Watkins Group – Various projects relating to inherited heart muscle disease
- Hugh Watkins
About the research
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.
A major area of focus is in developing nucleic acid therapies that have the potential to cure inherited cardiomyopathies – through gene silencing and base or prime editing. I lead an international program, CureHeart, that won the BHF’s Big Beat Challenge competition, that aims to develop transformational advances in this area (https://www.bhf.org.uk/what-we-do/our-research/cure-heart). To evaluate this we are modelling the effects of cardiomyopathy mutations in myofilament protein genes, and potential interventions, in iPSC-derived cardiomyocytes and in murine models. The iPSC-cardiomyocyte work is led by Assoc Prof Chris Toepfer, a Henry Dale Fellow (Wellcome) who brings biophysical expertise to the wider group.
Our genetic discovery efforts have included recent large scale GWAS in hypertrophic cardiomyopathy which have revealed surprisingly large influences of common variants on disease risk. We are now examining the utility of polygenic risk scores for individualised risk prediction as well as the underlying biological implications of the many new loci. We also have active projects using human genetic approaches to define novel disease genes (eg through the 100k genomes project), and downstream mechanisms, in families with unexplained familial cardiac syndromes. This continues to be a productive source of insights into fundamental cardiac biology and also often leads to direct improvements in patient care.
Additional supervision may be provided by Professor Charles Redwood, Associate Professor Anuj Noel, and Professor Chris Toepfer.
Depending on prior experience, projects in the group would provide training in computational and wet lab aspects of human genetic analysis, including gene discovery through WGS & GWAS, creation and analysis of mouse models and/or human iPSC-derived cardiomyocytes (both via genome-editing with CRISPR-cas9), bulk and single cell RNAseq, cardiac phenotyping of mouse and cellular models, and exploration of gene silencing (by antisense approaches) and/or 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.
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.
Thomson KL, Ormondroyd E, Harper AR, ….. Farrall M, Watkins H. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet Med. 2019 Jul;21(7):1576-1584
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.
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.
Tadros R, et al (H. Watkins joint senior author). Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nature Genetics 2021 Feb;53(2):128-134