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 language | English |
|---|---|
| Pages (from-to) | 2346-2363 |
| Number of pages | 18 |
| Journal | Human Molecular Genetics |
| Volume | 26 |
| Issue number | 12 |
| Early online date | 3 Apr 2017 |
| DOIs | |
| Publication status | Published - 15 Jun 2017 |
Bibliographical note
Individual studies1958BC: 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.
Keywords
- Journal Article
- heart rate
- lung
- chromatin
- follow-up
- genes
- genetics
- heart
- candidate disease gene
- genome-wide association study
- exome
- biobanks
- datasets
Access to Document
- Discovery of novel heart rate-associated loci using the Exome Chip
Copyright The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.