Periodic Reporting for period 2 - MOvE-ECG (Moving from genome wide association to elucidating causal mechanisms of electrocardiographic traits)
Reporting period: 2016-10-01 to 2017-09-30
Understanding how genes and genetic variants influence heart function is of major importance, not only from a basic science viewpoint but also as a foundation for future innovation in medicine and health-care. In this proposal, Dr. Niek Verweij has been working on the identification of genes and mechanisms that underlay heart growth and other ECG parameters. This has been performed in collaboration with the Dr. Chris Newton-Cheh (Harvard/Massachusetts General Hospital, Broad Institute of Harvard and MIT) and Dr. Laurie Boyer (MIT). This project was mainly focussed on the QRS-complex of the electrocardiogram in population-based studies as this reflects electrically active cardiac mass.
The main objectives were as follows.
1) To search for novel low-frequency genetic variants associated with the QRS-complex within the CHARGE consortium and within a Dutch population using dedicated reference panels.
2) To interrogate loci through the use of published and unpublished in silico big-data sets to further prioritize variants and regions for experimental follow-up aimed at elucidating biological mechanisms.
This overall aim of this project was to better understand heart failure susceptibility by bridging the gap between population-based genetic association studies and functional biology; to provide novel insights into cardiomyocyte functioning. This is a fundamental step to provide novel avenues for studying heart disease vulnerability and designing new treatment options.
The main objectives were as follows.
1) To search for novel low-frequency genetic variants associated with the QRS-complex within the CHARGE consortium and within a Dutch population using dedicated reference panels.
2) To interrogate loci through the use of published and unpublished in silico big-data sets to further prioritize variants and regions for experimental follow-up aimed at elucidating biological mechanisms.
This overall aim of this project was to better understand heart failure susceptibility by bridging the gap between population-based genetic association studies and functional biology; to provide novel insights into cardiomyocyte functioning. This is a fundamental step to provide novel avenues for studying heart disease vulnerability and designing new treatment options.
Summary of the main results achieved
- Increased electrocardiographic left ventricular mass (eLVM) is a characteristic of and risk factor for heart failure, as well as mortality in the general population. In total, from the start to the end of this project we have identified more than 70 genetic loci influencing eLVM; but even more genetic loci for electrocardiographic traits in general and coronary artery disease. 7 genes harboring rare/lowfrequency coding variants were associated with eLVM, of which several demonstrate tissue-specific expression in the heart.
- We found that many genetic loci identified for eLVM, share associations with other electrocardiographic parameters.
- The majority of electrocardiographic loci can be explained by epigenetic marks of the fetal heart, suggesting that the developmental stage of the heart is crucial for determining cardiac conduction and cardiac-size.
- Blood pressure is a causal factor determining Myocardial Mass.
- Furthermore, we continued our search for genetic determinants of heart failure by studying coronary artery disease (CAD) in up to 122,733 cases and 424,528 controls. We identified more than 75 new genetic loci associated with CAD that help to explain heart failure susceptibility. We showed that CAD is the major determinant of incident heart failure as 70% of CAD heritability is shared with heart failure. In addition, we highlight several potential drug targets for CAD.
Dissemination
- >12 peer-reviewed papers published.
- Numerous results are in preparation for publication, submitted or accepted at end of this project (about 5 papers)
- Results were presented at various international conferences and internal meetings across the Broad Institute of Harvard and MIT and The University of Groningen.
- We released press releases for the major publications. Several media outlets gave attention to research conducted by dr Verweij, including a front-page article in a major National newspaper (>200k print run) on a GWAS of heart rate and interviews of dr Verweij on his Marie Curie fellowship by 'the cardioloog'.
- dr. Verweij supervised several Master students during his Marie Curie Fellowship and is co-advisor (co-promoter) to 3Ph.D. students studying cardiovascular genetics ensuring knowledge transfer.
- To further engage the public, dr. Verweij gave lectures on Genetics during annual open days of the university medical center.
- Raw data can be found on www.cardiomics.net and open source repositories (e.g. Mendeley, GWAS catalog) which is referenced in each publication, to be used by other researchers to advance the field.
