The genetic architecture of heart rate and the electrocardiogram at rest and during exercise
Lead Research Organisation:
Queen Mary University of London
Department Name: William Harvey Research Institute
Abstract
Heart rhythm abnormalities (beating too fast or too slow) affect more than 2 million people per year in the UK, and the consequences are a significant clinical burden. At the most malignant end of the spectrum this can result in people dying suddenly but other patterns of heart rhythm abnormality are also a leading and underestimated cause of stroke. There are data indicating genes are important, but our knowledge is limited. Heart rhythm abnormalities can be detected as changes in electrical signals, and these are identified using an electrocardiogram (ECG), a test that shows the hearts electrical activity as line tracings on a piece of paper. Prior work has indicated that measures taken from the ECG, for example heart rate, during and after exercise are strongly associated with the risk of sudden death. We propose to study the effects of exercise on heart rhythm, and will determine the genes influencing this response, as we believe exercise will amplify inherited differences. UK Biobank is a national resource for scientific research, and it has ~ 95,000 individuals who have had an exercise ECG. In a pilot study we have derived a series of measures from the ECG taken at rest, during exercise and after exercise using custom-made methods from 85 individuals. The results indicate that we can successfully extract the exercise ECG measures we are interested in. We now wish to expand the study to everyone who has had an exercise ECG, and perform tests to assess if exercise ECG measures are inherited, and further genetic studies to discover new genes. The results from this study will provide important information on genes influencing our response to exercise and recovery that will provide new insights into mechanisms, and the project also has the potential to find new genes that we can target to develop new therapies.
Technical Summary
Rate and autonomic dependent changes in cardiac electrophysiology are fundamental in the genesis of many cardiac arrhythmias, including atrial and ventricular fibrillation. Genetic factors are known to be important, however we have limited knowledge of their identity. We wish to study the effects of exercise on cardiac excitability and establish the genetic architecture of dynamic electrophysiological parameters apparent on exercise. The results will reveal genes influencing our cardiovascular response to exercise and recovery. This knowledge will provide new insights into the molecular mechanisms of arrhythmias, and has the potential to identify drug targets for arrhythmia, and may also permit risk stratification for patients.
Hypothesis: There is a specific set of genetic loci that determine human cardiac electrophysiological parameters influenced by exercise.
Aims:
1.To derive resting and exercise ECG traits using bespoke algorithms.
2.To perform heritability analysis of dynamic electrophysiological parameters.
3.To perform GWAS to further understand the genetic architecture of resting and dynamic ECG traits.
Methodology: UK Biobank has exercise ECG data acquired from ~ 95,000 individuals who have corresponding genomic data, this offers a unique opportunity to test this hypothesis. In a pilot study, we have successfully extracted a range of dynamic ECG parameters from data on 89 individuals using bespoke algorithms. This project will expand analysis to all exercise ECGs enabling heritability analyses for ECG dynamic phenotypes for the first time. This will be complemented with existing work, particularly regarding resting heart rate data from genetic consortia (where we co-lead analyses).
Hypothesis: There is a specific set of genetic loci that determine human cardiac electrophysiological parameters influenced by exercise.
Aims:
1.To derive resting and exercise ECG traits using bespoke algorithms.
2.To perform heritability analysis of dynamic electrophysiological parameters.
3.To perform GWAS to further understand the genetic architecture of resting and dynamic ECG traits.
Methodology: UK Biobank has exercise ECG data acquired from ~ 95,000 individuals who have corresponding genomic data, this offers a unique opportunity to test this hypothesis. In a pilot study, we have successfully extracted a range of dynamic ECG parameters from data on 89 individuals using bespoke algorithms. This project will expand analysis to all exercise ECGs enabling heritability analyses for ECG dynamic phenotypes for the first time. This will be complemented with existing work, particularly regarding resting heart rate data from genetic consortia (where we co-lead analyses).
