Department of Psychological Medicine, University of Wales College of Medicine, Cardiff
Correspondence: Dr Gaynor Jones, Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK
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ABSTRACT |
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Aims To replicate these findings in a larger sample using the Overt Aggression Scale (OAS).
Method A sample of 180 people with DSMIV schizophrenia were rated for aggression using the OAS. KruskalWallis and contingency table analyses were applied to the OAS results.
Results The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03-4.15), whereas that for the heterozygotes was 0.54 (95% Cl=0.30-1.00).
Conclusions The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.
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INTRODUCTION |
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METHOD |
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Controls
We also genotyped 173 unaffected controls to establish COMT genotype
distribution in the general population. The controls were recruited from
volunteers attending the Blood Transfusion Service donor sessions in South
Wales, and were matched for age, gender and ethnicity.
Measurements
The OAS was used to rate episodes of aggression into four main categories
representing escalating violent behaviour
(Table 1). This scale was
designed initially for rating episodes of in-patient aggression and has been
shown to have an intraclass correlation coefficient of 0.87
(Yudofski et al,
1986).
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Each category (labelled OAS 1, 2, 3 and 4) represents a graded spectrum of aggression consisting of: verbal aggression (OAS 1, score 1-4), physical aggression against objects (OAS 2, score 5-8), physical aggression against self (OAS 3, score 9-11) and physical aggression against other people (OAS 4, score 12-16). Each episode of aggression was given a rating between 1 and 16, and the category of aggression (OAS 1-4) also was recorded. All episodes of aggression since the onset of schizophrenia were rated. A record was made of:
Two raters blind to the genotype carried out the ratings of aggression. Interrater reliability was assessed on 20 cases. The intraclass correlation for total OAS score was 0.92.
The genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assay, and was performed blind to history of aggressive behaviour.
Statistics
Analysis was performed using the Statistical Package for the Social
Sciences (SPSS). KruskalWallis (a non-parametric analysis of variance)
and 2 contingency analyses were applied to the OAS
distributions. The power of this study to detect an odds ratio of 2 for
aggressive behaviour between the low-activity homozygote and the other
genotypes was 0.8.
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RESULTS |
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The mean duration of illness for the whole sample was 19.88 years
(s.d.=12.27). There was no significant difference in duration of illness
compared across the genotypes (KruskalWallis test:
2=4.461, d.f.=1, P=0.107) or across gender
(KruskalWallis test:
2=0.001, d.f.=1,
P=0.969). There was no significant association between genotype and
alcohol misuse (
2=0.735, d.f.=2, P=0.963) or
substance misuse (
2=1.830, d.f.=2, P=0.400).
The mean total OAS was higher in males than females (19.3 v. 9.2),
and this difference was statistically significant (KruskalWallis:
2=5.921, d.f.=2, p=0.015). The mean highest OAS
scores for males and females were 7.7 and 5.8, respectively. For purposes of
the analysis, the highest OAS scores (0-16) were divided into four categories
(0-4, 5-8, 9-12, 13-16). Analysis of the highest OAS by gender showed no
ordinal by ordinal association: Kendall's tau-b=-0.089,
Psim=0.204 (P value obtained from 106
Monte-Carlo simulations).
The percentage of males having recorded episodes of verbal aggression (OAS
category 1) was 52%, aggression against objects (OAS category 2) was 39%,
aggression against self (OAS category 3) was 23% and aggression against other
people (OAS category 4) was 39%. The corresponding percentages for females
were 46%, 25%, 9% and 34%, and there was no significant association between
gender and OAS category scores (2=2.55, d.f.=3,
P=0.473).
The percentage of males having no recorded episodes of aggression was 23%,
those having only one recorded episode was 26% and those having more than one
episode was 52%. The corresponding percentages for females were 36%, 30% and
34%, and there was no significant association between gender and number of
episodes (2=3.45, d.f.=3, P=0.36).
