Brain imaging studies of the genetics of schizophrenia

If one identical twin has schizophrenia, their co-twin has an approximately 50% risk of developing the disorder. Similarly, having a sibling with the illness confers a 15% risk on other siblings. These figures contrast with a general prevalence rate of 1% in the general population. Therefore, even allowing for the effects of shared environment with families, it is clear that there is a genetic component to schizophrenia although non-genetic factors also play an important part.

There is a huge amount of research currently directed at identifying genes that may be involved in the development of schizophrenia. Although many potential "hot-spots" have been identified in the human genome, very few findings have been replicated. Therefore it is unlikely that a few genes of major effect exist that are involved in the disorder. Schizophrenia is likely to be a polygenic disorder, in which abnormalities in multiple genes interact with environmental risk factors to produce the range of schizophrenic spectrum illnesses.

Given that schizophrenia is characterized by abnormalities in brain structure and function (links), researchers have used neuroimaging to study whether brain abnormalities may represent the biological expression of possessing a genetic risk to develop schizophrenia. Brain imaging studies have studied many familial relationships in order to investigate the genetic transmission of brain changes in psychotic illness. There is now a great deal of evidence from structural and functional imaging studies that some of the brain abnormalities found in people with schizophrenia (link) are seen in their relatives.

Twins

Studies of twins with schizophrenia have suggested that brain changes in schizophrenia are partially - but only partially - genetically transmitted. Given that monozygotic (identical) twins are genetically identical, studies of discordant identical twin pairs - where one twin is schizophrenic and the other is not - allow us to study the extent of genetic and non-genetic factors on brain changes. Studies of identical twins discordant for schizophrenia have found some differences in brain structure and function between the schizophrenic and non-schizophrenic members of such pairs, such as reduced cerebral and hippocampal volume, increased ventricular volume, and lower brain activity in the prefrontal cortex in the ill twin (Suddath et al, 1990; Berman et al, 1992; Noga et al, 1996; Ohara et al, 1998). These studies suggest that in addition to having some degree of genetic risk for schizophrenia, there is an additional effect of actually having the disorder.

Genetic 'carriers'

Other studies have investigated people who are believed to carry the gene(s) for schizophrenia, while not being psychotic themselves. It has been shown that these Presumed Obligate Carriers (an example would be a person whose mother is schizophrenic and has a child with the disorder - it is assumed that this person is carrying and transmitting the genetic risk for schizophrenia) have enlarged ventricles compared to control subjects (Sharma et al, 1998).

Siblings and children

Many studies have looked at unaffected siblings and have found evidence of abnormal brain structure and function compared to healthy controls. For example, there is evidence of reduced hippocampal and thalamic volumes in unaffected siblings (Seidman et al, 1999; Staal et al, 2000a). Some studies have found a linear progression in abnormalities in the thalamus and hippocampus, such that unaffected siblings are intermediate between their affected siblings and healthy controls (Bertolino et al, 1999; Staal et al, 2000b).

There is growing interest in studying offspring of parents with schizophrenia, who are at an elevated risk of developing the disorder themselves. Studies of these offspring have found evidence of abnormalities similar to those reported in people with schizophrenia. For example, compared to offspring of non-schizophrenic parents, these subjects have been shown to have reduced cerebral, amygdala and thalamic volumes, and abnormal neurochemical activity, measured by MRS (Keshavan et al, 1997; Lawrie et al, 1999).

Conclusions

It is clear from all these strands of research that alterations in brain structure and function seen in schizophrenia are, at least in part, genetically transmitted. The fact that many of the abnormalities reported in people with schizophrenia are seen to some degree is their unaffected relatives suggests that these changes are not necessarily due to having the disorder, but instead partially represent some kind of genetic vulnerability. It may be that the greater the genetic similarity to a person with schizophrenia, the more brain abnormalities a person will possess.

The fact that abnormalities are seen in regions implicated in the pathogenesis of schizophrenia in unaffected relatives, suggest that it is likely that differences in one or two structures such as the hippocampus are neither necessary nor sufficient for the development of psychotic illness. It may be that the difference between affected and unaffected siblings (for example) lies in an overall cumulative degree of widespread brain changes (Leonard et al, 1999).

Ideally, it would be possible to use brain imaging or some other measure (such as neuropsychological function, or brain electrical activity) in order to identify people who are at greatest risk of developing schizophrenia, in order to permit some kind of interventional strategy. However, we are still some way from this as a realistic clinical prospect. Although it is clear that abnormalities exist in the brains of people at increased genetic risk of developing schizophrenia, only a relatively small percentage of these will actually go on to develop the disorder. Researchers are now beginning to undertake follow-up studies of these high risk groups, in order to try to identify measures which distinguish those who go on to psychotic illness, from those who do not (Copolov et al, 2000).