Planned Impact
Academia:
We expect our project to have a strong direct impact in the academic community in near and short term. Our work will generate new scientific knowledge about the genetic determinants of heart rate and dynamic electrophysiological parameters, and therefore basic scientists, geneticists and researchers in electrophysiology and cardiology will all benefit from the research outputs. We have an agreement with UK Biobank to deposit results of the ECG analysis, including heart rate profile and dynamics of the most important cardiac intervals during exercise. This will be valuable information for anyone working in cardiac epidemiology that has expertise to develop improved strategies to combat and predict sudden cardiac death. Our detailed analysis of the pattern of response of heart rate and cardiac activation/repolarization to exercise is expected to be of interest for researchers in cardiology. This analysis performed at large scale on this unique data-set will help to define the normal and abnormal dynamic response to exercise and this will be of interest to clinicians. Over the three-years, we will improve existing software for ECG analysis and develop new statistical techniques related to big-data analysis. This work will be of also be of great value for researchers working in biomedical engineering.
Commercial, policy makers and regulators:
The results from this project will not be clinically or commercially relevant in the near or short term. However, the methods and results from the research could help in the predicting sudden cardiac death based on dynamic electrophysiological markers, and may identify new therapeutic targets. We would be in a position to follow this up as we have established collaborations with both academia and industry. We do not expect any major impact of our research findings on clinical practice in the near or short term, however with the big data-sets we are analyzing and the rich phenotypic dataset we have access to in UK Biobank it maybe that the genetic modifiers we identify will be useful for diagnosis and treating disease earlier and more efficaciously than is currently possible.
We expect our project to have a strong direct impact in the academic community in near and short term. Our work will generate new scientific knowledge about the genetic determinants of heart rate and dynamic electrophysiological parameters, and therefore basic scientists, geneticists and researchers in electrophysiology and cardiology will all benefit from the research outputs. We have an agreement with UK Biobank to deposit results of the ECG analysis, including heart rate profile and dynamics of the most important cardiac intervals during exercise. This will be valuable information for anyone working in cardiac epidemiology that has expertise to develop improved strategies to combat and predict sudden cardiac death. Our detailed analysis of the pattern of response of heart rate and cardiac activation/repolarization to exercise is expected to be of interest for researchers in cardiology. This analysis performed at large scale on this unique data-set will help to define the normal and abnormal dynamic response to exercise and this will be of interest to clinicians. Over the three-years, we will improve existing software for ECG analysis and develop new statistical techniques related to big-data analysis. This work will be of also be of great value for researchers working in biomedical engineering.
Commercial, policy makers and regulators:
The results from this project will not be clinically or commercially relevant in the near or short term. However, the methods and results from the research could help in the predicting sudden cardiac death based on dynamic electrophysiological markers, and may identify new therapeutic targets. We would be in a position to follow this up as we have established collaborations with both academia and industry. We do not expect any major impact of our research findings on clinical practice in the near or short term, however with the big data-sets we are analyzing and the rich phenotypic dataset we have access to in UK Biobank it maybe that the genetic modifiers we identify will be useful for diagnosis and treating disease earlier and more efficaciously than is currently possible.
Publications
Besleaga T
(2020)
Real Time Non-Invasive Hemodynamic Assessment of Ventricular Tachycardia
in IEEE Access
Fung K
(2019)
Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants.
in Scientific reports
Jafarkhanloo Rezaei M
(2020)
Data augmentation for heart arrhythmia classification
Mensah-Kane J
(2021)
No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis.
in Frontiers in genetics
Munroe PB
(2019)
Resting Heart Rate and Type 2 Diabetes: A Complex Relationship in Need of Greater Understanding.
in Journal of the American College of Cardiology
Munroe PB
(2018)
Heritability of resting heart rate and association with mortality in middle-aged and elderly twins.
in Heart (British Cardiac Society)
Ntalla I
(2020)
Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.
in Nature communications
Orini M
(2023)
Long-term association of ultra-short heart rate variability with cardiovascular events.
