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 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 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 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 Stricker, Patricia B Munroe

Research output: Contribution to journalArticle

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Abstract

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

  • Journal Article
  • heart rate
  • lung
  • chromatin
  • follow-up
  • genes
  • genetics
  • heart
  • candidate disease gene
  • genome-wide association study
  • exome
  • biobanks
  • datasets

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

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; 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; 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; 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; Munroe, Patricia B.

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

Research output: Contribution to journalArticle

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, 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, 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, N, 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, A, 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, BH & 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
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
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 ; 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 ; 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 ; 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 ; 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{468b78a71256446eaef291f0024f9116,
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. 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 = "Journal Article, heart rate , lung, chromatin, follow-up, genes, genetics, heart, candidate disease gene, genome-wide association study , exome, biobanks, datasets",
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 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 Neil Poulter 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 Andr{\'e} Uitterlinden 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} and Munroe, {Patricia B}",
note = "Individual studies 1958BC: We are grateful for using the British 1958 Birth Cohort DNA collection. ARIC: The authors thank the staff and participants of the ARIC study for their important contributions. ASCOT: We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. BRIGHT: The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. CROATIA-Korcula: We would like to acknowledge the contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. Exome array genotyping was performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. ERF: We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions to the ERF study and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. GoDARTs: We are grateful to all the participants in this study, the general practitioners, the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The study complies with the Declaration of Helsinki. We acknowledge the support of the Health Informatics Centre, University of Dundee for managing and supplying the anonymized data and NHS Tayside, the original data owner. GRAPHIC: This work falls under the portfolio of research supported by the NIHR Leicester Cardiovascular Biomedical Research Unit. GS:SFHS: We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/89). HELIC: The MANOLIS cohort is named in honour of Manolis Giannakakis, 1978–2010. We thank the residents of the Mylopotamos villages, and of the Pomak villages, for taking part. The HELIC study has been supported by many individuals who have contributed to sample collection (including Antonis Athanasiadis, Olina Balafouti, Christina Batzaki, Georgios Daskalakis, Eleni Emmanouil, Chrisoula Giannakaki, Margarita Giannakopoulou, Anastasia Kaparou, Vasiliki Kariakli, Stella Koinaki, Dimitra Kokori, Maria Konidari, Hara Koundouraki, Dimitris Koutoukidis, Vasiliki Mamakou, Eirini Mamalaki, Eirini Mpamiaki, Maria Tsoukana, Dimitra Tzakou, Katerina Vosdogianni, Niovi Xenaki, Eleni Zengini), data entry (Thanos Antonos, Dimitra Papagrigoriou, Betty Spiliopoulou), sample logistics (Sarah Edkins, Emma Gray), genotyping (Robert Andrews, Hannah Blackburn, Doug Simpkin, Siobhan Whitehead), research administration (Anja Kolb-Kokocinski, Carol Smee, Danielle Walker) and informatics (Martin Pollard, Josh Randall). JHS: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN 268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. KORA: We thank all KORA participants and staff members as well as Nadine Lindemann and Franziska Scharl involved in the generation of the SNP data. Lifelines: We thank U. Bultmann (1), J.M. Geleijnse (2), P. van der Harst (3), S. Mulder (4), J.G.M. Rosmalen (5), E.F.C. van Rossum (6), H.A. Smit (7), M. Swertz (8), E.A.L.M. Verhagen (9) (1) Department of Social Medicine, University Medical Center Groningen, University of Groningen, The Netherlands, (2) Department of Human Nutrition, Wageningen University, The Netherlands, (3) Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands, (4) Lifelines Cohort Study, The Netherlands, (5) Interdisciplinary Center of Psychopathology of Emotion Regulation (ICPE), Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands, (6) Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands, (7) Department of Public Health, University Medical Center Utrecht, The Netherlands, (8) Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands, (9) Department of Public and Occupational Health, VU Medical Center, Amsterdam, The Netherlands. NEO: The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de G{\'e}notypage (Paris, France), headed by Jean-Francois Deleuze. RS: The generation and management of the Illumina Exome Chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Ms Mila Jhamai, Ms Sarah Higgins and Mr Marijn Verkerk for their help in creating the Exome Chip database, and Carolina Medina-Gomez, MSc, Lennard Karsten, MSc and Linda Broer PhD for QC and variant calling. Variants were called using the best practice protocol developed by Grove et al. as part of the CHARGE consortium Exome Chip central calling effort SardiNIA: We thank all the volunteers who generously participated in this study and made this research possible. SHIP: We thank all SHIP and SHIP-TREND participants and staff members as well as the genotyping staff involved in the generation of the SNP data. WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents{\%}20{\%}20Write{\%} 20a{\%}20Paper/WHI{\%}20Investigator{\%}20Long{\%}20List.pdf YFS: The expert technical assistance in the statistical analyses by Irina Lisinen is gratefully acknowledged. UK Biobank: This research has been conducted using the UK Biobank Resource Application Number 9628. Conflicts of Interest statement. Dr B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr P.T.E. is the PI on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. Dr N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents or both and consultancy fees. Dr P.S. has received research awards from Pfizer. Dr M.J.C. is Chief Scientist for Genomics England, a UK government company.",
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",

