Genetic analyses of ventricular depolarisation and repolarisation and prediction of cardiovascular risk.

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

Abnormal electrical conduction through the heart is associated with dangerous heart rhythms that can cause sudden death. At present, the exact causes of these abnormal heart rhythms are unknown, however research has shown that genetics plays a significant role in an individual's risk profile. Genes are made of DNA, and they provide instructions to make proteins which influence growth and development of all cells in the body. Small changes in the make up of a gene can alter its function or change the way it provides information to the body. It is becoming increasingly understood that a person's risk of sudden death is due to many small variations in genes combined rather than one single change.
Electrocardiograms (ECGs) are a non-invasive method of recording electrical activity within the heart. Different time points on the ECG refer to when the bottom chambers of the heart (ventricles) contract to pump blood around the body, or relax to their resting state. The QRS interval on an ECG is related to ventricle contraction, while the JT interval is specific for when the ventricles return to their resting state. The QT interval refers to the period from the beginning of the QRS interval to the end of the JT interval. Another important marker which is calculated from many leads on an ECG is spatial QRS-T angle. This represents electrical conduction in the heart in a three dimensional manner during ventricle contraction and relaxation and could represent different biological processes compared with other ECG parameters. Changes in the duration of these ECG parameters are associated with the development of abnormal heart rhythms and sudden cardiac death.
Previous smaller studies have identified genetic changes (variants) influencing the duration of QT, JT and QRS intervals however a large proportion of the genetic contribution to these ECG markers remains unexplained. This is likely due to the size of previous studies and lack of power to detect rare variants. We will conduct the largest study to date, for QT, JT and QRS intervals which will have greater power to detect variants that are as yet unidentified including less common or rare variants which may have a greater effect on the duration of these ECG traits.
We will also perform a study to determine the genetic contribution to spatial QRST angle, which has never been studied before. As it offers a global assessment of cardiac ventricular conduction compared with other ECG traits, we anticipate we will identify new pathways and biological mechanisms for the generation of abnormal heart rhythms. Significant genetic variants identified from these studies will be extensively investigated using publically available datasets to map variants to pathways in cardiac function and arrhythmia generation. These analyses will help to improve our understanding of the role of these genetic variants in causing abnormal heart rhythms and could give insights into how to prevent or treat them in the future. We will also test for association between genetic variants and clinical outcomes including hospital admissions for abnormal heart rhythms, changes in heart chamber dimensions on scans and the risk of heart attacks or death.
At present, current markers for predicting abnormal heart rhythms and sudden death are not specific or sensitive enough to be used to test the general population. This research is designed to identify new genetic contributions to abnormal heart rhythms in order to improve risk prediction for sudden cardiac death and other adverse cardiac events. It will help identify people in the general population who would benefit from early treatment or monitoring to prevent disease. The results will aid physician decision making and help us understand what influences the health of the general population and their risk of significant cardiac disease.

Technical Summary

Genome wide association studies (GWAS) for QT, JT and QRS interval have provided new information on the underlying mechanisms behind ventricular depolarisation and repolarisation. However, the heritability of these traits is not fully explained, and further investigation is required into the utility of adopting common genetic variants for cardiac risk prediction in the clinical setting. The aims of this project are to identify new variants to utilise in multi-biomarker risk prediction for adverse cardiac events.

Methodology
We will perform the largest meta-analysis of GWAS to date, of QT, JT and QRS intervals in ~300,000 individuals using 1000 genomes and HRC imputation in collaboration with the CHARGE EKG consortium. We will also derive spatial QRS-T angle from 12 lead resting ECGs acquired from UK Biobank, and perform the first ever heritability study and GWAS on this trait in ~100,000 individuals using BOLT-RMM and BOLT-LMM software respectively. Identified variants will be extensively annotated using bioinformatics methods and publically available datasets, which will provide insight into their putative function in electrophysiological pathways and identify candidate genes. Using identified variants, using genetic risk scores, we will test for association with cardiovascular outcomes including left ventricular measurements on cardiac MRI, hospital admissions for tachyarrhythmia and mortality.

Scientific and medical opportunities
This project will contribute to our understanding of the pathophysiology of arrhythmia generation and sudden cardiac death. It may identify new targets for medical therapy by novel drug development or existing drug re-profiling. The data will enable Mendelian Randomisation studies to test the effects of specific drug interventions on clinical outcomes. Finally through inclusion of new biomarkers and subsequent risk score development, risk prediction for adverse cardiovascular outcomes in the general population could be improved.

