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Genetics of inherited cardiovascular disease

   Radcliffe Department of Medicine

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  Prof H Watkins  No more applications being accepted  Self-Funded PhD Students Only

About the Project

My group uses molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets. We work on rare/Mendelian genetic diseases, as well as common complex traits, and are currently also interested in the interface – the influence of common variants on outcome in inherited disease.

In inherited heart disease genetics, I have had a longstanding focus on heart muscle diseases, in particular hypertrophic cardiomyopathy, which is a relatively common Mendelian condition which puts affected individuals at risk of sudden cardiac death.  My group's work, using molecular biological, model organism and clinical research approaches, has defined underlying disease mechanisms and treatment targets.  Our work on genetic diagnosis of cardiomyopathy and other ‘sudden cardiac death’ syndromes has changed practice worldwide. My cardiomyopathy work is integrally linked with the groups of Prof. Charles Redwood and Prof. Houman Ashrafian as we have worked closely together for many years. 

One current area of focus is in laying the groundwork for nucleic acid therapies that have the potential to cure inherited cardiomyopathies – through gene silencing, replacement or editing. To evaluate this we are modelling the effects of cardiomyopathy mutations in myofilament protein genes, and potential interventions, in iPSC-derived cardiomyocytes. The iPSC-cardiomyocyte work is led by Dr Chris Toepfer, a Henry Dale Fellow (Wellcome) who brings biophysical expertise to the wider group. 

A related area of focus is exploring the basis of cardiac remodelling in hypertrophic cardiomyopathy, in particular the role of the immune system. We have shown that there is metabolic crosstalk between stressed cardiomyocytes and neighbouring cells, mediated, at least in part, by cells of the immune system that accumulate in HCM myocardium. We hypothesise that local cardiac immune activity, both acquired and innate, plays an essential and dynamic role in HCM with, as is typical in immunity, a balance of deleterious and protective effects. We are testing this in mouse models.

Additional supervision may be provided by Professor Charles Redwood, Dr Chris Toepfer and Professor Houman Ashrafian.

Depending on the prior experience of the successful candidate, projects in the group would provide training in computational and wet alb aspects of human genetic analysis, including gene discovery through whole genome sequencing, creation and analysis of mouse models and/or human iPSC-derived cardiomyocytes (both via genome-editing with CRISPR-cas9), cardiac phenotyping of mouse and cellular models, and exploration of gene silencing/gene editing (including use of Base editors and Prime editors) as potentially curative strategies for genetic diseases. 

Students will be encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


1 Watkins H, Ashrafian, Redwood C. Mechanisms of Disease: Inherited Cardiomyopathies. New Engl J Med 2011; 364:1643-56.
2 Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 Aug 17. doi: 10.1038/gim.2016.90.
3 Robinson P, Liu X, Sparrow A, Patel S, Zhang YH, Casadei B, Watkins H, Redwood C. Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+-dependent signaling. J Biol Chem. 2018;293:10487-10499.
4 Toepfer CN, Wakimoto H, Garfinkel A, McDonough B, Liao D, Jiang J, Tai AC, Gorham JM, Lunde IG, Lun M, Lynch TL 4th, McNamara JW, Sadayappan S, Redwood CS, Watkins H, Seidman JG, Seidman CE. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med. 2019 Jan 23;11(476). pii: eaat1199. doi: 10.1126/scitranslmed.aat1199.
5 Harper AR, Goel A, Grace C, Thomson K, Petersen SE, Xu X, Waring A, Ormondroyd E, Kramer C, Neubauer S, Tadros R, Wars JS, Bezzina C, Farrall M, Watkins H. Common genetic variants, and modifiable risk factors, underpin susceptibility and expressivity in hypertrophic cardiomyopathy. Nature Genetics 2021 Feb;53(2):135-142. doi: 10.1038/s41588-020-00764-0.

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