Antisocial and aggressive behaviours represent a widespread and
expensive social problem. Recent research has convincingly shown
that there is a strong interaction between genetic inheritance and
environment for development of personality and behaviour. It
appears to be common knowledge that childhood maltreatment often
causes psychiatric problems (e.g. depression or anxiety) or
behavioural problems (e.g. aggression or antisocial behaviour)
later in life. The risk for such a development is, however,
different between individuals and can to a large extent be
explained by genetic factors. The identification of neural
mechanisms underlying human personality and temperament seems to be
promising due to their considerable importance as highly heritable
risk mediators for aggressive behaviour, criminal activity, as well
as somatic and psychiatric disorders (Buckholtz et al., 2008;
Buckholtz & Meyer-Lindenberg, 2008; Nilsson et al., 2006).
MAOs: key molecules for personality and behaviour
Monoamine oxidases (MAOs) are two enzymes (MAO-A and MAO-B)
which inactivate the so called monoamine transmitter substances
serotonin, noradrenalin and dopamine. The brain systems which
utilise those transmitters are of great importance for the
fine-tuning of personality traits, as well as state-dependent
features such as mood, appetite, attention, etc. MAOs are present
in almost all cells in the body, however, naturally, it is the
activities of MAOs in the brain that are of major interest in
relation to personality and behaviour.
In association with a complete lack of MAO-A, as in mice in
which the MAO-A gene has been knocked out, and in a Dutch family
with a dysfunction of this gene, aggressiveness has been reported
(Brunner, 1996). In the Dutch family aggressiveness was also
combined with arson and cases of rape indicating a lack of impulse
control. Extensive search for more families with this abnormality
has, however, been negative.
Measurements of MAO activities in brain tissue, either
post-mortem or using various imaging techniques, are, however,
tedious and not suitable for larger samples of individuals.
Furthermore, unless combined with functional tasks, as in
functional Magnetic Resonance Imaging (fMRI), findings in relation
to behaviour have usually not been particularly rewarding. This
could possibly be explained by the fact that the majority of the
enzyme is localised in glial cells, and that the population of
enzyme molecules of immediate interest for monoamine inactivation
is difficult to measure.
One of the MAO enzymes – the MAO-B – is localised in
blood platelets and is therefore accessible for activity
measurements in larger samples of individuals. MAO-B enzyme
activity is highly inheritable, as shown in twin studies, and is
stable in the individual during lifetime. Interestingly, decades
ago low platelet MAO-B activity was shown to be associated with
personality traits such as impulsiveness, monotony avoidance and
aggressiveness, and, as a consequence, vulnerability for the type
of alcoholism characterised by strong heritability and antisocial
behaviour (type 2). While low platelet MAO-B activity thus involves
a risk for the individual, it also might be associated, at the
other end of the spectrum, with positive outcomes of impulsiveness
and ´sensation seeking´ such as creativity and
success.
Antisocial behaviour: biological factors
In some non-clinical series of individuals the association with
aggressiveness or antisocial behaviour, however, becomes
significant only if the interaction with the environment is
considered, particularly in girls/females. Personality is,
naturally, a result of the influence of a large number of genes,
all of which result in the formation of their respective proteins,
e.g. enzymes such as the MAOs.
Another protein of importance for the elimination of the
neurotransmitter serotonin is the serotonin reuptake pump (5-HTT),
which is the target for the currently most commonly used
antidepressant drugs, the selective serotonin reuptake inhibitors
(SSRIs). The gene producing this protein exists in variants among
different individuals. Those variants are usually referred to as
the short and the long variant, shown to be of importance for the
risk of anxiety or depression (Harro et al., 2009). Not
surprisingly, the association between platelet MAO-B activity and
personality gets stronger if other independent factors affecting
personality are eliminated. Thus, if only individuals carrying the
short variant of the 5-HTT gene were investigated, the association
between platelet MAO-B activity and behaviour became considerably
strengthened, both with regard to impulsiveness in a large series
of adolescents, and, in a small series of boys, with dimensional
scores for ADHD.
The gene producing MAO-B also exists in variants. One variant of
the gene is weakly associated with platelet MAO-B activity, but
strongly interacts with poor psychosocial environment to predict
antisocial behaviour, particularly in girls. An interesting
question that remains to be answered is why the association between
the MAO-B gene variant and antisocial behaviour was found to be
considerably stronger than with the activity of platelet MAO-B.
