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PhD in psychiatric genetics - Integrating microarray and sequencing data to identify rare risk and protective genetic variants for schizophrenia


Cardiff School of Medicine

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Dr E Rees , Prof James Walters No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Schizophrenia is a severe psychiatric disorder that can have a dramatic impact on the wellbeing of affected individuals and their families. Although the exact biological and environmental causes of schizophrenia are not fully understood, genetic factors are known to have a significant role in its development. Recent research has shown that many rare and common genetic variants contribute to the risk of developing schizophrenia; however, few studies have empirically evaluated the joint effects of common and rare genetic variants in people with the disorder.

The principal aim of this 4-year project is to integrate microarray and whole-exome sequencing data sets produced from large schizophrenia samples (>15K cases and >16K controls).The student will have unique access to genetic data that also has rich phenotype information, including the largest genetic resource of individuals diagnosed with treatment resistant schizophrenia. The combined effects of common SNPs, rare coding variants and rare structural variants in schizophrenia will be analysed to test the following hypotheses: 1) Rare schizophrenia risk variants are enriched among cases with low genetic risk from common variants 2) Rare variants that protect against schizophrenia are enriched among unaffected individuals at high genetic risk for schizophrenia.

The main outputs of this work will be the identification of novel genes and mutations that have a role in schizophrenia, which will advance our understanding of the underlying biology that, when combined with psychological and social risk factors, can give rise to the condition. The hope is that a greater understanding of the causes of schizophrenia will lead to the development of better treatments that will have fewer adverse side effects and will help alleviate the distressing symptoms experienced by many people with schizophrenia.

The project is supported by a grant from Mental Health Research UK and the Schizophrenia Research Fund and is aligned to a UKRI Future Leaders Fellowship recently awarded to Elliott Rees. The project builds on previous work from our group that showed common variants still contribute to the development of schizophrenia in affected individuals carrying rare, high risk genetic variants (Tansey et al 2016). We have also shown that within cases, the burden of common risk alleles is lower in affected individuals carrying rare, high risk variants (Rees et al 2020). These findings suggest that rare and common variants act together to increase liability to schizophrenia, and being a carrier of rare, high risk mutations predicts a lower burden of common risk alleles in individuals with schizophrenia.

The project offers a unique opportunity to develop a broad range of skills in the analysis of microarray and sequencing data. The student will use leading-edge computational techniques for the identification and statistical analysis of common variants, rare coding variants and structural variants. Novel methods will be developed for jointly analysing rare and common variants, which could be applicable for research of other psychiatric and non-psychiatric conditions. The Wales Supercomputer facilities (https://www.supercomputing.wales/) will be used for data processing and variant calling. If needed, memory and CPU intensive computations will be executed using the Google-Cloud Platform.

The project is interdisciplinary and will involve training and collaboration with bioinformaticians, statisticians, biologists and psychiatrists. Dr Elliott Rees will provide training in sequencing data analysis and statistical analysis of genetic data. Professor James Walters, who is the Director of the MRC Centre for Neuropsychiatric Genetics and Genomics in Cardiff and co-chairs the Schizophrenia Group of the Psychiatric Genomics Consortium, has extensive experience of developing programmes of research on the role of common variants in schizophrenia and is senior author of the largest GWAS study of schizophrenia to date (Pardiñas et al 2018).

The student will be based in the MRC Centre for Neuropsychiatric Genetic and Genomics (https://www.cardiff.ac.uk/mrc-centre-neuropsychiatric-genetics-genomics) and will join >50 other PhD students investigating psychiatric and neurological disorders within the Division of Psychological Medicine & Clinical Neuroscience.

References:

Tansey, K. et al. ‘Common Alleles Contribute to Schizophrenia in CNV Carriers’. Mol Psych 21 (2016): 1085–89.

Rees, E. et al ‘De Novo Mutations Identified by Exome Sequencing Implicate Rare Missense Variants in SLC6A1 in Schizophrenia’. Nat Neuro 23 (February 2020): 179–84.

Pardiñas, A, et al. ‘Common Schizophrenia Alleles Are Enriched in Mutation-Intolerant Genes and in Regions under Strong Background Selection’. Nat Genet 50 (2018): 381–89.

Funding Notes

The studentship is generously funded by the Fieldrose Charitable Trust
Studentship is funded for 4 years.
Full UK tuition fees  PLEASE NOTE this studentship is open to EU students who would be able to start in July 2021.
If looking to start in October 2021, EU students will need to fund the difference in tuition fees.
Doctoral stipend matching UK Research Council National Minimum.
International applicants are also welcomed if the difference in fees can be covered.

Additional funding is available over the course of the programme and will cover costs such as research consumables and training.

References

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) 

HOW TO APPLY
This studentship has a start date of July 2021 or October 2021. In order to be considered you must submit a formal application via Cardiff University’s online application service.
To access the system click the 'institution website'' button on this advert,  or use this link https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/medicine

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’ (July 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 
• References x 2 
• Proof of English language (if applicable)


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