Identification of bipolar disorder susceptibility genes

Bipolar affective disorder is a severe mood disorder, which is characterised by episodes of mania and depression. The aetiology of bipolar disorder remains elusive, with little known about the underlying biological, anatomical, or biochemical effects. However, family, twin and adoption studies provide evidence for a strong genetic component to the disorder. Due to the high heritability, familial clustering, and common population prevalence of the illness, molecular genetic studies can be implemented to identify bipolar disorder susceptibility genes. This thesis investigated the candidate gene serotonin 2A receptor (HTR2A), which lay within a region on chromosome 13q14 previously identified by bipolar disorder genome-wide linkage scans. Significant association was found with bipolar disorder and a SNP within intron 2 of HTR2A in an Australian case-control cohort. Haplotype association analysis identified a 5-SNP protective haplotype within HTR2A. Conducting a new genome-wide linkage scan on 35 Australian bipolar disorder pedigrees found significant evidence for linkage on chromosome 15q25-26. Subsequent fine-mapping of the region verified the linkage peak with a significant maximum multipoint LOD score of 4.58. Haplotype analysis, based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within a 6.2Mb confidence interval. The candidate gene sialyltransferase 8B (ST8SIA2), which had previously shown association with SNPs within the gene’s promoter region and schizophrenia in two independent Asian cohorts, lies within the chromosome 15q25-26 locus. Failing to replicate the association found with these specific SNPs, and without finding association with two additional SNPs in an upstream conserved putative regulatory region, a fine-mapping association study was conducted across the entire 6.2Mb interval. The strongest association signals were observed at SNPs 16kb upstream from and within the fourth intron of ST8SIA2. A specific bipolar disorder risk haplotype was identified for ST8SIA2, and this was also observed to be over-represented in a cohort of Australian schizophrenia cases. This finding suggests that the ST8SIA2 gene, for which strong developmental regulation was observed, may be a shared susceptibility gene for both bipolar disorder and schizophrenia. In summary, this thesis has provided evidence identifying both HTR2A and ST8SIA2 as bipolar disorder susceptibility genes