Functional genomic analysis of genetic susceptibility loci for coronary artery disease

Coronary artery disease is now the leading cause of mortality in both developed and developing countries. While we have good treatments that target cholesterol metabolism, we believe that many other important causes of the disease are under-explored and not used as treatment targets. Recent genome-wide association studies have led to exciting discoveries of entirely novel susceptibility loci for coronary artery disease. Our Oxford-based collaboration, linking my group with that of Professor Martin Farrall and with colleagues at the CTSU, has had a leading role in these analyses. This includes the PROCARDIS Study and the C4D Genetics Consortium, and now the CardiogramPlusC4D Consortium (see references). We have invested substantial effort in collecting the patient samples and genetic data that have now taken us to the point where we are ready to start unravelling these susceptibility loci.

These large-scale projects generate important opportunities for statistical and bioinformatics analysis and for students with such computational interests there will be other suitable projects (see, in particular, Professor Farrall’s projects). The focus of this proposed studentship is downstream, functional analysis which will aim to identify the causal gene(s) at a given locus and to investigate the impact of genetic manipulation of that gene in a relevant cell or experimental model. We will not seek to recapitulate the subtle genetic effects of the susceptibility SNPs themselves, but rather to find the roles of the relevant genes by knockdown (siRNA) or knockout (using either existing targeted ES lines or CRISPR technology). Depending on the interests of the candidate and the precise direction taken, this work will likely be co-supervised by senior colleagues whose research groups are expert either in atherosclerosis biology (Professor Keith Channon, Dr Gillian Gouglas) or high throughput screening in cellular assays (Dr Theo Kyriakou and Dr Ayman Al Haj Zen).

TRAINING OPPORTUNITIES

This DPhil will be based at the Wellcome Centre for Human Genetics, where we have the resources and expertise to provide a perfect training ground, both for computational aspects and the downstream functional characterisation. Although there will be some opportunities to acquire bioinformatics skills, the main focus of this project will be on cell and model organism experiments. These will provide valuable transferable skills that will be of wide importance as the challenge of understanding the impact of common genetic variation is key in many disease areas; thus the project will provide an opportunity to pioneer some of these approaches at exactly the time when they are becoming important.

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. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

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.

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 support the careers of female students and staff.