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 & 101 others 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 A. 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, Ivana Kolcic, Lenore J. Launer, Man Li, Jie Yao, Allan Linneberg, Simin Liu, Peter W Macfarlane, Massimo Mangino, Andrew D Morris, Antonella Mulas, Alison D. Murray, Christopher P. Nelson, Marco Orrú, Sandosh Padmanabhan, Annette Peters, David J. Porteous, Neil R. Poulter, Bruce M. Psaty, Lihong Qi, Olli T. Raitakari, Fernando Rivadeneira, Carolina Roselli, Igor Rudan, Naveed Sattar, Peter Sever, Moritz F. Sinner, Elsayed Z. Soliman, Timothy D. Spector, Alice V. Stanton, Kathleen E. Stirrups, Kent D. Taylor, Martin D. Tobin, André G. Uitterlinden, Ilonca Vaartjes, Arno W Hoes, Peter van der Meer, Uwe Völker, Melanie Waldenberger, Zhijun Xie, Magdalena Zoledziewska, Andrew Tinker, Ozren Polasek, Jonathan Rosand, Yalda Jamshidi, Cornelia M. van Duijn, Eleftheria Zeggini, J Wouter Jukema, Folkert W. Asselbergs, Nilesh J. Samani, Terho Lehtimäki, Vilmundur Gudnason, James Wilson, Steven A. Lubitz, Stefan Kääb, Nona Sotoodehnia, Mark J. Caulfield, Colin N A Palmer, Serena Sanna, Dennis O. Mook-Kanamori, Panos Deloukas, Oluf Pedersen, Jerome I. Rotter, Marcus Dörr, Chris J O'Donnell, Caroline Hayward, Dan E. Arking, Charles Kooperberg, Pim van der Harst, Mark Eijgelsheim, Bruno H. C. Stricker, Patricia B. Munroe

Research output: Contribution to journalArticle

6 Citations (Scopus)
72 Downloads (Pure)

Abstract

Background: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.

Aim: To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.

Methods: 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.

Results: 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, 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, 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.

Conclusion: Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Original languageEnglish
Pages (from-to)2346-2363
Number of pages18
JournalHuman Molecular Genetics
Volume26
Issue number12
Early online date3 Apr 2017
DOIs
Publication statusPublished - 15 Jun 2017

Fingerprint

Exome
Heart Rate
Genes
Nerve Tissue
Fetal Heart
Tibial Nerve
Genetic Loci
Genome-Wide Association Study
Deoxyribonuclease I
Embryonic Stem Cells
Computational Biology
Chromatin
Pulse
Meta-Analysis
Stem Cells
Muscles
Lung

Keywords

  • Heart rate
  • Embryonic stem cells
  • Lung
  • Stem cells
  • Chromatin
  • Deoxyribonuclease i
  • Fetal heart