in Scientific reports
Description | ECG morphology clusters for sudden cardiac death risk stratification in coronary artery disease using genetics and human-based computational models. PI Ramirez, Munroe and Electrogenomics Team collaborator |
Amount | € 122,210 (EUR) |
Funding ID | a. PID2021-128972OA-I00 |
Organisation | Ministry of Science and Innovation (MICINN) |
Sector | Public |
Country | Spain |
Start | 09/2022 |
End | 08/2024 |
Description | Genetic analyses of ventricular depolarisation and repolarisation and prediction of cardiovascular risk. |
Amount | £206,595 (GBP) |
Funding ID | MR/R017468/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2018 |
End | 04/2021 |
Description | Marie Curie |
Amount | € 183,454 (EUR) |
Funding ID | 786833 |
Organisation | Marie Curie |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 02/2021 |
Description | Pathways of calcium signalling in atrial fibrillation highlighted by genomic and transcriptomic studies |
Amount | £246,443 (GBP) |
Funding ID | MR/T00052X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2019 |
End | 09/2022 |
Description | WHRI-ACADEMY - William Harvey International Translational Research Academy, International Fellowship Programme, FP7 Marie Curie Actions - People, Co-funding of regional, national and international programmes (COFUND) |
Amount | € 69,272 (EUR) |
Funding ID | PCOFUND-GA-2013-608765 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 10/2017 |
End | 12/2018 |
Title | GWAS Summary statistics for PR interval |
Description | We have provided summary statistics for our GWAS for PR interval |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease. |
Title | GWAS Summary statistics for TMR (repolarisation dynamics) |
Description | We have provided summary statistics for our GWAS for TMR |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease. |
Title | GWAS Summary statistics for dynamic QT traits |
Description | We have provided summary statistics for our GWAS for QT dynamic traits. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease. |
Title | GWAS Summary statistics for resting QT interval |
Description | We have provided summary statistics for our GWAS for resting QT interval. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease and genetic pleiotropy. |
Title | GWAS Summary statistics for resting and dynamic Tpe traits |
Description | We have provided summary statistics for our GWAS results. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease. |
Title | GWAS lead variants for calcium and albumin corrected calcium |
Description | We have provided lead variants from the largest calcium and albumin-corrected calcium to date |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for other related diseases. |
Title | GWAS summary statistics for heart rate dynamic traits |
Description | We have provided summary statistics for our GWAS for heart rate dynamic traits. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Our results provide a resource for other investigators analysing risk factors for CV disease. |
Title | Lead GWAS variants for QT, JT intervals and QRS duration |
Description | We provide lead variants from multi-ancestry and ancestry specific analyses of the QT, JT intervals and QRS duration from genome-wide association study. We also highlighted potential druggable targets. The data has been made freely available on GWAS catalog (https://www.ebi.ac.uk/gwas/publications/36050321) . This data will be used by other researchers to explore biological mechanisms of disease and develop risk stratification tools. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | There is no impact at this stage. |
Title | Lead variants for spatial and frontal QRS-T angles |
Description | We provide lead variants from multi-ancestry and ancestry specific analyses of the frontal and spatial QRS-T angles from genome-wide association study. The data has been made freely available on GWAS catalog (https://www.ebi.ac.uk/: Study accession numbers GCST90246318, GCST90246320, GCST90246322, GCST90246324 for Multi-ancestry, European, African and Hispanic ancestry meta-analyses for the spatial QRS-T angle, respectively. Study accession numbers GCST90246319, GCST90246321, GCST90246323, GCST90246325 for Multi-ancestry, European, African and Hispanic ancestry meta-analyses for the frontal QRS-T angle, respectively). This data will be used by other researchers to explore biological mechanisms of disease and develop risk stratification tools. |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | Yes |
Impact | No impact yet |
Description | BHF Press release - Could your smart watch alert you to risk of sudden death? |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | This press release describes results from development of an algorithm able to quantify sudden cardiac death risk from a single beat in a single lead. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2021/june/smart-watch-alert-to-risk... |
