Functional analysis of novel rare coding variants for schizophrenia using zebrafish. MRC GW4 BioMed DTP PhD studentship for 2026/27 Entry, Department of Clinical and Biomedical Sciences Ref: 5641

Supervisors

Lead Supervisor:  Professor Soojin Ryu  - University of Exeter - Department of Clinical and Biomedical Sciences 

Co-Supervisors:  

Dr Nicholas Clifton  - University of Exeter - Department of Clinical and Biomedical Sciences 

Dr Emma Dempster - - University of Exeter - Department of Clinical and Biomedical Sciences 

Dr Elliott Reese - Cardiff University - Centre for Neuropsychiatric Genetics and Genomics 

The GW4 BioMed2 MRC DTP is offering up to 17 funded studentships across a range of biomedical disciplines, with a start date of October 2026.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 80 students over 4 cohorts in its second phase.

The 122 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

Applications open on 1 September 2025 and close at 5.00pm on 20th October 2025.

Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check our website for details.

Studentships will be 4 years full time. Part time study may also be available.

Project Information

Research Theme:  Neuroscience & Mental Health

Summary:  

Schizophrenia is a severe psychiatric disorder with debilitating effects on a patient's quality of life. Because current medications do not work well, we need to study its molecular cause to develop new therapeutics.  Recent research identified a number of genetic mutations in Schizophrenia patients called “rare coding variants.” These mutations change the proteins they produce, but for many of them, we do not yet know the functional consequences. In this project we will study the functions of the rare coding variants using zebrafish and compare the results with mouse models of equivalent mutations and human post-mortem brain tissue. 

Description:

Schizophrenia is a severe psychiatric disorder with debilitating effects on a patient's quality of life and reduction of life expectancy. Despite the significant lifetime risk of disease at 0.7%, existing therapies do not adequately target its varied symptoms. Also, responses to current medications are highly variable with 30% of patients classified as treatment resistant. Improved development in therapy requires better understanding of the molecular aetiology of Schizophrenia. It is crucial to understand how molecular alterations contribute to disease-relevant phenotypes. In this project we will carry out functional analysis of so-called “rare coding variants” (RCV) of schizophrenia which are large- effect risk variants which appear at much lower frequencies in the population. These mutations are often found within gene coding regions altering protein functions and/or gene expression. They are therefore more tractable for functional analysis in animal models as protein-coding regions and protein functions are much more likely to be conserved across species compared to non-coding regions. 

Identification of RCV in schizophrenia is an active and emerging area of current schizophrenia research. Mouse models are available for some of the published RCV and are beginning to be analysed, but for most other unpublished rare coding variants, animal models do not exist yet. Therefore the first goal of this study is to develop new animal models to study those RCVs that have not been functionally characterised before. We propose to take advantage of the zebrafish model, which offers low cost genetic manipulation combined with ease of whole brain activity analysis. We will generate mutants that harbour mutations representing human RCV and analyse their function in the context of the whole animal. In parallel, we will generate zebrafish mutants for two RCVs for which mouse models are already available in the Clifton lab to compare and synergise the functional analyses of those RCVs using two species. Further, we will combine zebrafish mutants with one of the strongest risk factors for developing schizophrenia, namely early life stress. We will then assess the effects of combining genetic and environmental risk factors in a large number of functional assays already established in the Ryu lab. Finally, we will perform RNA sequencing analysis of select brain regions in the zebrafish mutants to identify molecular alterations caused by RCVs and compare them to a wide range of molecular data available from human post-mortem cortex with and without a schizophrenia diagnosis. 

Specific Aims: 

1:

• Generate zebrafish KO of 5 rare coding variants of Schizophrenia and perform behavioural and whole-brain activity analysis
• Using CRISPR-Cas9 technology, we will generate zebrafish mutants. We will choose 2 variants for which mouse models are already available in the Clifton lab. In addition, we will generate mutants for 3 additional unpublished variants guided by the human data obtained by Dr Elliott Rees
• A battery of behavioural assays will be used to assess the phenotype in larval, juvenile and adult fish including – social behaviour, pre-pulse inhibition, stimuli responsiveness, and anxiety-related assays
• Whole brain activity analysis of the mutants will be carried out using histological methods to detect immediate early gene expression and compared with anatomical atlas

2: 

• Determine how early life stress exposure affects the mutant phenotype
• The Ryu lab has established an early life stress zebrafish model where the level of stress hormone, cortisol, can be elevated during development. This model has been well-characterized and shows behavioural and transcriptomic alteration in adulthood. We will combine RCV mutants with this early life stress model and carry out phenotypic analysis as above

3:

• Perform RNA sequencing of affected regions from the mutant to identify altered genes- To identify molecular consequences of the RCV mutation, we will carry out RNA seq using dissected tissues representing hippocampus from mutant zebrafish 

4:

• Determine whether any of the identified genes are also altered in mouse models and human post mortem tissue multi-omic data. The RNA seq data from zebrafish will be compared with equivalent data sets in mouse and human brain. The student can take ownership and steer the project throughout the project. In particular phenotypic analyses proposed in specific aims 1 and 2 will require evaluation of the results obtained and planning and choosing the appropriate next assays. This will require the student to steer the project based on the results that he/she has obtained. Also, molecular analyses proposed in specific aims 3 and 4 require the student to take ownership in deciding which molecular alterations to focus and characterise further. 

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£20,780 p.a. for 2025/26, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Please check the relevant English Language requirements of the university that will host the PhD project.  

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

Please check the relevant English Language requirements of the university that will host the PhD project. 

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 20th October 2025.  Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the DTP’s website for details and updates

If you are shortlisted for interview, you will be notified from Tuesday, 23rd December 2025.  Interviews will be held virtually on 27th and 28th January 2026.  

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary