin, \{Henry J.\} and Niels Grarup and Ruifang Li-Gao and Giorgio Pistis and Nabi Shah and Brody, \{Jennifer A.\} and Martina M{\"u}ller-Nurasyid and Honghuang Lin and Hao Mei and Smith, \{Albert V.\} and Lyytik{\"a}inen, \{Leo Pekka\} and Hall, \{Leanne M.\} and \{Van Setten\}, Jessica and Stella Trompet and Prins, \{Bram P.\} and Aaron Isaacs and Farid Radmanesh and Jonathan Marten and Aiman Entwistle and Kors, \{Jan A.\} and Silva, \{Claudia T.\} and Alvaro Alonso and Bis, \{Joshua C.\} and \{De Boer\}, Rudolf and \{De Haan\}, \{Hugoline G.\} and \{De Mutsert\}, Ren{\'e}e and George Dedoussis and Dominiczak, \{Anna F.\} and Doney, \{Alex S.F.\} and Ellinor, \{Patrick T.\} and Eppinga, \{Ruben N.\} and Felix, \{Stephan B.\} and Xiuqing Guo and Yanick Hagemeijer and Torben Hansen and Harris, \{Tamara B.\} and Heckbert, \{Susan R.\} and Huang, \{Paul L.\} and Hwang, \{Shih Jen\} and Mika K{\"a}h{\"o}nen and Kanters, \{J{\o}rgen K.\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author 2017. Published by Oxford University Press.",

year = "2017",

month = jun,

day = "15",

doi = "10.1093/hmg/ddx113",

language = "English (US)",

volume = "26",

pages = "2346--2363",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "12",

}

Van Den Berg, ME, Warren, HR, Cabrera, CP, Verweij, N, Mifsud, B, Haessler, J, Bihlmeyer, NA, Fu, YP, Weiss, S, Lin, HJ, Grarup, N, Li-Gao, R, Pistis, G, Shah, N, Brody, JA, Müller-Nurasyid, M, Lin, H, Mei, H, Smith, AV, Lyytikäinen, LP, Hall, LM, Van Setten, J, Trompet, S, Prins, BP, Isaacs, A, Radmanesh, F, Marten, J, Entwistle, A, Kors, JA, Silva, CT, Alonso, A, Bis, JC, De Boer, R, De Haan, HG, De Mutsert, R, Dedoussis, G, Dominiczak, AF, Doney, ASF, Ellinor, PT, Eppinga, RN, Felix, SB, Guo, X, Hagemeijer, Y, Hansen, T, Harris, TB, Heckbert, SR, Huang, PL, Hwang, SJ, Kähönen, M & Kanters, JK 2017, 'Discovery of novel heart rate-associated loci using the Exome Chip', Human Molecular Genetics, vol. 26, n.º 12, pp. 2346-2363. https://doi.org/10.1093/hmg/ddx113

TY - JOUR

T1 - Discovery of novel heart rate-associated loci using the Exome Chip

AU - Van Den Berg, Marten E.

AU - Warren, Helen R.

AU - Cabrera, Claudia P.

AU - Verweij, Niek

AU - Mifsud, Borbala

AU - Haessler, Jeffrey

AU - Bihlmeyer, Nathan A.

AU - Fu, Yi Ping

AU - Weiss, Stefan

AU - Lin, Henry J.

AU - Grarup, Niels

AU - Li-Gao, Ruifang

AU - Pistis, Giorgio

AU - Shah, Nabi

AU - Brody, Jennifer A.

AU - Müller-Nurasyid, Martina

AU - Lin, Honghuang

AU - Mei, Hao

AU - Smith, Albert V.

AU - Lyytikäinen, Leo Pekka

AU - Hall, Leanne M.

AU - Van Setten, Jessica

AU - Trompet, Stella

AU - Prins, Bram P.

AU - Isaacs, Aaron

AU - Radmanesh, Farid

AU - Marten, Jonathan

AU - Entwistle, Aiman

AU - Kors, Jan A.

AU - Silva, Claudia T.

AU - Alonso, Alvaro

AU - Bis, Joshua C.

AU - De Boer, Rudolf

AU - De Haan, Hugoline G.

AU - De Mutsert, Renée

AU - Dedoussis, George

AU - Dominiczak, Anna F.

AU - Doney, Alex S.F.

AU - Ellinor, Patrick T.

AU - Eppinga, Ruben N.

AU - Felix, Stephan B.

AU - Guo, Xiuqing

AU - Hagemeijer, Yanick

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Heckbert, Susan R.

AU - Huang, Paul L.

AU - Hwang, Shih Jen

AU - Kähönen, Mika

AU - Kanters, Jørgen K.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

AB - Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

UR - https://www.scopus.com/pages/publications/85031038119

UR - https://www.scopus.com/pages/publications/85031038119#tab=citedBy

U2 - 10.1093/hmg/ddx113

DO - 10.1093/hmg/ddx113

M3 - Research Article

C2 - 28379579

AN - SCOPUS:85031038119

SN - 0964-6906

VL - 26

SP - 2346

EP - 2363

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

ER -

Discovery of novel heart rate-associated loci using the Exome Chip

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