O'Brien, NL; (2016) Bipolar disorder related functional variants in the calcium channel gene family. Doctoral thesis , UCL (University College London).

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Abstract

Bipolar disorder (BD) is a common highly heritable disorder. The calcium channel gene family has been widely implicated in BD aetiology and these genes include CACNA1C, and CACNG4. The association signal for CACNA1C with BD is located in the middle of the third intron of the gene. CACNG4 encodes a transmembrane AMPA receptor regulator that is involved in trafficking AMPA receptors to the neuronal post-synaptic density. High-resolution melting curve (HRM) analysis and whole genome sequencing (WGS) methods were used to identify functional variants in calcium channels genes in the UCL BD cohort. Variants that were predicted to impact gene regulation, transcription or to be damaging to protein structure were genotyped in the larger UCL BD and control cohort. HRM analysis identified 26 calcium channel gene variants. These included two non-synonymous CACNG4 variants that were associated with mental illness (rs371128228, p=1.05x10-4, OR=4.39 and 17:65026851 (C/T), p=5x10-4, OR=9.52). Fluorescent activated cell sorting analysis was used to determine the effect of rs371128228 on trafficking of GluR1 and GluR2 to the cell surface. This analysis demonstrated that the risk allele of rs371128228 significantly decreased cell surface trafficking of GluR1 (p=0.026) but no effect was observed on GluR2 trafficking. WGS analysis of CACNA1C intron 3 identified two BD associated (p=0.015, OR=1.15) variants 105bp apart that were in complete LD. Both variants are predicted to create YY1 transcription factor binding sites. Luciferase reporter assays show a significant decrease in gene expression in the presence of both variants (p=0.004). Protein-DNA complex assays of the CACNA1C variants demonstrate increased nuclear proteins binding affinity for the variant alleles. If these calcium channel variants are confirmed to be important risk factors for BD they could be used as markers for personalised treatment or in the identification of genetic subtypes of BD or other psychiatric illness.

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