Out of our sample of 180 individuals, 43 (24%) were high-activity
homozygote genotype, 91 (50%) were heterozygotes and 46 (26%) were
low-activity homozygotes (see Table
2). The distribution of genotypes was in HardyWeinberg
equilibrium (2=0.02, d.f.=1, P=0.88). Within our
unaffected control group, 37 (21%) were high-activity homozygote genotype, 84
(49%) were heterozygotes and 52 (30%) were low-activity homozygotes. There was
no significant difference in genotype frequencies between our sample group and
our control group (
2=0.121, d.f.=2, P=0.94).
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The mean total OAS score for the high-activity homozygote was 23.5 (range
0-95), for the heterozygote was 12.3 (range 0-140) and for the low-activity
homozygote was 19.7 (range 0-92). There was a statistically significant effect
of genotype on total OAS score (KruskalWallis: 2=8.31,
d.f.=2, P=0.016). When the genotype groups were compared individually
using Dunn's multiple comparison procedure, the only significant difference
was between the high-activity homozygote and the heterozygote
(P=0.025).
Comparison of total OAS scores between the heterozygotes versus both high-
and low-activity homozygotes grouped together resulted in significantly lower
aggression scores (KruskalWallis: 2=7.682, d.f.=1,
P=0.006). When the high-activity homozygotes were compared with the
two other genotypes, a significantly higher total OAS score was seen
(
2=4.939, d.f.=1, P=0.026). This indicated a
statistically significant association between the high-activity COMT
homozygote and higher total OAS scores. This mainly reflected the difference
between the high-activity homozygote and the heterozygote genotypes.
Analysis of allelic association with total OAS score was non-significant
(KruskalWallis: 2=0.521, d.f.=1, P=0.471).
The association between COMT genotype and highest OAS score also was investigated. The mean highest OAS score for the high-activity homozygote was 9.1, for the heterozygote was 6.0 and for the low-activity homozygote was 7.2. Analysis of highest OAS score against genotype using an ordinal by ordinal association test was non-significant (Kendall's tau-b=-0.59, Psim=0.376). There was no association between genotype and ratings for OAS category or number of episodes.
Logistic regression was used to see if OAS category could predict the genotype. The item that best predicted the high-activity genotype was OAS 4: physical aggression against other people (P=0.04). The odds ratio for aggression against others (OAS 4) comparing the high-activity homozygote with the other genotypes was 2.07, with a 95% CI of 1.03-4.15. The odds ratio for aggression against others (OAS 4), comparing the heterozygote with the other genotypes, was 0.54, with a 95% CI of 0.30-1.00.
When analysing the genders separately, the association between genotype and
total OAS score remained statistically significant in males
(KruskalWallis: 2=9.346, d.f.=2, P=0.009) and
comparing the high-activity variant with other genotypes in males resulted in
2=3.818, d.f.=1 and P=0.051. There were no
significant associations found between genotype and either highest OAS, OAS
category or number of episodes in males. For females no significant difference
was found between genotype and any of the measures of aggression.
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DISCUSSION |
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It is interesting that a significant difference was found between the homozygote high-activity genotype and the heterozygote, but not between the high- and low-activity homozygotes. If the high-activity genotype is indeed a risk factor for aggression, we would expect individuals with two copies of this allele to have a higher risk than those with one copy, and an even higher risk relative to those with none. One possible explanation of our findings is that heterozygosity confers some kind of protection against aggressive behaviour. This would be an example of the phenomenon of heterosis that has been observed in other situations (Falconer & Mackay, 1996). The lack of a significant allelic association with total OAS score in our study lends further support to the possible existence of heterosis.