A well-studied variant in the MAO-A gene is also associated with
antisocial behaviour. Usually this association has been found only
in individuals in a poor psychosocial environment, where the gene
variant associated with low activity (i.e. a low rate of synthesis
of MAO-A enzyme) has been strongly linked with antisocial behaviour
in males (Nilsson et al., 2007). Recent studies, however,
repeatedly also found an association in girls/females, in some
series of such a magnitude that MAO-A genotype alone –
independently of environment – showed a significant
association. Remarkably, all series showed that, in contrast to the
case in males, the high-activity variant is the one associated with
vulnerability for antisocial behaviour in females (Nilsson et al.,
2008) (see figure 1). This is in line with a marked sex difference
between the gene variants with regard to changes in blood flow in
specific brain regions as a response to emotional stimuli, using
fMRI, which has been shown by the group of Meyer-Lindenberg.
Genetic influences on impulsiveness and ´sensation
seeking´
Our findings raise a number of questions:
- How are stable factors such as personality and temporal factors
and current mood or appetite related to each other if brain
serotonin activity is involved in both?
- How can platelet MAO-B activity be associated with a stable
factor such as impulsiveness?
The view on the first question is that the personality, which is
a life-long characteristic of the individual, is mainly a
consequence of the size or capacity of the brain monoamine systems,
while state-dependent factors such as mood are dependent on the
current activity, large or small, in the system. It is obvious that
an impulsive, ´sensation-seeking´ person, as well as a
more introvert and monotony-resistant individual can be in a high
or low mood, depending on the current situation.
Probably events during life development explain the associations
between MAO gene variants and personality. During foetal
development, high levels of serotonin have been shown to be an
effective inhibitor of the growth of the serotonin system. Hence,
gene variants inferring a low rate of inactivation of serotonin,
especially during foetal life, will lead to a small or low-capacity
brain serotonin system in the adult. Both experiments with animals,
using serotonin specific neurotoxins, and studies on humans, e.g.
by measuring levels of degradation products of serotonin in the
cerebrospinal fluid, have shown that a reduced or low capacity of
the brain serotonin system is linked to a personality characterised
by impulsiveness and ´sensation seeking´. High
´sensation seeking´ in turn has been linked to
increased risk for negative behavioural outcomes such as drug abuse
etc. (Joseph et al., 2009).
With regard to the association between platelet MAO-B and
personality, experimental results make us hypothesise that part of
the explanation is to be found in the regulation of the activity of
genes. Regardless of individual variants in the structure of genes,
their activity is also regulated by activators or inhibitors
(transcription factors), which bind to a specific part, the
regulatory or promoter part, of the gene. There is reason to
believe that the gene producing MAO-B and a number of genes
producing proteins that constitute important parts of the brain
monoamine systems are regulated by the same transcription
factors.
One candidate for being such a common transcription factor is
AP2ß (Nilsson et al., 2009). A low transcriptional activation
of both the gene responsible for the production of platelet MAO-B
and for a number of genes responsible for building up brain
monoamine pathways could in this way explain how a low activity (or
level) of platelet MAO-B protein is mirroring a weak or low
capacity of the monoamine systems in the brain. These would in turn
constitute the biological basis for personality traits such as
impulsiveness and ´sensation seeking´.
Clinical implications
- Our gene-environment interaction findings, as well as those of
others in this field, show a way of understanding biological
mechanisms underlying the individual's degree of dependence on the
environment for the development of e.g. substance abuse, antisocial
behaviour, suicidal behaviour, etc.
- Thus, individuals with one set of MAO gene variants seem to be
virtually independent of environment for the risk of e.g.
antisocial behaviour, and in this way could explain resilience
towards an unfavourable environment, while those with another set
of MAO gene variants are highly dependent on psychosocial
environment for behaviour.
- Another clinically important result is the finding of dramatic
sex differences with regard to the direction of behaviour related
to the interaction between MAO gene variants and environment.
Conclusion
Apart from psychosocial influences, biological factors have a
major influence on personality traits and behaviour.
The aggregation of certain risk factors in the same individual
has been shown to contribute to the development of antisocial
behaviour. Research findings suggest that both the molecular and
the psychosocial mechanisms underlying emotional response and
antisocial behaviour may differ between males and females.
Based on gene-environment interactions, the brain monoamine
systems play a crucial role in shaping personality traits and
conduct disorder. The MAO genes appear to be the first genes
strongly linked with either antisocial behaviour or conduct
disorder.
Individuals with one set of MAO gene variants seem to be
virtually independent of environment for the risk of e.g.
antisocial behaviour, and in this way could explain resilience
towards an unfavourable environment. In contrast, those with
another set of MAO gene variants are highly dependent on
psychosocial environment and have considerable vulnerability for
antisocial behaviour.
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