Discovering off-target side-effects and drug repurposing candidates using expression perturbation data

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

Mendelian Randomization (MR) is a genetic epidemiology method which utilises variants sourced from genome-wide association studies (GWAS) to assess causality between risk/protective factors and disease outcomes in a manner less biased to observational studies¹. Recently, applications of MR to drug target prioritization have gained a lot of interest. One approach is to use expression or protein quantitative trait loci (QTL) for a drug target gene/protein as exposures with the aim of establishing the effects of perturbing the intended target directly (“on-target”)².

However, most drugs will have broader molecular consequences, either in parallel (“off-target”) or downstream of the intended target. These will sometimes cause adverse side-effects (adverse drug reactions). In some cases, they may also cause beneficial effects which can be exploited to repurpose drugs for other diseases. One way to identify these broader molecular consequences is to mine high-throughput expression datasets of various cell lines exposed to small molecule drugs and genetic perturbations³. These could then be subjected to MR (including 2-step MR and multivariable MR) to gain an understanding of the specificity of action of a drug, and its broader effects.

Aims and objectives

Using publicly-available experimental molecular perturbation datasets the project will develop and apply novel approaches to discover:

1. off-target side effects of drugs and
2. drug repurposing opportunities

Methods

You will use data on transcriptional responses to drugs from expression perturbation databases and other resources to identify additional genes and proteins for off-target side effect prediction, using multivariable MR to identify direct effects. In addition, you will use protein-protein interaction and pathway data collated in our locally developed resource EpiGraphDB⁴ to further refine gene sets to instrument.

You will also use drug perturbation data sources to evaluate the potential to repurpose drugs with a previously-published approach⁵ that compares disease-associated transcriptomic profiles to in vitro

drug transcriptomic profiles to identify profiles that may reverse the effect of disease on gene expression. You will consider tissue-specific and pathway-specific transcriptomic profiles for a variety of diseases and explore whether this identifies additional repurposing opportunities. You will validate drug repurposing and off-target side effect predictions using observational data from UK Biobank and electronic health records, in addition to MR.

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 (£17,668 for 22/23), covers the cost of tuition fees and provides £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.

Closing Date: 5pm, 10th April 2024