Planned Impact

Currently the genomics industry is focused on sequencing and with costs continuing to fall this will facilitate the clinical application of genomic medicine. Through the production of risk scores using genomic variants, the industry will benefit from utilising sequencing techniques for application in clinical medicine. This will influence the genomic strategy at a government and private sector level, and will increase the output from an industry which is already significantly contribution to the UK economy. With the rapidly expanding genomic industry, development of skills in bioinformatics and genomics is necessary to meet its growth. This project will offer the fellow intensive training in this field including statistical genetics, bioinformatics tools and the use of genomics in translational medicine.

New candidate genes and pathways will facilitate further academic and clinical research into their functional role in arrhythmia. The pharmaceutical industry will benefit from the identification of new pathways or clarification of the roles of others in arrhythmogenesis, to use as targets for novel drug therapy or existing drug re-profiling; a cost and time effective method of drug development. Our research will also enable Mendelian Randomisation studies to test the effects of specific drug interventions on clinical outcomes as undertaken by the pharmcogenetics group under Prof. Hingorani at UCL. This represents a highly cost effective strategy to plan and execute clinical trials at a population level utilising genomic data. By stratifying specific groups according to their genomic profile, patients most likely to benefit form an intervention can be identified and targeted for therapy. Such an approach has already been used in coronary artery disease and type 2 diabetes. This will facilitate the de-risking of extremely expensive clinical trials.

Currently, general population screening for sudden cardiac death is not recommended due to concerns regarding the sensitivity and specificity of current risk prediction models and the potential cost implications; as recently debated in parliment. It was however agreed that there is an economic and social benefit to improving models to be able to implement general screening in the UK. By improving models through our research with the addition of new bio-risk markers, including low cost electrocardiographic genetic traits, risk prediction will be improved and affordable, supporting policy making for sudden cardiac death screening in the general population. Risk calculators could be incorporated into apps or websites facilitating use by clinicans as seen with current hypertrophic cardiomyopathy sudden cardiac death risk tools (http://www.doc2do.com/hcm/webHCM.html). By supporting clinical decision making, unnecessary device implantations could be prevented, avoiding adverse consequences from procedural complications or inappropriate shock therapy. By improving policy and incorporation into NICE guidelines, the quality of life of those at risk will be improved by ensuring those who need therapy receive it.

Importantly, this research could reduce mortality from sudden cardiac death. By reducing morbidity and mortality from arrhythmias, the nation's health and wealth would improve and positively affect the economy by increasing the number of people available for work as lethal arrhythmias often strike otherwise well individuals with preserved heart function. This impact following completion of our planned research, could be realised in the medium term. Arrhythmia and sudden cardiac death is a significant cause of morbidity and mortality internationally and thus there is a significantly wider impact of our research, potentially affecting policy globally. Charities and public health organisations including the British Heart Foundation and Arrhythmia Alliance will be able to use our findings to facilitate education and prevention strategies amongst the public and clinicians.

People

ORCID iD

Publications

10 25 50
 
Title ECG phenotypes in UK Biobank 
Description Use of ECG signal processing algorithms in Matlab to derive ECG parameters from raw ECG data obtained from participants of the UK Biobank study ECG parameters derived will at the end of the project, be returned to UK Biobank for other researchers to utilise (as with genotype-phenotype association results) Novel method for extracting the spatial QRS-T angle in the context of incorrect marker placement reported and published. 
Type Of Material Data analysis technique 
Year Produced 2021 
Provided To Others? Yes  
Impact ECG parameters derived will at the end of the project, be returned to UK Biobank for other researchers to utilise (as with genotype-phenotype association results) Algorithm derived for extracting the spatial QRS-T angle has been published and made freely available for download with the manuscript 
 
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. 
 