Cite this

van den Berg, M. E., Warren, H. R., Cabrera, C. P., Verweij, N., Mifsud, B., Haessler, J., ... Munroe, P. B. (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
van den Berg, Marten E ; Warren, Helen R. ; Cabrera, Claudia P ; Verweij, Niek ; Mifsud, Borbala ; Haessler, Jeffrey ; Bihlmeyer, Nathan A. ; Fu, Yi-Ping ; Weiss, Stefan ; Lin, Henry J ; Grarup, Niels ; Li-Gao, Ruifang ; Pistis, Giorgio ; Shah, Nabi ; Brody, Jennifer A. ; Müller-Nurasyid, Martina ; Lin, Honghuang ; Mei, Hao ; Smith, Albert V. ; Lyytikäinen, Leo-Pekka ; Hall, Leanne M. ; van Setten, Jessica ; Trompet, Stella ; Prins, Bram P ; Isaacs, Aaron ; Radmanesh, Farid ; Marten, Jonathan ; Entwistle, Aiman ; Kors, Jan A. ; Silva, Claudia T ; Alonso, Alvaro ; Bis, Joshua C. ; de Boer, Rudolf A. ; de Haan, Hugoline G. ; de Mutsert, Renée ; Dedoussis, George ; Dominiczak, Anna F. ; Doney, Alex S F ; Ellinor, Patrick T. ; Eppinga, Ruben N ; Felix, Stephan B. ; Guo, Xiuqing ; Hagemeijer, Yanick ; Hansen, Torben ; Harris, Tamara B. ; Heckbert, Susan R. ; Huang, Paul L. ; Hwang, Shih-Jen ; Kähönen, Mika ; Kanters, Jørgen K ; Kolcic, Ivana ; Launer, Lenore J. ; Li, Man ; Yao, Jie ; Linneberg, Allan ; Liu, Simin ; Macfarlane, Peter W ; Mangino, Massimo ; Morris, Andrew D ; Mulas, Antonella ; Murray, Alison D. ; Nelson, Christopher P. ; Orrú, Marco ; Padmanabhan, Sandosh ; Peters, Annette ; Porteous, David J. ; Poulter, Neil R. ; Psaty, Bruce M. ; Qi, Lihong ; Raitakari, Olli T. ; Rivadeneira, Fernando ; Roselli, Carolina ; Rudan, Igor ; Sattar, Naveed ; Sever, Peter ; Sinner, Moritz F. ; Soliman, Elsayed Z. ; Spector, Timothy D. ; Stanton, Alice V. ; Stirrups, Kathleen E. ; Taylor, Kent D. ; Tobin, Martin D. ; Uitterlinden, André G. ; Vaartjes, Ilonca ; Hoes, Arno W ; van der Meer, Peter ; Völker, Uwe ; Waldenberger, Melanie ; Xie, Zhijun ; Zoledziewska, Magdalena ; Tinker, Andrew ; Polasek, Ozren ; Rosand, Jonathan ; Jamshidi, Yalda ; van Duijn, Cornelia M. ; Zeggini, Eleftheria ; Wouter Jukema, J ; Asselbergs, Folkert W. ; Samani, Nilesh J. ; Lehtimäki, Terho ; Gudnason, Vilmundur ; Wilson, James ; Lubitz, Steven A. ; Kääb, Stefan ; Sotoodehnia, Nona ; Caulfield, Mark J. ; Palmer, Colin N A ; Sanna, Serena ; Mook-Kanamori, Dennis O. ; Deloukas, Panos ; Pedersen, Oluf ; Rotter, Jerome I. ; Dörr, Marcus ; O'Donnell, Chris J ; Hayward, Caroline ; Arking, Dan E. ; Kooperberg, Charles ; van der Harst, Pim ; Eijgelsheim, Mark ; Stricker, Bruno H. C. ; Munroe, Patricia B. / Discovery of novel heart rate-associated loci using the Exome Chip. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 12. pp. 2346-2363.
@article{1fd5aca468d0434eadb615fe17018312,
title = "Discovery of novel heart rate-associated loci using the Exome Chip",
abstract = "Background: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9{\%} of the variation.Aim: To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods: 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.Results: 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, 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, 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.Conclusion: Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.",
keywords = "Heart rate, Embryonic stem cells, Lung, Stem cells, Chromatin, Deoxyribonuclease i, Fetal heart",
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 Yi-Ping Fu 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 Leo-Pekka Lyytik{\"a}inen 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 A.} 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 Shih-Jen Hwang and Mika K{\"a}h{\"o}nen and Kanters, {J{\o}rgen K} and Ivana Kolcic and Launer, {Lenore J.} and Man Li and Jie Yao and Allan Linneberg and Simin Liu and Macfarlane, {Peter W} and Massimo Mangino and Morris, {Andrew D} and Antonella Mulas and Murray, {Alison D.} and Nelson, {Christopher P.} and Marco Orr{\'u} and Sandosh Padmanabhan and Annette Peters and Porteous, {David J.} and Poulter, {Neil R.} and Psaty, {Bruce M.} and Lihong Qi and Raitakari, {Olli T.} and Fernando Rivadeneira and Carolina Roselli and Igor Rudan and Naveed Sattar and Peter Sever and Sinner, {Moritz F.} and Soliman, {Elsayed Z.} and Spector, {Timothy D.} and Stanton, {Alice V.} and Stirrups, {Kathleen E.} and Taylor, {Kent D.} and Tobin, {Martin D.} and Uitterlinden, {Andr{\'e} G.} and Ilonca Vaartjes and Hoes, {Arno W} and {van der Meer}, Peter and Uwe V{\"o}lker and Melanie Waldenberger and Zhijun Xie and Magdalena Zoledziewska and Andrew Tinker and Ozren Polasek and Jonathan Rosand and Yalda Jamshidi and {van Duijn}, {Cornelia M.} and Eleftheria Zeggini and {Wouter Jukema}, J and Asselbergs, {Folkert W.} and Samani, {Nilesh J.} and Terho Lehtim{\"a}ki and Vilmundur Gudnason and James Wilson and Lubitz, {Steven A.} and Stefan K{\"a}{\"a}b and Nona Sotoodehnia and Caulfield, {Mark J.} and Palmer, {Colin N A} and Serena Sanna and Mook-Kanamori, {Dennis O.} and Panos Deloukas and Oluf Pedersen and Rotter, {Jerome I.} and Marcus D{\"o}rr and O'Donnell, {Chris J} and Caroline Hayward and Arking, {Dan E.} and Charles Kooperberg and {van der Harst}, Pim and Mark Eijgelsheim and Stricker, {Bruno H. C.} and Munroe, {Patricia B.}",
note = "Several pages of acknowledgements, includes COAF and RCUK funding",
year = "2017",
month = "6",
day = "15",
doi = "10.1093/hmg/ddx113",
language = "English",
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, Y-P, 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, L-P, 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, RA, 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, S-J, Kähönen, M, Kanters, JK, Kolcic, I, Launer, LJ, Li, M, Yao, J, Linneberg, A, Liu, S, Macfarlane, PW, Mangino, M, Morris, AD, Mulas, A, Murray, AD, Nelson, CP, Orrú, M, Padmanabhan, S, Peters, A, Porteous, DJ, Poulter, NR, Psaty, BM, Qi, L, Raitakari, OT, Rivadeneira, F, Roselli, C, Rudan, I, Sattar, N, Sever, P, Sinner, MF, Soliman, EZ, Spector, TD, Stanton, AV, Stirrups, KE, Taylor, KD, Tobin, MD, Uitterlinden, AG, Vaartjes, I, Hoes, AW, van der Meer, P, Völker, U, Waldenberger, M, Xie, Z, Zoledziewska, M, Tinker, A, Polasek, O, Rosand, J, Jamshidi, Y, van Duijn, CM, Zeggini, E, Wouter Jukema, J, Asselbergs, FW, Samani, NJ, Lehtimäki, T, Gudnason, V, Wilson, J, Lubitz, SA, Kääb, S, Sotoodehnia, N, Caulfield, MJ, Palmer, CNA, Sanna, S, Mook-Kanamori, DO, Deloukas, P, Pedersen, O, Rotter, JI, Dörr, M, O'Donnell, CJ, Hayward, C, Arking, DE, Kooperberg, C, van der Harst, P, Eijgelsheim, M, Stricker, BHC & Munroe, PB 2017, 'Discovery of novel heart rate-associated loci using the Exome Chip', Human Molecular Genetics, vol. 26, no. 12, pp. 2346-2363. https://doi.org/10.1093/hmg/ddx113

