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Title: Molecular genetics of bipolar disorder
Author: Kandaswamy, R.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Bipolar affective disorder has a strong genetic heritability. In the UCL laboratory, a locus on chromosome 1p36 was found to be linked to bipolar and related unipolar affective disorders with a log of the odds score above 3.00. This region was subjected to fine mapping using tests of allelic association in a case-control sample as part of this thesis in order to identify the genes involved in bipolar disorder. In addition, a GWAS was also employed to fine map other bipolar affective disorder susceptibility genes. The tests of allelic association found evidence for the involvement of the PRKCZ gene. Markers D1S243 and rs3128396 at the PRKCZ gene were significantly associated with bipolar disorder with empirical P = 0.037 and P = 0.040, respectively. Other loci encoding brain expressed proteins found to be associated in the UCL GWAS sample were the genes - GRM3 and GRM7. Therefore, these genes were sequenced using PCR-based genomic sequencing. A 3'-UTR base pair change (rs56173829) in the GRM7 gene was found to be significantly associated with the disorder, although the minor allele was more frequent in controls. A base pair mutation (rs148754219) was found in the GRM3 exon 1 two bases before the translation start codon (forming part of Kozak sequence) of a GRM3 receptor isoform. The mutation was associated with bipolar disorder (P = 0.0046, odds ratio 4.2 (95% CI 1.42-12.37)). Transcription factor binding assays and cloning experiments comparing the gene expression activity of wild-type and mutant alleles showed that the mutant allele strongly affected the reporter gene activity in SH-SY5Y and HEK293 cells. If the GRM3 Kozak sequence mutation is confirmed as an important mutation in the aetiology of bipolar disorder, then it could be used as a marker for personalised treatment for a genetic subtype of affective disorders.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available