The MRC Integrative Epidemiology Unit at the University of Bristol is the leading group for the development and application of causal analysis and evidence triangulation in health research to improve lives. This student will be supported by an interdisciplinary team of academic staff who are experts in their fields. For more information about the MRC Integrative Epidemiology Unit and the PhD programme, please visit the website.
Rationale
Genetic evidence has been retrospectively shown to increase the odds of a success of given drug target (1), and offers a lot of potential to decrease the costs of drug development and identify drug repurposing opportunities. However, despite the abundance of genome-wide association studies (GWAS) for almost all common complex diseases, researchers still face a lot of difficulty in how to interpret these findings to best identify drug targets (2). Integrating the evidence from common genetic variants (from GWAS) with other sources of genetic and molecular evidence could aid this process and help strengthen the evidence for valid drug targets.
In this project, you will exploit the growing wealth of genetics data resources to help better prioritise drug targets for a variety of human disease. In particular, you will use data bridging the gap between common disease variants and rare Mendelian disease mutations with matching underlying molecular targets and symptoms (3).
Aims and objectives
- investigate how the use of rare mutations can complement the evidence from common, less deleterious, mutations targeting the same genes towards drug target prioritisation
- map text descriptions of disease phenotypes to identify Mendelian disease variants that have similar phenotypic effects to those of common molecular quantitative trait loci (QTL) controlling transcript expression, protein abundance, methylation etc. (4)
- integrate population-level molecular QTL evidence from with evidence from rare exome mutations (AstraZeneca PheWAS Portal, Genebass), Mendelian disease mutations (OMIM, ClinVar, Born in Bradford) and mouse knockouts (Mouse Genome Informatics database)
- utilize molecular pathway and protein-protein interaction data to provide supporting evidence of functional relevance from related proteins
Methods
You will apply a variety of genetic epidemiology methods to predict the effects of drug targets, including Mendelian Randomization (MR) (5). MR uses genetic polymorphisms, such as obtained in GWAS and QTL mapping studies, as instruments to help establish risk/protective factors for common human disease.
You will also learn how to deploy Natural Language Processing techniques to map common disease phenotypes to rare Mendelian disorders.
You will also use a range of biomedical databases, information resources and algorithms used in drug target prioritisation.
Candidate requirements:
We strongly encourage applications from a range of disciplines (e.g., mathematics, statistics, computer science, life or natural sciences, psychology, social sciences or other related quantitative discipline). Applications are sought from high performing individuals who have, or are expected to obtain, a 2.1 or higher degree (or equivalent). Possession of a relevant Master's degree or research experience would be advantageous but is not expected.
How to apply
When applying, candidates must select the Population Health PhD programme and enter supervisor names as listed under the project title for which they are applying. Please state IEU funding in the funding box. Full details on what to include in your application can be found in the Admissions Statement.
Personal statement: Please also provide a personal statement that describes your training and experience so far, your motivation for doing a PhD, your motivations for applying to the University of Bristol, and why you think we should select you. We are keen to support applicants from minority and under-represented backgrounds (based on protected characteristics) and those who have experienced other challenges or disadvantages. We encourage you to use your personal statement to ensure we can take these factors into account.
Funding:
The studentship is funded by the MRC Integrative Epidemiology Unit at standard MRC rates (£19,237 for 2024/25), covers the cost of tuition fees and provides up to £15000 per PhD for training costs. Standard MRC eligibility criteria apply. Only applicants from the UK are eligible for full funding. International students can apply but would need to cover the difference between home and overseas fees.
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