Discovery of novel heart rate-associated loci using the Exome Chip. / van den Berg, Marten E; Warren, Helen R.; Cabrera, Claudia P; Verweij, Niek; Mifsud, Borbala; Haessler, Jeffrey; Bihlmeyer, Nathan A.; Fu, Yi-Ping; Weiss, Stefan; Lin, Henry J; Grarup, Niels; Li-Gao, Ruifang; Pistis, Giorgio; Shah, Nabi; Brody, Jennifer A.; Müller-Nurasyid, Martina; Lin, Honghuang; Mei, Hao; Smith, Albert V.; Lyytikäinen, Leo-Pekka; Hall, Leanne M.; van Setten, Jessica; Trompet, Stella; Prins, Bram P; Isaacs, Aaron; Radmanesh, Farid; Marten, Jonathan; Entwistle, Aiman; Kors, Jan A.; Silva, Claudia T; Alonso, Alvaro; Bis, Joshua C.; de Boer, Rudolf A.; de Haan, Hugoline G.; de Mutsert, Renée; Dedoussis, George; Dominiczak, Anna F.; Doney, Alex S F; Ellinor, Patrick T.; Eppinga, Ruben N; Felix, Stephan B.; Guo, Xiuqing; Hagemeijer, Yanick; Hansen, Torben; Harris, Tamara B.; Heckbert, Susan R.; Huang, Paul L.; Hwang, Shih-Jen; Kähönen, Mika ; Kanters, Jørgen K; Kolcic, Ivana; Launer, Lenore J.; Li, Man; Yao, Jie; Linneberg, Allan; Liu, Simin; Macfarlane, Peter W; Mangino, Massimo; Morris, Andrew D; Mulas, Antonella; Murray, Alison D.; Nelson, Christopher P.; Orrú, Marco; Padmanabhan, Sandosh; Peters, Annette; Porteous, David J.; Poulter, Neil R.; Psaty, Bruce M.; Qi, Lihong; Raitakari, Olli T.; Rivadeneira, Fernando; Roselli, Carolina; Rudan, Igor; Sattar, Naveed; Sever, Peter; Sinner, Moritz F.; Soliman, Elsayed Z.; Spector, Timothy D.; Stanton, Alice V.; Stirrups, Kathleen E.; Taylor, Kent D.; Tobin, Martin D.; Uitterlinden, André G.; Vaartjes, Ilonca; Hoes, Arno W; van der Meer, Peter; Völker, Uwe; Waldenberger, Melanie; Xie, Zhijun; Zoledziewska, Magdalena; Tinker, Andrew; Polasek, Ozren; Rosand, Jonathan; Jamshidi, Yalda; van Duijn, Cornelia M.; Zeggini, Eleftheria; Wouter Jukema, J; Asselbergs, Folkert W.; Samani, Nilesh J.; Lehtimäki, Terho; Gudnason, Vilmundur; Wilson, James; Lubitz, Steven A.; Kääb, Stefan; Sotoodehnia, Nona; Caulfield, Mark J.; Palmer, Colin N A; Sanna, Serena; Mook-Kanamori, Dennis O.; Deloukas, Panos; Pedersen, Oluf; Rotter, Jerome I.; Dörr, Marcus; O'Donnell, Chris J; Hayward, Caroline; Arking, Dan E.; Kooperberg, Charles; van der Harst, Pim; Eijgelsheim, Mark; Stricker, Bruno H. C.; Munroe, Patricia B. (Lead / Corresponding author).

