Using human genetics and functional genomics to understand inherited heart disease
Prof Hugh Watkins leads the Inherited Heart Muscle Diseases Group. The group uses a broad range of approaches to discover the underlying effects of rare genetic variants that cause inherited heart disease. We principally focus on cardiomyopathies which affect more than 1 in 500 people globally. Cardiomyopathies are hidden killers and can cause sudden cardiac death without warning. Research from the group has changed the way we care for patients and families with cardiomyopathy over the last two decades. We have helped to establish the first NHS diagnostic laboratory for genetic cardiac diseases in the country, provided data that has made genetic testing the standard of care in the most recent European Guidelines on the treatment of cardiomyopathy, and developed new technology to study myocardial disease (such as cardiac imaging). Discoveries from the laboratory have helped establish some of the most fundamental molecular and cellular mechanisms that underlie different forms of cardiomyopathy and these are informing novel treatments. The group has extensive breadth of expertise, consisting of several collaborating principle investigators (linked below), each with their own distinct project interests. Research aims include:
- Searching for genetic variants in patients and families to define novel syndromes and enable better genetic diagnosis of the known ones
- Develop next generation sequencing to better characterise complex genetic backgrounds in disease and learn to use whole genome sequencing optimally in practice
- Functionally characterise new mutations and disease genes using gene editing in iPS derived cardiomyocytes and model organisms
- Model myocardial disease and assess the fundamental molecular mechanisms that cause cardiac remodelling with a focus on defining therapeutic targets
- Employ advances in cardiac imaging to diagnose and monitor changes in cardiac form and function
- Develop and rigorously test novel pharmaceutical agents and treatment paradigms
To facilitate this our group has an extensive network of collaborators both within and outside the Radcliffe Department of Medicine. Together, we from a multidisciplinary team consisting of clinicians, scientists and support staff, who all have a singular goal of understanding and treating inherited cardiac diseases.
Genetic Susceptibility to Coronary Artery Diseases
Prof Watkins also leads a research group investigating common variants in susceptibility genes for coronary artery disease, now the main cause of premature mortality worldwide, in the Wellcome Trust Centre for Human Genetics in collaboration with Prof Martin Farrall.
With colleagues in Oxford (Profs Farrall and Collins) and in Europe (Prof Hamsten, Karolinska) we assembled the large scale case:control collections needed to tackle this challenge. This has led to leadership roles in the major national and international consortia (the C4D Consortium and the CARDIoGRAMplusC4D Consortium). Our collaborative studies have led to the identification of numerous novel common susceptibility variants for coronary artery disease risk that appear to operate independent of known risk factors and pathways. Early clinical inferences derive from Mendelian Randomisation approaches, in collaboration with colleagues in CTSU (Profs Clarke and Hopwell), for example evidence that lipoprotein Lp(a) levels are causally related to coronary disease risk.
This work is now entering an exciting phase where we can use functional genomic tools to understand new biology, thus drawing on some of the approaches we have developed in our Mendelian genetic work and collaborating with groups in RDM with vascular biology expertise (eg Channon, Douglas and Tzima groups).