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Title: Identification and characterisation of rare CACNG5 genetic variants in bipolar disorder and schizophrenia
Author: Lin, Y.-C.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Schizophrenia (SCZ) and bipolar disorder (BPD) are common, highly heritability psychiatric disorders. Genome-wide association studies have found evidence of shared genetic susceptibility to both diseases. The most notable example is CACNA1C which encodes the 1 subunit of L-type calcium channels. Several other calcium channel genes have also been implicated in BPD and/or SCZ and together there is support for a role for these genes in both diseases. The primary function of several  subunit calcium channel genes appears to be the regulation of AMPA receptor localisation and function. Collectively these are known as Transmembrane AMPA receptor Regulatory Proteins (TARPs). This thesis aimed to identify disease relevant genetic variation in one such TARP, CACNG5, and to study the effect of these variants. CACNG5 variants in the exons and promoter region were identified in 1098 BPD, 618 SCZ, and 1087 control individuals. Four novel non-synonymous SNPs (nsSNPs) and four nsSNPs were identified. Burden analysis of nsSNPs in BPD and SCZ found evidence for association (p=0.0022). This association was strengthened by inclusion of data from European samples in the 1000 Genomes project (p=0.00057). However, combined data with the UK10K and Swedish exome sequence studies founds a weakened association signal (p=0.0082). Functional analyses using co-expression of AMPAR2 and CACNG5 constructs containing the eight nsSNPs were used to analyse changes in the expression and/or trafficking of 5 and AMPA receptors. Four of the variants were associated with decreased AMPAR2 expression as a consequence of altered trafficking to the cell surface. V146M (identified in 2 SCZ patients) overexpression increased AMPAR2 trafficking to the cell surface (p<0.005); conversely, T164L (identified in one SCZ patient) overexpression decreased the expression of AMPAR2 and its cell surface trafficking (p<0.05). Our results suggest a role for CACNG5 variants in SCZ and/or BPD and that this may be mediated via dysregulation of AMPARs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available