In: Human Molecular Genetics, Vol. 26, No. 12, 15.06.2017, p. 2346-2363.

Research output: Contribution to journalArticle

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 A.

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

AU - Kolcic, Ivana

AU - Launer, Lenore J.

AU - Li, Man

AU - Yao, Jie

AU - Linneberg, Allan

AU - Liu, Simin

AU - Macfarlane, Peter W

AU - Mangino, Massimo

AU - Morris, Andrew D

AU - Mulas, Antonella

AU - Murray, Alison D.

AU - Nelson, Christopher P.

AU - Orrú, Marco

AU - Padmanabhan, Sandosh

AU - Peters, Annette

AU - Porteous, David J.

AU - Poulter, Neil R.

AU - Psaty, Bruce M.

AU - Qi, Lihong

AU - Raitakari, Olli T.

AU - Rivadeneira, Fernando

AU - Roselli, Carolina

AU - Rudan, Igor

AU - Sattar, Naveed

AU - Sever, Peter

AU - Sinner, Moritz F.

AU - Soliman, Elsayed Z.

AU - Spector, Timothy D.

AU - Stanton, Alice V.

AU - Stirrups, Kathleen E.

AU - Taylor, Kent D.

AU - Tobin, Martin D.

AU - Uitterlinden, André G.

AU - Vaartjes, Ilonca

AU - Hoes, Arno W

AU - van der Meer, Peter

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Xie, Zhijun

AU - Zoledziewska, Magdalena

AU - Tinker, Andrew

AU - Polasek, Ozren

AU - Rosand, Jonathan

AU - Jamshidi, Yalda

AU - van Duijn, Cornelia M.

AU - Zeggini, Eleftheria

AU - Wouter Jukema, J

AU - Asselbergs, Folkert W.

AU - Samani, Nilesh J.

AU - Lehtimäki, Terho

AU - Gudnason, Vilmundur

AU - Wilson, James

AU - Lubitz, Steven A.

AU - Kääb, Stefan

AU - Sotoodehnia, Nona

AU - Caulfield, Mark J.

AU - Palmer, Colin N A

AU - Sanna, Serena

AU - Mook-Kanamori, Dennis O.

AU - Deloukas, Panos

AU - Pedersen, Oluf

AU - Rotter, Jerome I.

AU - Dörr, Marcus

AU - O'Donnell, Chris J

AU - Hayward, Caroline

AU - Arking, Dan E.

AU - Kooperberg, Charles

AU - van der Harst, Pim

AU - Eijgelsheim, Mark

AU - Stricker, Bruno H. C.

AU - Munroe, Patricia B.

N1 - Several pages of acknowledgements, includes COAF and RCUK funding

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Background: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim: To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods: 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.Results: 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, 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, 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.Conclusion: Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

AB - Background: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim: To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods: 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.Results: 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, 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, 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.Conclusion: Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

KW - Heart rate

KW - Embryonic stem cells

KW - Lung

KW - Stem cells

KW - Chromatin

KW - Deoxyribonuclease i

KW - Fetal heart

U2 - 10.1093/hmg/ddx113

DO - 10.1093/hmg/ddx113

M3 - Article

VL - 26

SP - 2346

EP - 2363

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -

van den Berg ME, Warren HR, Cabrera CP, Verweij N, Mifsud B, Haessler J et al. Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics. 2017 Jun 15;26(12):2346-2363. https://doi.org/10.1093/hmg/ddx113