Bipolar disorder is a heritable psychiatric disorder, and several of the genes associated with
bipolar disorder and related psychotic disorders are involved in the development and
maintenance of white matter in the brain. Patients with bipolar disorder have an increased
incidence of white matter hyper-intensities, and quantitative brain imaging studies collectively
indicate subtle decreases in white matter density and integrity in bipolar patients. This suggests
that genetic vulnerability to psychosis may manifest itself as reduced white matter integrity, and
that white matter integrity is an endophenotype of bipolar disorder. This thesis comprises a series
of studies designed to test the role of white matter in genetic risk to bipolar disorder by analysis
of diffusion tensor imaging (DTI) data in the Bipolar Family Study. Various established analysis
methods for DTI, including whole-brain voxel-based statistics, tract-based spatial statistics
(TBSS) and probabilistic neighbourhood tractography, were applied with fractional anisotropy
(FA) as the outcome measure. Widespread but subtle white matter integrity reductions were
found in unaffected relatives of patients with bipolar disorder, whilst more localised reductions
were associated with cyclothymic temperament. Next, the relation of white matter to four of the
most prominent psychosis candidate genes, NRG1, ErbB4, DISC1 and ZNF804A, was
investigated. A core haplotype in NRG1, and three of the four key single nucleotide
polymorphisms (SNPs) within it, showed an association with FA in the anterior thalamic
radiations and the uncinate fasciculi. For the three SNPs considered in ErbB4, results were
inconclusive, but this was consistent with the background literature. Most notable however, was
a clear association of a non-synonymous DISC1 SNP, Ser704Cys, with FA extending over most
of the white matter in the TBSS and voxel-based analyses. Finally, FA was not associated with a
genome-wide supported risk SNP in ZNF804A, a finding which could not be attributed to a lack
of statistical power, and which contradicts a strong, but previously untested hypothesis. Whilst
the above results need corroboration from independent studies, other studies are needed to
address the cellular and molecular basis of these findings. Overall, this work provides strong
support for the role of white matter integrity in genetic vulnerability to bipolar disorder and the
wider psychosis spectrum and encourages its future use as an endophenotype
