Finding a missing link in the genes

 

The winner of the 2003 Royal Irish Academy/'Irish Times'biochemistry essay competition, Dr Brendan Kelly, took firstplace in the competition with this report entitled, Schizophrenia: solvingthe puzzle.

Schizophrenia is a common, disabling mental illness. Some 40,000 people in Ireland suffer from the illness at any one time. Across the world, some 20 million people are directly affected by it.

Acute schizophrenia is characterised by distressing symptoms, including hallucinations (hearing voices) and delusions (believing things that are demonstrably untrue). In the long-term, the illness can lead to difficulties with relationships, social withdrawal and reduced employment prospects.

In the US, the annual cost of schizophrenia to the economy is estimated at some $40 billion, three times the annual budget of the US space programme. The true cost of the illness, however, is more difficult to quantify, and can only be described in terms of individual suffering, family stress and reductions in quality of life.

The causes of schizophrenia are unknown. There are many theories and several promising leads, but little is known for certain. There is, however, one single, important fact that has emerged time and again from many studies of the illness: schizophrenia has a strong tendency to run in families.

In the general population, any given individual has a 1 per cent chance of developing schizophrenia at some point in their lives. However, if an individual's parent or brother or sister is affected by the illness, the individual's chance of developing schizophrenia increases to 10 per cent. This is a very significant increase.

The reason for this increase in risk is related to genes, the genetic blueprint that we inherit from our parents, and that we share in large part with close family members. The importance of genes is further emphasised by studies of twins with schizophrenia.

Monozygotic twins develop from the same cells and have the exact same genes as each other. Studies show that if one monozygotic twin develops schizophrenia, there is a 50 per cent chance that the other one will also develop the illness. This is a huge increase from the baseline population risk of 1 per cent - an increase that underlines the importance of genetic inheritance in the genesis of schizophrenia.

To date, some $400 billion has been spent trying to identify specific genes that increase the risk of schizophrenia. Searching for such genes is a daunting task, given both the variety and complexity of mammalian genes. In the last two years, however, large-scale collaborative studies have started to produce some exciting results.

Some of the most significant findings to date have emerged from a joint Ireland-US project investigating the role of specific regulatory genes in the nervous system of individuals with schizophrenia. The Irish arm of the study is based in the Health Research Board, Dublin, under the direction of Dr Dermot Walsh.

The US side of the study is based in the Virginia Institute for Psychiatric and Behavioural Genetics, under the direction of Dr Kenneth Kendler. In recent years, this work has been extended to Northern Ireland, under the direction of Dr Tony O'Neill of Queen's University, Belfast.

The aim of this ongoing study is to identify specific genes that are present to excess in families with schizophrenia and so play a role in increasing the risk of illness in affected individuals. For their most recent paper, the researchers contacted 270 families in which a number of family members were affected by schizophrenia.

Overall, they carried out genetic analysis on some 1,425 individuals. Following both genetic and statistical analysis, the researchers found that schizophrenia is strongly associated with abnormalities of a specific gene on chromosome six.

In genetic notation, the gene is described as '6p22.3'. This means that the gene is located on the short arm (P for petite) of chromosome six, at the particular point on the map of the chromosome denoted by the number 22.3. This gene is known to regulate the production of a protein called "dysbindin" and is now most commonly known as the dysbindin gene.

Dysbindin is a protein that serves a number of functions in mammals. In the mouse, dysbindin is found in a number of anatomical locations including the brain, suggesting it plays a variety of roles in a range of different areas around the body. In humans, dysbindin and related proteins are found in all 24 body tissues, including the heart, the lungs and - most importantly - the brain.

While some of the functions of dysbindin have become clear in recent years, others remain unknown. This is attributable to the enormous complexity of the human brain, which comprises some one hundred billion brain cells or neurons. Each neuron is less than 10 microns wide (one micron is one thousandth of a millimetre), and each has multiple connections with its neighbouring neurons.

Neurons communicate with each other by releasing chemicals (known as neurotransmitters) which travel across the spaces between neurons (known as synapses). These neurotransmitters convey messages from one neuron to the next, resulting in a complex network of interactions involving millions of neurons and dozens of neurotransmitters at any one time. This is the complicated but highly-organised web of activity that produces all of our brain activities, including thinking, feeling and goal-directed behaviours.

Dysbindin appears to have multiple functions both within the brain and in the connections between the brain and other tissues in the body. For example, dysbindin is involved in building and maintaining connections between neurons and muscle cells - connections that ensure our muscles do exactly what our brains instruct them to do.

Dysbindin is also involved in the modulation of chemical messages across synapses, playing a direct role in the communication between neurons and muscle cells. Current evidence suggests that dysbindin plays a very similar role within the brain, supporting and modulating communication between neurons. Such activity is vital in ensuring that the complex network of interactions in the brain stays in optimal working condition.

All of this makes very good sense in the context of schizophrenia. It is already known that schizophrenia is associated with disordered communication between neurons, especially neurons that use a particular neurotransmitter known as dopamine. Individuals with schizophrenia tend to have a variety of disturbances of dopamine function, with evidence of dopamine over-activity in certain areas of the brain and dopamine under-activity elsewhere.

This disturbance of dopamine function produces many of the core symptoms of schizophrenia and is also the target for most treatments. The reasons for the disturbance in dopamine function in schizophrenia have always been unclear. However, the association between schizophrenia and the dysbindin gene has opened up a range of new possibilities.

Since its publication, the results of the Ireland-US study have been replicated by an independent group of researchers at the University of Bonn in Germany. However, another group of leading researchers, based at the Department of Genetics in Trinity College, Dublin, have not found an association between the dysbindin gene and schizophrenia in their work.

These findings may reflect the existence of different sub-types of schizophrenia or the effects of genetic variations between people with the illness. Clearly, further study is needed to explain the precise implications of these advances in the genetics of schizophrenia. But what do these advances in genetics mean for patients? What do such advances mean for the 40,000 people in Ireland who suffer from schizophrenia, for the families who support them, and for the mental health workers who help treat and manage the illness?

In the first instance, any advances in our understanding of an illness are important steps toward designing better treatments.

Secondly, the identification of specific genes involved in schizophrenia (such as the dysbindin gene) may help tailor treatments to meet the particular needs of individuals with the illness. Researchers in the field of pharmaco-genetics are developing ways in which genetic tests might be used to help predict which medication is likely to produce the best response in any particular individual.

Information about the Ireland-U.S. study is available at the Health Research Board website (www.hrb.ie) Schizophrenia Ireland (www.sirl.ie) provides information and support in relation to schizophrenia. Further information from its helpline: 1890 621 631.

Dr Brendan Kelly is a senior registrar in psychiatry working at the Central Mental Hospital, Dublin. He is studying for a doctorate in medicine at the Department of Psychiatry, NUI Galway. Yamanouchi (Ireland) Co Ltd sponsors the writing competition.