Comparison with previous studies
Our results apparently contradict the findings of previous authors. Lachman
et al (1998) studied a
sample of patients with DSMIV schizophrenia or schizoaffective disorder
and compared those with a history of multiple physical assaults against those
with no history of violence, based on a review of all the information
available. Any subjects showing intermediate levels of violence were excluded
from the study, resulting in a sample size of 55. Their results showed a
significant association between homozygosity for the low-activity COMT
genotype and the violent group. Strous et al
(1997) studied a sample of 37
patients of mixed ethnicity and found that low-activity homozygotes were more
likely to be judged by their psychiatrist to be at a higher risk for
aggressive and dangerous behaviour. Kotler et al
(1999) compared the COMT
genotype across three groups: a group with schizophrenia who had committed
homicide (n=30), a group with schizophrenia who were non-violent
(n=62) and a non-violent unaffected control group (n=415).
They found a significant excess of the low-activity genotype in the homicidal
schizophrenia group compared with the controls, but the difference between the
homicidal and non-violent schizophrenia groups did not achieve statistical
significance.
There are several reasons why our findings may appear to contradict those reported previously. First, the different studies have taken samples from very different patient groups with different levels of aggressive behaviour. It is perhaps of note that two of the studies reporting associations with the low-activity genotype studied patients with extreme levels of violence (homicide and multiple history of physical assault), whereas our patients were unselected for forensic history and were rated across a wide spectrum of aggressive behaviour. It is possible therefore that whereas heterozygosity reduces the risk of aggressive behaviour, as indicated by our study, low-activity homozygotes are at greatest risk of extreme aggression, a finding that our study did not have significant power to detect. Second, the results of previous studies may have been false positives owing to small sample size and/or population stratification due to poor ethnic matching of cases and controls.
Finally, given the difficulties in interpreting the results of genetic association studies, the conflict between our findings and those of other studies may well reflect the fact that no real relationship exists between aggressive behaviour and COMT genotype in schizophrenia.
Ethical issues and future implications
There are a number of ethical issues raised by findings such as these,
which are worthy of wider debate. The discovery of any risk factors for
aggression might have implications for clinical management and detention of
patients in the future. It is widely known that prediction of aggressive
behaviour is, at best, little better than chance
(Monahan, 1984). There are
advocates of an actuarial approach involving the use of statistically weighted
risk pro formas, and the genotype of an individual (being a fixed biological
marker) potentially may be of use in this approach. However, it should be
noted that our results are preliminary and need to be replicated, given that
our findings differ from those of previous studies and given the high rate of
false positive results in genetic studies. Also, even if our result can be
confirmed, the effective size is relatively small and it is unlikely to be
useful for predictive testing. The public view of people with mental illness
is of individuals affected by loss of reason, unaccountable behaviour and
dangerousness (Lawrie et al,
1998). Those with mental illness are subject to stigmatisation and
results such as these may serve to increase that stigmatisation, although
clearly it is not our intention to do so. Indeed, COMT genotype may be a risk
factor for aggression in the general population and not just in those with
schizophrenia.
Replicated findings of genetic associations are necessary steps towards determining the aetiology of schizophrenia and towards understanding the behaviours such as aggression that are associated with this disorder. Catechol-O-methyltransferase is an enzyme that is involved in the degradation of catecholamines such as dopamine, noradrenaline and adrenaline. It is known that catecholamines have an effect on the limbic system and variation in COMT activity may be one of the mechanisms mediating aggressive behaviour. Indeed, a mutation in the gene coding for monoamine oxidase A (an enzyme also involved in the metabolism of catecholamines) has been associated with aggressive and impulsive behaviour in a large Dutch kindred (Brunner et al, 1993), lending further support for the theory that catecholamines may play an important role in this behaviour. However, translating functional studies of polymorphisms associated with aggression into the mechanism that brings about this behaviour is clearly complex and likely to involve several interactions, with other genes as well as with environmental factors. An understanding of these processes also will be essential for the future development of pharmacological agents that might influence phenotypic variables associated with schizophrenia, including that of aggressive behaviour.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication September 29, 2000. Revision received April 24, 2001. Accepted for publication April 26, 2001.
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