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Exploring the early genetic origins of schizophrenia at the cellular level


Cardiff School of Medicine

About the Project

Summary
Schizophrenia is a severe psychiatric disorder with an unclear biological basis. This project will combine single cell RNA sequencing technology with the latest data on genetic risk factors for schizophrenia to identify cell types and mechanisms within the developing human brain mediating genetic risk for the condition. The project will provide training in stateof-the-art laboratory and bioinformatic techniques for analysing cellular gene expression.

Description
Schizophrenia is a severe psychiatric disorder affecting ~1% of the population. Recent large-scale genomic studies have identified hundreds of schizophrenia genetic risk loci, paving the way for much-needed biological insights into the condition. Our own research (e.g. 1-3) and that of others (e.g. 4) has indicated that many of these genetic risk variants operate in utero, substantiating long-held neurodevelopmental theories of the disorder. However, the prenatal brain regions and cell types through which these genetic risk variants operate remain unclear. This PhD project will build upon a current MRC project grant to lead supervisor Bray which is using single-cell sequencing to assess gene expression and its regulation in the constituent cell types of the human foetal brain. The student will combine use of this cutting-edge wet-lab technology with the latest genetic data for schizophrenia (available through the host MRC Centre for Neuropsychiatric Genetics & Genomics) to identify cell types of the prenatal brain mediating genetic risk for the disorder. Through the two host centres, they will be trained in both state-of-the-art laboratory techniques for profiling cellular gene expression and sophisticated biostatistical methods for its analysis and integration with large-scale genetic data. The student will additionally benefit from use of related epigenomic and transcriptomic data generated by the Cardiff and Exeter supervisors’ groups (from both foetal and adult human brain) as well as from established international collaborations (e.g. with the Psychiatric Genomics Consortium, PsychENCODE). The impact of the student’s research will be maximised through their regular attendance at international conferences (e.g. World Congress on Psychiatric Genetics, Society for Neuroscience), publication in leading journals and dissemination through data-sharing repositories. 1. Hill MJ, Bray NJ (2012) Evidence that schizophrenia risk variation in the ZNF804A gene exerts its effects during fetal brain development. Am J Psychiatry 169: 1301-8. 2. Hannon E,…Bray NJ, Mill J (2016) Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nature Neurosci. 19: 48-54. 3. O’Brien HE, Hannon E,….O’Donovan MC, Mill J, Bray NJ (2018) Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 19: 194. 4. Walker RL,…Geschwind DH (2019) Genetic control of expression and splicing in developing human brain informs disease mechanisms. Cell 179: 750-771. Year 1 (Cardiff) Training in single cell transcriptomics using human foetal brain tissue (wet-lab and data analysis), advanced computing and psychiatric genetics. Principal aim:
identify cell types within the developing human brain mediating genetic risk for schizophrenia. Year 2 (Exeter) Training in epigenomics and further bioinformatics, including integration with / comparisons against other cell-specific epigenomic and transcriptomic data generated by Mill’s group (e.g. from adult brain). Principal aim: refining neurodevelopmental mechanisms mediating genetic risk for schizophrenia (e.g. specific cellular processes, developmental timepoints). Year 3 Depending on findings and interest of student, could have a wet lab or bioinformatic focus (e.g. spatial transcriptomics or potential refinement of schizophrenia subtypes associated with genetic risk operating prenatally).

Funding Notes

A GW4 BioMed MRC DTP studentship includes full tuition fees at the UK/Home rate, a stipend at the minimum UKRI rate, a Research & Training Support Grant (RTSG) valued between £2-5k per year and £300 annual travel and conference grant based on a 3.5-year, full-time studentship.
These funding arrangements will be adjusted pro-rata for part-time studentships. Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

References

ELIGIBILITY

International and EU students are eligible to apply for these studentships but should note that they may have to pay the difference between the home UKRI fee ( https://www.ukri.org/skills/funding-for-research-training/ ) and the institutional International student fee ( https://www.cardiff.ac.uk/__data/assets/pdf_file/0008/1735154/Fees-Template-PGR-International-2020-21-Version-1-04.12.2019.pdf ). We will update applicants when further information becomes available.

ENTRY REQUIREMENTS

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject. 
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS) 

In addition to those with traditional biomedical or psychology backgrounds, the DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics and the physical sciences. Further training can be provided to assist with discipline conversion for students from non-medical backgrounds.

HOW TO APPLY

Stage 1: Applying to the DTP for an Offer of Funding
Please follow the instructions at the following link to apply to the DTP.
https://www.gw4biomed.ac.uk/doctoral-students/

Stage 2: Applying to the lead institution for an Offer of Study

This studentship has a start date of October 2021. In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the application system, click the 'Visit Institution' button on this advert) 
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2021). This will take you to the application portal. 
In order to be considered candidates must submit the following information: 

• Supporting statement 
• CV 
• Qualification certificates 
• Proof of English language (if applicable)
• In the research proposal section of the application, please specify the project title and supervisors of the project and copy the project description in the text box provided. In the funding section, select “I will be applying for a scholarship/grant” and specify advertised funding from GW4 BioMed MRC DTP. If you are applying for more than one Cardiff University project, please note this in the research proposal section as the form only allows you to enter one title.

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