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Aims: Previous family, adoption and twin studies of schizophrenia have shown that genetic factors contribute significantly to the risk of schizophrenia. The aim of the present study was therefore to investigate whether exploratory eye movement (EEM) abnormalities are related to the genetic markers linked to schizophrenia.
Methods: Twenty-three probands with schizophrenia, 23 of their healthy siblings (23 proband–sibling pairs), and 43 unrelated normal controls performed EEM tasks. Two parameters were measured: (i) number of eye fixations in responsive search (NEFRS) and (ii) responsive search score (RSS).
Results: Abnormalities in NEFRS and RSS were more frequent in schizophrenia probands than in their unaffected siblings and in normal controls, and were also more frequent in the healthy siblings than in normal controls. Thus, the EEM test performances of the healthy siblings were intermediate between those of the probands with schizophrenia and those of normal controls.
Conclusion: Abnormalities of the EEM test parameters may be related to the genetic etiology of schizophrenia. The use of EEM parameters as an endophenotype for schizophrenia may facilitate linkage and association studies in schizophrenia.
PREVIOUS FAMILY, ADOPTION and twin studies of schizophrenia have indicated that genetic components contribute significantly to the development of schizophrenic disorder. The mode of inheritance in schizophrenia, however, is complex. In addition, schizophrenia probably has etiologic heterogeneity, including locus heterogeneity, in genetic-associated cases of schizophrenia.1–4 The conflicting results of recent linkage studies involving schizophrenia as the phenotype may be due to the complexity of genetic transmission.5,6 Current findings of genetic studies in schizophrenia cannot completely account for the genetic factors of schizophrenia. One approach to resolving this issue is to search for a biological marker that fulfils the following criteria: (i) characteristic of schizophrenia; and (ii) related to the genetic predisposition to schizophrenia. Such an indicator may facilitate linkage analysis of schizophrenia.7 Linkage analysis with such a biological marker of schizophrenia may lead to identification of chromosomal loci for susceptibility to schizophrenia.
Our group previously developed a method to study eye movements while subjects viewed geometric figures, called the exploratory eye movement (EEM) test.8–10 We have obtained responsive search scores (RSS) for the EEM test. In previous studies we did not identify any patients with psychiatric diseases in whom the RSS was similar to that of schizophrenia patients. RSS abnormalities were found only in schizophrenia patients.8–10 Moreover, we conducted a worldwide collaborative EEM study to analyze the stability of parameters of EEM. The EEM tests were performed at seven World Health Organization collaborative centers in six countries. The RSS of patients with schizophrenia were significantly lower than those of depressed patients or healthy controls in all centers.10 Thus, we believe that RSS may be a candidate indicator of schizophrenia.
The aim of the present study was to investigate whether EEM abnormalities are related to genetic vulnerability to schizophrenia. For that purpose, this project was designed to compare EEM test data between schizophrenia probands, their healthy siblings, and normal controls. We investigated the possibility that the EEM test can assist with the clarification of genetic components in schizophrenia.
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The principal findings of the present study are that abnormalities of EEM test parameters are more frequent in schizophrenia probands than in their unaffected siblings or in normal controls, and are also more frequent in healthy siblings than in normal controls. The EEM test performances of the healthy siblings were intermediate between those of the probands with schizophrenia and those of the normal controls.
EEM studies of schizophrenia patients have indicated consistent disturbances. In our previous and present investigation we did not identify any normal individuals or patients with other psychiatric diseases in whom the RSS was similar to that of schizophrenia patients. Not only chronic and acute schizophrenia patients but also those in remission can be distinguished on RSS from patients with depression, neurosis, methamphetamine psychosis, temporal lobe epilepsy, and frontal lobe lesions, and from normal controls.8–10,13,14 The present findings are consistent with those of previous studies in that we were able to replicate abnormalities in the EEM test in schizophrenia patients. Thus, we believe that the RSS in the EEM test may be specific to schizophrenia and may be a predictor for schizophrenia.
Because the NEFRS is a new parameter, there are no previous studies that have investigated differences of the NEFRS between schizophrenia patients, non-schizophrenic psychosis patients and normal controls. Thus, the present results do not prove that the NEFRS is specific to schizophrenia. In the present study, we did confirm that there is a significant difference between schizophrenia patients and normal controls. Further investigation is needed to examine the possible presence of NEFRS abnormalities in non-schizophrenic psychosis. If NEFRS is not specific to schizophrenia, it cannot be presumed to be an indicator of genetic vulnerability to schizophrenia. RSS, however, is scored from the NEFRS (Fig. 2), and there were significant correlations between NEFRS and RSS in all groups. The correlation coefficient of the control group was lower than that of the proband or sibling group, but there was a marginal correlation between the NEFRS and the RSS even though the correlation coefficient was low in the control group. Therefore, based on the evidence that the RSS may be specific to schizophrenia, it is possible that the NEFRS may also be one of the characteristics of schizophrenia.
From the fact that siblings share 50% of their genes on average, the present findings indicate that the NEFRS and the RSS may relate to genetic liability to schizophrenia. But siblings also share many environmental features with the schizophrenia probands. Therefore, it is possible that the NEFRS and the RSS may reflect environmental factors. From our previous data and the present study, however, we propose that each of the EEM test parameters may be a trait indicator.8,9,13,15 It seems likely that genetic factors influence the NEFRS and the RSS more potently than do environmental factors.
According to these discussions, the NEFRS and the RSS may be an intermediate phenotype of schizophrenia, and may be useful for linkage studies of schizophrenia. We found a significant linkage to chromosome 22q11.2-q12.1 in our previous linkage study using the NEFRS as an endophenotype for schizophrenia.16 Chromosome 22q11 is one of the most interesting regions for schizophrenia. Several studies have found that adults with 22q11 microdeletions have a high risk of schizophrenia, and suggested linkage between 22q11 and schizophrenia.17,18 Moreover, there are several candidate genes for schizophrenia, for example COMT, PRODH and ZDHHC8 and so on, in this area.17,18 Therefore, based on the fact that the NEFRS is linked to 22q11, we also consider that the NEFRS may be characteristic of schizophrenia, and be related to genetic predisposition to schizophrenia.
In the light of abnormalities of brain function in schizophrenia, we investigated brain activation during a visual exploration task that was similar to the EEM task using functional magnetic resonance imaging (fMRI) in schizophrenia patients and normal controls. The normal control subjects had activations at the bilateral thalamus and the left anterior medial frontal cortex. In contrast, the schizophrenia subjects had activations at the right anterior cingulate gyrus, but no activations at the thalamus and the left anterior medial frontal cortex.19 These findings indicate that the RSS abnormality of schizophrenia may be associated with dysfunctions of the thalamus, frontal cortex or cingulate gyrus.
In conclusion, we suggest that the present EEM test parameters may be markers of genetic predisposition to schizophrenia. In the future, the EEM test may facilitate advances in linkage and association studies of schizophrenia. Mapping EEM abnormalities to a specific chromosome, and finding an association between EEM deficits and a candidate gene for schizophrenia may yield further knowledge concerning genetic influences on schizophrenia.