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.
Original language | English |
---|---|
Journal | Human Molecular Genetics |
Volume | 26 |
Issue number | 12 |
Pages (from-to) | 2346-2363 |
Number of pages | 18 |
ISSN | 0964-6906 |
DOIs | |
Publication status | Published - 15 Jun 2017 |
Keywords
- Journal Article
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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, Xiao Jie; Linneberg, Allan; Liu, Simin; Macfarlane, Peter W; Mangino, Massimo; Morris, Andrew D; Mulas, Antonella; Murray, Alison D; Nelson, Christopher P; Orrù, Marco; Padmanabhan, Sandosh; Peters, Annette; Porteous, David J; Poulter, Neil; 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, Andre; 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, Cornélia M; Zeggini, Eleftheria; Jukema, J Wouter; 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 Ch; Munroe, Patricia B.
In: Human Molecular Genetics, Vol. 26, No. 12, 15.06.2017, p. 2346-2363.Research output: Contribution to journal › Journal article › Research › peer-review
}
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, Xiao 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 - Orrù, Marco
AU - Padmanabhan, Sandosh
AU - Peters, Annette
AU - Porteous, David J
AU - Poulter, Neil
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, Andre
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, Cornélia M
AU - Zeggini, Eleftheria
AU - Jukema, J Wouter
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 Ch
AU - Munroe, Patricia B
N1 - © The Author 2017. Published by Oxford University Press.
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.
KW - Journal Article
U2 - 10.1093/hmg/ddx113
DO - 10.1093/hmg/ddx113
M3 - Journal article
C2 - 28379579
VL - 26
SP - 2346
EP - 2363
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 12
ER -