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Proving the existence of recessively inherited Mendelian Schizophrenia and characterising the proteins involved


   Leeds Institute of Molecular Medicine

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  Prof C Inglehearn  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Professor Chris Inglehearn (Lead supervisor), Dr Steve Clapcote and Dr Alastair Cardno
Schizophrenia is the 9th leading cause of disability worldwide and is a huge burden on families and healthcare providers. Current antipsychotic medications fail to treat many patients and have unacceptable side effects. Family, twin and adoption studies show a strong genetic contribution to the condition. Genetic studies should therefore identify aetiological pathways, leading to a clearer understanding of the neurobiology, so that more effective means of diagnosis, treatment and prevention can be developed. However, though studies to date have found common polymorphisms with small effects, these account for only a small fraction of the heritability of schizophrenia. Current thinking is therefore moving towards the hypothesis that there may be family specific rare variants that have arisen recently and confer high risk, effectively Mendelian schizophrenia alleles, in at least a proportion of families. A few copy number variants and translocations have shown Mendelian transmission but no causative missense or nonsense mutations have yet been identified and some have suggested they will not exist.
We hypothesised that such alleles will exist but are more likely to be found in endogamous (reducing genetic complexity), consanguineous (simplifying identification of recessive predisposing alleles) populations. One such population is the West Yorkshire Pakistani community, where a high level of first cousin marriage leads to increased incidence of recessively inherited diseases. Autozygosity mapping in this population has led to the identification of many rare Mendelian disease-causing alleles (http://autozygosity.org/). We proposed to determine whether a similar approach could reveal recessive alleles of large effect predisposing patients to schizophrenia. We therefore set about identifying families with multiple cases of schizophrenia. In one such family we have indeed found clear linkage to a single chromosomal region, and we are now sequencing to identify the gene involved.
The aims of this project are to characterise the gene and mutation involved in schizophrenia in this family, using the techniques of confocal and immuno-fluorescence and confocal microscopy, cell biology, proteomics and, where applicable, animal studies; and to apply the technique of autozygosity mapping in new families as they are identified in order to find new genes and proteins underlying schizophrenia.


Funding Notes

PhD project based in the section of Ophthalmology and Neuroscience (OPNE), Leeds Institute of Molecular Medicine (LIMM), University of Leeds.

Informal enquiries should be addressed to [Email Address Removed]. This project is available immediately to self-funded applicants with government scholarships or other sources of funding. Tuition and bench fees are payable for this project. Exceptional applicants may be nominated for Leeds University funded scholarships at the discretion of the supervisors.

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