MOLECULAR GENETICS OF BIPOLAR AFFECTIVE DISORDER

Bipolar disorder and certain types of severe depression run in families and are strongly genetic. Genetic research can therefore identify DNA changes that cause susceptibility to these mental illnesses. Genetic linkage studies of families have identified which chromosomes the genes for these types of depression are localised on. However, new technology borrowed from the microelectronics industry has enabled the University Collele London research group and their USA collaborators to rapidly identify at least thirty nine new genes likely to be causing genetic susceptibility to depression. We now wish to develop this research by identifying the precise genetic abnormalities in these genes that increase susceptibility to bipolar disorder. Abnormalities that are found will be studied for their clinical effects and their role in the variability of psychiatric symptoms and responsiveness to drug treatments. The identification of pathways involved in disease susceptibility should lead to the creation of new treatments and prevention strategies for bipolar and other types of affective disorders.

The applicants have carried out a family based genome wide linkage study of bipolar disorder and more recently a genome wide association study with [Lambert, 2005 #1245]single nucleotide polymorphisms in the UCL Bipolar case control sample. After comparison with genome wide association tests in an independent sample from our USA collaborators we have identified thirty eight new affective disorder susceptibility genes. It is now proposed that we resequence DNA from the top twenty most significantly associated genes in those UCL bipolar cases contributing to the positive allelic associations. This will enable potential aetiological base pair changes for affective disorders to be detected. Once these DNA changes have been found this will form a solid scientific foundation for studies of clinical phenotype and treatment response variation, as well as studies of gene expression, protein interaction, animal models and new drug design based on valid protein targets. With the proposed MRC support we propose to select the one or two of the 20 genes sequenced that is most strongly implicated in terms of new aetiological base pair changes and to carry out in depth gene expression, protein interaction and animal model studies over the five year period.