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Title: Analysis of rare genetic variation in psychotic disorders with complex aetiology
Author: Al Eissa, Mariam
ISNI:       0000 0004 7660 6682
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Schizophrenia (SCZ) and bipolar disorder (BPD) are both severe psychiatric diseases which can give rise to debilitating symptoms. To understand the nature of molecular pathologies, it is important to look into the genetics underlying the phenotype to understand its role in disease formation. Using recent exome sequence data sets such as those from the UK10K project and SCZ-Swedish exome data facilitated the identification of rare variants which contribute to the risk of developing those illnesses. To identify rare variants with potential susceptibility and strong effects, UCL SCZ families with multiple members affected by the condition contributed to the UK10K data. The pedigrees included in these sets were analysed using GeneSAOcs to find rare variants which run in families and segregate them according to disease. In order to validate this finding, a second data set was investigated for those variants. Another gene variant burden approach was also used which involved analysing unrelated individuals from the UK10K and SED. Variants which were implicated in the risk for disease were analysed bioinformatically and genotyped or replicated in UCL case/control samples. The use of a family-based approach revealed a variant in rs199929459 in WD-repeat domain 6 (WDR6) which was found to have a nominal level of association with both SCZ (P = 4.29x10-7 ) and psychosis (P = 0.0004). Another variant in the MCPH1 gene, rs61749465, previously reported in SCZ Leonenko et al. (2017), was analysed further in BPD (P = 0.0009). Functional analysis, cell viability, cell count assays, DNA damage assays and mRNA stability did not indicate significant changes. However, gene expression analysis using RNA-seq indicated that a number of heat shock and ribosomal proteins were affected by introducing this variant. Combined with gene network analysis, this indicates that this variant may impact protein translation and cellular aging. Using the KEGG pathway, the expression of 47 genes seems to have been significantly affected and the Alzheimer's disease pathway was activated. The data indicates that rare variants may have a role in disease susceptibility. However, validation through larger SCZ/BPD case and control cohorts provide more evidence of association. This applies in most of the variants extracted in our study, especially those in WDR6. Further functional analysis is required to understand the effects of the rs61749465 variant allele on protein folding.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available