Deliverable and milestones
All deliverables and milestones of the project were successfully completed.
Final results and their potential impact and use
Dr. Verweij's research on Myocardial mass, electrocardiography and coronary artery disease in relation with heart failure, proved to significantly advance our fundamental understanding of myocardial biology and heart failure development. The results advance our understanding of cardiac development, coronary artery disease and heart failure; but it also provides a starting point for the development of new therapeutic targets. Furthermore we provided a wealth of in-silico and experimental data that can be used by other researchers to study cardiovascular genetics and advance the field forward.
- Increased electrocardiographic left ventricular mass (eLVM) is a characteristic of and risk factor for heart failure, as well as mortality in the general population. In total, from the start to the end of this project we have identified more than 70 genetic loci influencing eLVM; but even more genetic loci for electrocardiographic traits in general and coronary artery disease. 7 genes harboring rare/lowfrequency coding variants were associated with eLVM, of which several demonstrate tissue-specific expression in the heart.
- We found that many genetic loci identified for eLVM, share associations with other electrocardiographic parameters.
- The majority of electrocardiographic loci can be explained by epigenetic marks of the fetal heart, suggesting that the developmental stage of the heart is crucial for determining cardiac conduction and cardiac-size.
- Blood pressure is a causal factor determining Myocardial Mass.
- Furthermore, we continued our search for genetic determinants of heart failure by studying coronary artery disease (CAD) in up to 122,733 cases and 424,528 controls. We identified more than 75 new genetic loci associated with CAD that help to explain heart failure susceptibility. We showed that CAD is the major determinant of incident heart failure as 70% of CAD heritability is shared with heart failure. In addition, we highlight several potential drug targets for CAD.
Dissemination
- >12 peer-reviewed papers published.
- Numerous results are in preparation for publication, submitted or accepted at end of this project (about 5 papers)
- Results were presented at various international conferences and internal meetings across the Broad Institute of Harvard and MIT and The University of Groningen.
- We released press releases for the major publications. Several media outlets gave attention to research conducted by dr Verweij, including a front-page article in a major National newspaper (>200k print run) on a GWAS of heart rate and interviews of dr Verweij on his Marie Curie fellowship by 'the cardioloog'.
- dr. Verweij supervised several Master students during his Marie Curie Fellowship and is co-advisor (co-promoter) to 3Ph.D. students studying cardiovascular genetics ensuring knowledge transfer.
- To further engage the public, dr. Verweij gave lectures on Genetics during annual open days of the university medical center.
- Raw data can be found on www.cardiomics.net and open source repositories (e.g. Mendeley, GWAS catalog) which is referenced in each publication, to be used by other researchers to advance the field.
Deliverable and milestones
All deliverables and milestones of the project were successfully completed.
Final results and their potential impact and use
Dr. Verweij's research on Myocardial mass, electrocardiography and coronary artery disease in relation with heart failure, proved to significantly advance our fundamental understanding of myocardial biology and heart failure development. The results advance our understanding of cardiac development, coronary artery disease and heart failure; but it also provides a starting point for the development of new therapeutic targets. Furthermore we provided a wealth of in-silico and experimental data that can be used by other researchers to study cardiovascular genetics and advance the field forward.
Heart failure (HF) is an important contributor to both the burden and cost of healthcare expenditures, with older people suffering from HF more than from any other medical condition. With the aging of the population, the impact of HF is expected to increase substantially. Despite few advances in pharmacological treatment of HF, the prognosis remains very poor. The results of this project will advance our knowledge surrounding cardiomyocyte dysfunction which will eventually lead to novel therapeutic targets, better risk assessment and progress HF-health care and contribute to healthy ageing. In contrast to relative stagnation of HF-treatment, remarkable progress has been made in understanding human genetics, enabled by the sequence of the human genome and technologies for DNA analysis. To date, understanding the functional consequences of genetic variation is eagerly awaited in biomedical and genetic research. This study provides detailed insight into cardiomyocyte functioning, HF vulnerability and provide a pipeline approach to other groups performing similar studies, though in different organ systems.