Description CHARGE EKG Consortium 
Organisation Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE)
Country Global 
Sector Academic/University 
PI Contribution Provided data from UK Biobank and BRIGHT study analyses of ECG phenotypes. Contributed to a large study evaluating the impact of serum electrolyte levels on ECG phenotypes. Lead analyst for three projects in collaboration with CHARGE as part of the CHARGE EKG working group. These involve large GWAS meta-analyses and the datasets generated from these are being used for bioinformatic analyses and risk prediction.
Collaborator Contribution n/a
Impact PMID: 31514169 PMID: 31221261
Start Year 2017
 
Description Calcium QT JT MR analysis 
Organisation Leiden University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Group meetings, analyses, dissemination of results, publication of relevant manuscript and presentation at an international cardiology conference
Collaborator Contribution Group meetings, analyses, dissemination of results, publication of relevant manuscript
Impact Manuscript published (see publication section) Presented at British Cardiovascular Society conference (see relevant section)
Start Year 2019
 
Description Collaboration with cardiomyopathy GWAS investigators 
Organisation Sorbonne University
Country France 
Sector Academic/University 
PI Contribution Performing relevant genetic analyses using summary data shared and sharing of our summary statistics
Collaborator Contribution Sharing of GWAS meta-analysis summary statistics for purpose of mendelian randomisation
Impact None at present - manuscript in process of being draft
Start Year 2021
 
Description Collaboration with cardiomyopathy GWAS investigators 
Organisation University of Oxford
Department Oxford Hub
Country United Kingdom 
Sector Academic/University 
PI Contribution Performing relevant genetic analyses using summary data shared and sharing of our summary statistics
Collaborator Contribution Sharing of GWAS meta-analysis summary statistics for purpose of mendelian randomisation
Impact None at present - manuscript in process of being draft
Start Year 2021
 
Description Attendance at China Kadoorie Biobank Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Attendance at China Kadoorie Biobank symposium to discuss current and future potential work.
Year(s) Of Engagement Activity 2018
 
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 teach 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.
Year(s) Of Engagement Activity 2021
 
Description Electrogenomics group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Presentation on the pilot study I completed, performing a GWAS on QT interval change on exercise. No significant variants were identified in this small pilot group however important learning points were identified which has assisted the group in performing a GWAS on the entire cohort. This includes how we were performing the signal processing, phenotype quality control and ajustment for confounding variables.
Year(s) Of Engagement Activity 2017
 
Description Genetically-determined serum calcium levels influence markers of ventricular repolarisation: a mendelian randomisation study - Conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Oral presentation at BCS annual conference.

Genetically-determined serum calcium levels influence markers of ventricular repolarisation: a mendelian randomisation study. Young W. British Cardiovascular Society Annual Conference, June 2021.
Year(s) Of Engagement Activity 2021
 
Description Presentation at CHARGE virtual meeting series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation during CHARGE virtual meeting on behalf of the CHARGE EKG working group detailing preliminary results of ongoing analyses. This increased awareness of current work and facilitated discussion afterwards with input from other working groups.
Year(s) Of Engagement Activity 2020
 
Description Special session - Role of Statistical Genetics in Assessing Cardiovascular 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. Along with other members of the electrogenomics group (J Ramirez, M Orini and S van Duijvenboden) I organised 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.
Year(s) Of Engagement Activity 2020
URL https://www.cinc2020.org/scientific-program-overview
 
Description TRANS-ANCESTRY GWAS OF 252,730 INDIVIDUALS IDENTIFIES 114 NOVEL LOCI ASSOCIATED WITH THE QT INTERVAL - Oral presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Oral presentation at the Heart Rhythm Society conference

TRANS-ANCESTRY GWAS OF 252,730 INDIVIDUALS IDENTIFIES 114 NOVEL LOCI ASSOCIATED WITH THE QT INTERVAL. July 2021.
Year(s) Of Engagement Activity 2021
 
Description Trans-ancestry GWAS of 118,780 Individuals Reveals Biological Mechanisms Underlying the Spatial QRS-T angle, a marker of arrhythmogenesis - Poster presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation at European Society of Human Genetics Conference.

Trans-ancestry GWAS of 118,780 Individuals Reveals Biological Mechanisms Underlying the Spatial QRS-T angle, a marker of arrhythmogenesis. Young W. September 2021.
Year(s) Of Engagement Activity 2021
 
Description Trans-ancestry GWASs for ECG markers of ventricular depolarization and repolarization in 250,730 individuals identifies shared and distinct mechanisms - poster presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation at American Society of Human Genetics annual conference

Trans-ancestry GWASs for ECG markers of ventricular depolarization and repolarization in 250,730 individuals identifies shared and distinct mechanisms. Young W, Isaacs A, Lahrouchi N, Mifsud B, Munroe PB, Newton-Cheh C, Sotoodehnia N, CHARGE consortium EKG working group. American Society of Human Genetics. October 2021.
Year(s) Of Engagement Activity 2021
URL https://www.ashg.org/wp-content/uploads/2022/01/2021-ASHG-Meeting-Abstracts.pdf