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Genetic Basis of Schizophrenia
Schizophrenia affects 1% of the general population, with a peak onset typically in early adulthood. It is a constellation of symptoms which include hallucinations (hearing, smelling, feeling or seeing something that isn’t there), delusions, disordered thinking, impaired motivation and social and cognitive impairment (information processing impairment). The underlying causes are little understood and only subtle physical changes are seen. Currently available medications only control symptoms of the disease, have a high rate of side effects and do not affect overall disease process. However, several genes are thought to contribute to vulnerability to schizophrenia. The overall aim of my PhD thesis was to obtain an insight into the underlying genetic changes occurring in schizophrenia through a gene expression approach with the overall objective of demonstrating that genetic predisposition may play a part in the onset of this disease. Gene expression is the way a gene manifests itself in our physical attributes. It has long been known that schizophrenia occurs in families. People who have a close relative with schizophrenia are more likely to develop the disorder than are people who have no relatives with the illness. For example, an identical twin of an affected person has 50% risk of developing the illness. A child whose parent has schizophrenia has about a 10% chance. Schizophrenia is a complex disease i.e. multiple genes are involved in creating a predisposition (or a tendency) to develop the disorder. In addition, environmental factors such as difficulties before birth like fetal starvation or viral infections, complications occurring shortly before and after birth, and various stressors, seem to influence the development of schizophrenia. However, it cannot yet be accurately predicted whether a given person will or will not develop the disorder. Unfortunately, schizophrenia is a poorly understood condition and many people hold a number of misconceptions about it. These misconceptions include believing that people with schizophrenia have a split personality, acting perfectly normal one minute and then irrationally the next. However, this is totally untrue. Schizophrenia is a Greek word that means 'split mind', an unfortunate term first used long before the condition was properly understood. It would be more accurate to say that people with schizophrenia have a mind that can experience episodes of dysfunction and disorder. A person with schizophrenia develops hallucinations where he sees, hears, feels, tastes or smells something that has no external reality. These are very firmly held and cannot be shaken by any logical argument. They're often accompanied by delusions e.g. delusions about people or organisations being out to get them (paranoid delusions). Thoughts, in such cases, can be a rapid, disordered stream tumbling through the mind. There can also be delusions about thoughts: that they're being broadcast to everyone, or being implanted or removed. Some people will take abstract ideas - for instance, "An apple a day keeps the doctor away " – literally i.e. they may become incredibly obsessive about having apples in their possession all the time! Others may become preoccupied with vague, mystical ideas, but the connections between their ideas may not be logical. Neurogenetics contributes to better understanding of the genetic basis of normal and abnormal function of the nervous system. In diseases such as schizophrenia, identification of specific genes involved in its development is crucial to understanding what goes wrong in the brain to produce and sustain the illness and can be utilized for the development of new and better treatments. In short, neurogenetics would allow us to obtain an insight into the genetic and the physiological basis of a psychiatric illness. I will try to provide an insight into the genetic basis of schizophrenia through discussing gene expression analysis in schizophrenia briefly. Most gene expression analysis in schizophrenia has been performed on sections of the prefrontal cortex, the part of the brain which retains abilities to differentiate among conflicting thoughts, determine good and bad, better and best, same and different, future consequences of current activities, working toward a defined goal, prediction of outcomes, expectation based on actions, and social behaviour. These functions are highly deteriorated in schizophrenia. All living organisms have tens of thousands of genes encoded in their DNA, of which only a small fraction, perhaps 15%, are actually active in any individual cell. The regulation of this gene activation determines all life processes. The course of normal development as well as small physiological changes that arise in diseases such as schizophrenia are all believed to be driven by changes in gene activation or expression. A pressing problem is to identify those genes that are differentially or differently expressed in the affected individuals and subsequently to devise therapies. To date, no single gene has been consistently linked to schizophrenia. The consensus opinion is that there is no one major gene that is responsible for all cases of schizophrenia; in fact, many genes are capable, in various combinations, of contributing to the development of the disease. Indeed, gene expression studies have implicated many genes in schizophrenia. Certain genes are involved in regulating function of chemical messengers in the brain. These chemical messengers