McCarthy Group – Genetics and Genomics of Type 2 Diabetes
We focus on the use of human genetics to drive a mechanistic understanding of type 2 diabetes, and to identify novel translational opportunities.
About the research
We combine experimental and computational strategies, assembling diverse types of large-scale genetic genomic, molecular and clinical data, and deploying a wide range of statistical and computational approaches to mine them. We have a strong track record of providing postgraduate training in the analysis and interpretation of large-scale biomedical data sets, and several of our students have taken on projects that combine experimental and computational components. We interact closely with the research group led by Professor Anna Gloyn, and many of our students have been jointly supervised.
The foundation of our group’s work lies in the identification of DNA sequence variants influencing risk of T2D and related traits. I lead international consortia that have used large-scale genome wide association (~1.5M people) and exome sequencing analyses (~50,000) to uncover over 400 T2D-association signals: further expansion of these efforts is planned. We integrate genomic information from diabetes-relevant tissues (islet, fat, muscle) to understand the molecular and cellular impact of these variants, and to identify the effector transcripts through which they mediate their effects. In collaboration with Prof Gloyn, we seek to functionally validate these findings, using diverse techniques, including genome-editing and high-throughput screens. We aim to identify the shared pathways and networks through which multiple association signals operate.
A major focus of our activities lies in the development of partitioned polygenic risk scores: these set out to deconstruct T2D genetic risk into components mediated through particular pathophysiological defects (such as defective insulin secretion, insulin resistance or adiposity). These partitioned risk scores allow us to capture the clinical and phenotypic heterogeneity within T2D, and to determine whether these offer clinical utility with respect to the prediction of relevant clinical outcomes (such as drug response and complication risk).
Students accepted within the group could be engaged in any of these research areas, and the examples which follow are illustrative:
- Developing and implementing single-cell analyses of molecular phenotypes including assays of open chromatin, and the transcriptomic responses to gene perturbation (e.g. using CROP-Seq);
- Identifying process-specific metabolomic and proteomic biomarkers, able to provide a “real time” complement to the predictive inference available from partitioned polygenic risk scores;
- Exploring the impact of selection on variants associated with T2D and obesity;
- Mapping tissue-specific differences in allelic imbalance at open chromatin sites to known/presumed tissues of action at GWAS loci
Students within the lab will receive training in the analysis and interpretation of large biomedical data sets including (dependent on their decided project) genome-wide association analysis, exome sequencing, whole genome sequencing, NGS readouts of regulatory function (eg ATAC-Seq), RNA-Seq, network analysis and protein-protein interaction data. There are also opportunities to be trained in relevant experimental techniques (again dependent on the project) including cell-culture, genome-editing, stem-cell differentiation, single-cell analysis and high throughput genetic screens.
Students are 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.