Bipolar disorder is a relatively common and debilitating psychiatric illness which affects around 1% of the Australian population. Bipolar disorder is classified as a mood (or affective) disorder, and is characterised by mood swings from the extremes of elevated moods (so called the manic phase) and low moods (called the depressive phase). Patients often experience normal moods (euthymic phase) between these extreme episodes. In the depressive phase, individuals with bipolar disorder will have persistent feelings of sadness, anxiety, guilt, anger, irritability, isolation and/or hopelessness, disturbances in sleep and appetite, fatigue and loss of interest in usually enjoyed activities, and morbid/suicidal ideation. In the manic phase, an individual will have increase in energy, grandiose or delusional ideas, racing thoughts, and a decreased need for sleep. In addition to mood disturbance, an individual can also suffer from psychotic episodes, suffering a "loss of contact with reality" and may report hallucinations, delusions and exhibit personality changes. Individuals suffering from bipolar disorder can exhibit different patterns of mood disturbance, with individual phases lasting days or months or being mainly manic or depressive in presentation, resulting in a clinical diagnosis of any of the six different forms of bipolar disorder.
While we don't yet know exactly what causes bipolar disorder, we do know that it appears to have a biological basis. Individuals with bipolar disorder are 14 times more likely to have relatives who also suffer from fluctuations of mood, either in the form of bipolar disorder or in a related psychiatric condition, including major depression, schizoaffective disorder or schizophrenia. It is the appearance of these clinically distinct but related psychiatric conditions in the same families which suggests that the biological basis of these illnesses overlap.
Late adolescence and early adulthood are peak years for the onset of the illness. These are critical periods in a young adult's social and vocational development, and they can be severely disrupted by disease onset. Attention span is low and the individual may be easily distracted, experience impaired judgment or engage in behaviour that is quite abnormal for them, for example; gambling or risky sexual behaviour. Sufferers are more likely to engage in substance abuse, however it is unclear whether this is a risk factor for later illness, or whether it is an attempt at self-medication of existing symptoms.
Our group is focussed on identifying the genetic causes of bipolar disorder, and has been collecting Australian families and individuals with bipolar disorder for over 15 years. Using this resource, we have been studying the genetic transmission of DNA through individual family members, in order to identify regions of the genome which are commonly inherited in individuals who have been diagnosed with bipolar disorder, as compared to family members who do not suffer from mood disturbance. These are the genetic regions which are likely to contain susceptibility genes. We have so far collected 65 large extended pedigrees (with an average of 12 people in each family) which have been psychiatrically assessed and from which blood samples have been taken for DNA analysis.
Over the course of our research, we have identified a number of regions of the genome which may contain susceptibility genes for bipolar disorder. These include a region on chromosome 4, which was originally identified in a single large pedigree containing over 90 relatives, and a region on chromosome 15 which was recently discovered in a pooled analysis of 35 families. Further, more detailed analysis of these regions has identified two susceptibility genes which we believe increase a persons risk in developing bipolar disorder. Of particular interest is a gene involved in early brain development which, when defective, may result in inappropriate neuronal connections affecting brain plasticity. This gene defect may render the brain more vulnerable to secondary genetic and environmental insults into adulthood. We are continuing our research efforts to understand how alterations in these genes might translate into an increased genetic susceptibility and characterise the biological pathways involved.
Because of the nature of the disorder and the complex pattern of genetic transmission, we expect that multiple genes (acting alone or in concert) will contribute to susceptibility, and that no single gene will have a large effect on the development of the disorder. As a result, we have a number of projects investigating the role of genetic risk factors in bipolar disorder.
Project 1 – We have been following up our discovery of a novel bipolar susceptibility gene identified by our group on chromosome 4, by identification and functional assessment of the particular DNA variants which may increase risk to bipolar disorder.
Project 2 – A second bipolar disorder risk gene has been identified by our group on chromosome 15, which had previously been implicated as a risk factor for schizophrenia. Our research will characterize how this gene and its protein partners may be involved in early brain development, leading to increased risk to bipolar disorder and schizophrenia.
Project 3 – Using genetic transmission information from our extended families, we have been assessing whether regions of the genome might interact with each other to further increase disease risk. We have identified four genetic interactions which further increase disease risk. The genes responsible for these interaction regions will be investigated.
Project 4 – In addition to genes identified in our own laboratory, we have also been involved in assessing the risk attributed by genes identified by other groups, including NCAM, P2RX7 and genes involved in oxidative stress response.
Project 5 – We are also investigating whether a person’s temperament or disturbances in an individual’s natural biological rhythm may increase risk to developing bipolar disorder.