are substances that allow communication between nerve cells. Most of these studies have focused on the messenger called dopamine, which may be overactive in the brain of schizophrenia patients. Dopamine strongly influences both movement and thinking areas of the brain. Dopamine in the thinking areas of the brain might be considered the chemical messenger of focus and attention. If dopamine levels in the brain begin to raise, we become excited/energized, then suspicious and paranoid, then finally hyper-stimulated by our environment. There is strong evidence that supports the theory of an overactive dopamine system in the schizophrenic brain, but there are also some data that suggests the effects of dopamine blockers may be indirect. Many studies of people with schizophrenia have found abnormalities in brain structure or function. However, these abnormalities are quite subtle and are not characteristic of all people with schizophrenia, nor do they occur only in individuals with this illness. Microscopic studies of brain tissue after death have also shown small changes in distribution or number of brain cells in people with schizophrenia. It appears that many (but probably not all) of these changes are present before an individual becomes ill, and schizophrenia may be, in part, a disorder in development of the brain. Scientists have suggested that schizophrenia may be a disorder resulting from neurons forming abnormal connections during foetal development. These errors may be inactive until puberty, when changes in the brain that occur normally during this critical stage of maturation interact unfavorably with the faulty connections. Studies that have included finding of genes such as “neuregulin” suggest that variations of genes related to brain development and function may play a role in making people more susceptible to the development of schizophrenia. The neuregulin gene produces proteins which are growth factors involved in the growth of the brain, precisely the same areas have been found in numerous studies to be abnormal in schizophrenia. Some “zinc finger” protein genes have also been proposed to be candidate genes for schizophrenia. A zinc finger is a large protein that can bind to various sections of the DNA and control activation of other genes. Zinc finger proteins are also involved in mediating early brain development. In my thesis, and related research we found a Zinc finger protein gene, ZNF440, involved in inhibition of activation of other genes during foetal development. Indeed, another Zinc finger protein has been previously implicated in schizophrenia. Di George syndrome is an inherited condition that occurs when a part of the DNA, containing a zinc finger protein, is missing. Several different genes are lost, resulting in problems with the immune system, congenital heart defects and abnormalities of the parathyroid glands. Moreover, children and adults with DiGeorge syndrome have high rates of behavioral, psychiatric, and communication disorders. Adults, in particular, have high rates of psychotic disorders, especially schizophrenia. An estimated 25% of children with missing zinc finger genes develop schizophrenia in late adolescence or adulthood. This evidence indicates a role for zinc finger proteins in schizophrenia, possibly during foetal development. Zinc finger proteins have been isolated from frontal cortex of the brain, confirming the expression of zinc finger genes in this part of the brain which is strongly implicated in schizophrenia. This evidence suggests a possible developmental role for zinc finger proteins in the brain and more specifically in schizophrenia. The zinc finger proteins may be involved in regulating activation of genes, involved in correct development of the brain, which if activated incorrectly may lead to schizophrenia. Other genes associated with schizophrenia through gene expression studies include a gene that regulates myelin genes activation. As part of the nervous system, myelin lines nerve fibers to protect and insulate nerve cells. Myelin aids in the quick and accurate transmission of electrical current carrying data from one nerve cell to the next. This transmission is probably slowed down in schizophrenics since fewer myelin proteins and less myelin are probably produced through abnormal myelin gene activation. Another schizophrenia vulnerability gene that has been identified, is the dysbindin gene. The gene is known to be abundant throughout the brain and to impact IQ and the speed of information processing. As the function and role of these genes in schizophrenia is further revealed we will be able to identify people at risk for schizophrenia and these genes may be able to serve as targets for new types of schizophrenia therapy. However, a single genetic cause for schizophrenia remains elusive. This is due to the fact that the genetics of most psychiatric diseases are highly complex, presumably involving multiple genes, most which are still unknown. Moreover, in schizophrenia, non-genetic factors also play an important role in conferring susceptibility to the disease. However, despite these limitations gene expression studies are important for understanding gene functions of particular genes abnormally expressed in schizophrenia. The genes discussed in this article study have been linked to schizophrenia and studying their function in more detail will help identify their role in the development of schizophrenia and consequently in the search of a viable cure for the disease.
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