Bipolar disorder

EXTRA INFORMATION

Understanding the causes of bipolar disorder

WHAT WE KNOW

Symptoms

Bipolar disorder is classified as a mood (or affective) disorder, and is characterised by mood swings from the extremes of elevated moods (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.

Common causes 

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 that suggests 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 the onset of this disease. Attention span is often 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.

About our research 

Our research focuses on identifying the genetic causes of bipolar disorder. We have been recruiting Australian families and individuals with bipolar disorder for more than 15 years to study the genetic transmission of DNA through individual family members.

The aim of this work is 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 that are likely to contain susceptibility genes.

We have so far collected 65 large extended pedigrees (with an average of 12 people in each family) that we have psychiatrically assessed and taken blood samples for DNA analysis.

What we have discovered 

In the Schofield and Fullerton groups 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.

More detailed analysis of these regions has identified two susceptibility genes which we believe increase a person’s 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 have completed a detailed characterisation of genetic alterations within this gene in individuals with bipolar disorder. We are continuing our research efforts to characterise the biological pathways involved, and to understand how alterations in these genes might equate to an increased genetic susceptibility. Our patient samples have also been used in large international collaborative studies aimed at identifying a range of common genetic susceptibility factors for bipolar disorder, as well as genes which affect response to Lithium, a common pharmacological treatment for bipolar disorder.

Current projects 

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

Using our resource of extended families with multiple relatives affected with bipolar disorder, we have embarked on large scale “next-generation” sequencing studies to identify and characterise rare variants in the DNA sequence of affected relatives and compared these to rare variants in the DNA of unaffected relatives, both in the same family and across families. Using this approach we have identified a number of new risk genes, as well as providing additional support to the involvement of previously identified genes. These studies are further elucidating the molecular mechanisms underlying increased risk for bipolar disorder.

PROJECT 2

We are part of a multi-site collaboration with four Universities in the United States in a unique study of young kids and siblings of patients with bipolar disorder. These young people are at high risk of developing bipolar disorder themselves in the future (due to having a parent or sibling with the disorder) but are well at the time of entry into the study. We are following these participants over time to examine the sequence of emergence of symptoms, and to identify possible predictors which may give us an early indication as to which of these “high risk” individuals will ultimately convert to a bipolar diagnosis. Identification of accurate predictors would open up the opportunity for early intervention, to slow or even prevent illness in individuals identified as “high risk”.

PROJECT 3

A bipolar disorder risk gene has been identified by our group on chromosome 15. This gene has previously been implicated as a risk factor for schizophrenia. Our research will characterise how this gene and its protein partners may be involved in early brain development, leading to increased risk of both bipolar disorder and schizophrenia.

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 and in sharing data and samples in large international collaborative studies.

PROJECT 5

We have also been examining community attitudes and understanding of predictive genetic testing in psychiatry, especially the mood disorders.

Researchers at Garvan, Neuroscience Research Australia and UNSW Australia are embarking on a collaborative project to sequence the genomes of family groups living with bipolar disorder. In doing so, they anticipate identifying some of the complex genetic factors that underlie the disease. The project is supported by the MLC Community Foundation.

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