}

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

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

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

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

AU - Munroe, Patricia B

N1 - Individual studies 1958BC: We are grateful for using the British 1958 Birth Cohort DNA collection. ARIC: The authors thank the staff and participants of the ARIC study for their important contributions. ASCOT: We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. BRIGHT: The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. CROATIA-Korcula: We would like to acknowledge the contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. Exome array genotyping was performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. ERF: We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions to the ERF study and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. GoDARTs: We are grateful to all the participants in this study, the general practitioners, the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The study complies with the Declaration of Helsinki. We acknowledge the support of the Health Informatics Centre, University of Dundee for managing and supplying the anonymized data and NHS Tayside, the original data owner. GRAPHIC: This work falls under the portfolio of research supported by the NIHR Leicester Cardiovascular Biomedical Research Unit. GS:SFHS: We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/89). HELIC: The MANOLIS cohort is named in honour of Manolis Giannakakis, 1978–2010. We thank the residents of the Mylopotamos villages, and of the Pomak villages, for taking part. The HELIC study has been supported by many individuals who have contributed to sample collection (including Antonis Athanasiadis, Olina Balafouti, Christina Batzaki, Georgios Daskalakis, Eleni Emmanouil, Chrisoula Giannakaki, Margarita Giannakopoulou, Anastasia Kaparou, Vasiliki Kariakli, Stella Koinaki, Dimitra Kokori, Maria Konidari, Hara Koundouraki, Dimitris Koutoukidis, Vasiliki Mamakou, Eirini Mamalaki, Eirini Mpamiaki, Maria Tsoukana, Dimitra Tzakou, Katerina Vosdogianni, Niovi Xenaki, Eleni Zengini), data entry (Thanos Antonos, Dimitra Papagrigoriou, Betty Spiliopoulou), sample logistics (Sarah Edkins, Emma Gray), genotyping (Robert Andrews, Hannah Blackburn, Doug Simpkin, Siobhan Whitehead), research administration (Anja Kolb-Kokocinski, Carol Smee, Danielle Walker) and informatics (Martin Pollard, Josh Randall). JHS: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN 268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. KORA: We thank all KORA participants and staff members as well as Nadine Lindemann and Franziska Scharl involved in the generation of the SNP data. Lifelines: We thank U. Bultmann (1), J.M. Geleijnse (2), P. van der Harst (3), S. Mulder (4), J.G.M. Rosmalen (5), E.F.C. van Rossum (6), H.A. Smit (7), M. Swertz (8), E.A.L.M. Verhagen (9) (1) Department of Social Medicine, University Medical Center Groningen, University of Groningen, The Netherlands, (2) Department of Human Nutrition, Wageningen University, The Netherlands, (3) Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands, (4) Lifelines Cohort Study, The Netherlands, (5) Interdisciplinary Center of Psychopathology of Emotion Regulation (ICPE), Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands, (6) Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands, (7) Department of Public Health, University Medical Center Utrecht, The Netherlands, (8) Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands, (9) Department of Public and Occupational Health, VU Medical Center, Amsterdam, The Netherlands. NEO: The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. RS: The generation and management of the Illumina Exome Chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Ms Mila Jhamai, Ms Sarah Higgins and Mr Marijn Verkerk for their help in creating the Exome Chip database, and Carolina Medina-Gomez, MSc, Lennard Karsten, MSc and Linda Broer PhD for QC and variant calling. Variants were called using the best practice protocol developed by Grove et al. as part of the CHARGE consortium Exome Chip central calling effort SardiNIA: We thank all the volunteers who generously participated in this study and made this research possible. SHIP: We thank all SHIP and SHIP-TREND participants and staff members as well as the genotyping staff involved in the generation of the SNP data. WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write% 20a%20Paper/WHI%20Investigator%20Long%20List.pdf YFS: The expert technical assistance in the statistical analyses by Irina Lisinen is gratefully acknowledged. UK Biobank: This research has been conducted using the UK Biobank Resource Application Number 9628. Conflicts of Interest statement. Dr B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr P.T.E. is the PI on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. Dr N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents or both and consultancy fees. Dr P.S. has received research awards from Pfizer. Dr M.J.C. is Chief Scientist for Genomics England, a UK government company.

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. 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 - 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 - Journal Article

KW - heart rate

KW - lung

KW - chromatin

KW - follow-up

KW - genes

KW - genetics

KW - heart

KW - candidate disease gene

KW - genome-wide association study

KW - exome

KW - biobanks

KW - datasets

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 -