Description | Barts & Queen Mary Science festival June 2021"Beat your heart!" |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 16 pupils, their teacher and a member of the patient advisory panel attended a virtual session as part of the Barts Science Festival in June 2021 for a one hour session covering the relationships of heart rhythm disorders with genetics. This sparked many questions afterwards and a discussion. Four members of the team organised this activity. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.qmul.ac.uk/whri/patient-public-engagement/barts-and-queen-mary-science-festival/ |
Description | Career Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Mini-Symposium on "Clinical Translation of Genetic Research: A Path from Academia to Industry" Wednesday 28th April 2018. London, UK, https://allevents.in/london/clinical-translation-of-genetic-research-a-path-from-academia-to-industry/1000043017286863. This activity was organised by the two post-docs on the grant - they were interested in engaging with other genetic researchers across academia and industry to gauge their experiences and set up new collaborations. The workshop was very well attended and excellent feedback was received which we have recorded. |
Year(s) Of Engagement Activity | 2018 |
Description | I Newspaper Press release - Smart watches could detect risk of sudden cardiac death - and save lives. |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | This press release describes results from development of an algorithm able to quantify sudden cardiac death risk from a single beat in a single lead. |
Year(s) Of Engagement Activity | 2021 |
URL | https://inews.co.uk/news/health/smart-watches-could-detect-risk-sudden-cardiac-death-1037966 |
Description | News on QMUL website - Discovery of New Genes Modulating the Tpe Interval: an Electrocardiographic risk marker for Sudden Cardiac Death |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | We wished to highlight our recent study discovering 38 new gene regions that influencing the Tpe interval, an electrocardiographic marker associated with susceptibility to malignant ventricular arrhythmias and sudden cardiac death. Feedback has included interest from students wishing to study with us. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.qmul.ac.uk/whri/latest-news/items/discovery-of-new-genes-modulating-the-tpe-interval-an-... |
Description | Press release - QMUL and UCL joint study identifies genes linked to impaired capacity to modulate heart rate during and after exercise |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | This press release describes results from the first analysis investigating the genetic basis of how heart rate responds during and following exercise. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.qmul.ac.uk/whri/latest-news/items/qmul-and-ucl-joint-study-identifies-genes-linked-to-im... |
Description | Press release - Scientists discover more than 200 genetic factors causing heart arrhythmias |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | We wished to widely disseminate results from this study a wide audience as results could one day lead to advanced screening methods to discern who is at greatest risk of developing cardiovascular disease. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.qmul.ac.uk/media/news/2020/smd/scientists-discover-more-than-200-genetic-factors-causing... |
Description | Public engagement - Genetics and the Electrocardiogram to predict arrhythmic risk |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Let's Talk Hearts is supported by NIHR Barts Biomedical Research Centre. It is open to all providing a forum to learn about heart conditions and latest research. Dr Ramirez described work from both her fellowship and the Electrogenomics group, showcasing the research we do. The session provoked lots of interest, questions and discussion to the local community. |
Year(s) Of Engagement Activity | 2020 |
URL | http://www.letstalkhearts.info |
Description | QMUL Press release - Could your smart watch alert you to risk of sudden death? |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | This press release describes results from development of an algorithm able to quantify sudden cardiac death risk from a single beat in a single lead. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.qmul.ac.uk/whri/latest-news/items/could-your-smart-watch-alert-you-to-risk-of-sudden-dea... |
Description | Special session - Role of Statistical Genetics in Assessing Cardiovas-cular Risk. Challenges and Potential |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a special session at the Computing in Cardiology conference in September 2020. The format was hybrid - participants online and in Rimini. Members of the group organised, chaired and presented at the session. The purpose was to introduce genetics to this meeting, highlighting our work and to encourage new collaborations. The feedback was excellent and there was over 100 attendees. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.cinc2020.org/scientific-program-overview/ |