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Review of the Neurobiological Mechanisms Which Underpin Reactive Aggression in Humans: a Closer Look at Monoamine Oxidase A (MAOA)
Module 1: Prosocial and antisocial behaviours across the lifespan
Violent acts have a significant toll on human societies: annually over 1.6 million deaths worldwide occur due to human violence (Viding & Frith, 2006). Although acts of aggression have an important adaptive purpose, when overexpressed, they may result in destructive consequences. Conventionally, aggression has been defined as an intentional action with a purpose to inflict physical damage on another individual (Nelson & Trainor, 2007). Currently two forms of aggression have been recognized in humans: controlled aggression – instrumental subtype, and reactive aggression – impulsive subtype (Vatiello & Stoff, 1997). Instrumental aggression, also referred to as premeditated and predatory, is generally planned and goal-oriented and has often been linked to psychopathy (Blair, 2001). This kind of aggression is thought to be regulated primarily by higher cortical systems and is characterized by diminished amygdala response (Nelson & Trainor, 2007). Reactive aggression on the other hand, is dependent on the limbic and hypothalamic systems, and is characterized by high autonomic arousal (Siever, 2008). Impulsive aggression generally represents a direct response to stimuli and accounts for the majority of violent acts. Individuals with borderline personality disorder, intermittent explosive disorder, or ADHD are particularly prone to reactive aggression and impulsivity. Previous research on the neurobiology of aggression pointed out that for such individuals, repetitive acts of aggression are often influenced by the underlying neurobiological susceptibility (Nelson & Trainor, 2007). Indeed, one remarkable feature of aggression is its apparent heritability. Twin and adoption studies suggest that genetic factors account for between 40% and 50% of population variance in risk of antisocial aggression (Buckholtz & Meyer-Lindenberg, 2008). However, the relationship between aggression and the underlying neurobiology is far from being simple (Nelson & Trainor, 2007; Siever, 2008).
Previous research in individuals prone to impulsivity and reactive aggression as well as a number of studies based on animal models identified numerous genetic loci and neurotransmitters associated with reactive violence, including, but not limited to, Dopaminergic genes (DRD4, DRD5, and DAT1), Serotonergic genes (5HTT, HTR1B), and genes responsible for encoding enzymes involved in regulating the levels of these neurotransmitters, particularly catechol-O-methyltransferase (COMT), and Monoamine Oxidase A (MAOA), often referred to as “the warrior gene”. However, the association between genotype and phenotype of aggression is only beginning to be properly understood (Caspi, McClay, Moffitt, Mill, Martin, Craig, Taylor, & Poulton, 2002; Nelson & Trainor, 2007; Siever, 2008). While there have been many studies showing the association between different genes and aggression, results were often mixed and inconclusive. Currently, the best candidate gene with the most supportive evidence appears to be Monoamine Oxidase A (see: Brunner, Nelen, Breakefield, Ropers, van Oost, 1993; Byrd & Manuck, 2014; Cases, Seif, Grimsby, Gaspar, Chen, Pournin, Muller, et al.,1995; Caspi, et al., 2002).
The MAOA gene, located on the X chromosome, is a functional polymorphism with high activity (MAOA-H) and low activity (MAOA-L) variants, which encodes the MAOA enzyme, responsible for breaking-down neurotransmitters such as serotonin, dopamine, and norepinephrine (Shih, Chen, & Ridd, 1999; Viding & Frith, 2006). Previous research using animal models as well as humans demonstrated an association between aggression and genetic deficiency in MAOA activity (Rowe, 2001). Transgenic mice without the gene encoding MAOA had higher amounts of brain serotonin (5-HT), dopamine (DA), and norepinephrine (NE), and displayed increased aggression (Cases, et al., 1995). After restoring MAOA activity, mice aggression was stabilized (Shih & Thompson, 1999). In humans, point mutation in the MAOA gene led to MAOA deficiency and was found to be associated with reactive aggression in several men from the Dutch family. Moreover, across generations, these men with MAOA knockout also showed frequent violent outbursts, particularly in response to mild provocation, and impulsive antisocial behaviour such as assault, rape, and attempted murder. (Brunner, et al., 1993). This condition, however, is quite uncommon and is unlikely to explain much variation in human violence and aggression.
Findings of the studies that only looked at levels of MAOA activity and antisocial outcomes in adulthood have been mixed and thus problematic to interpret since both MAOA-H and MAOA-L were linked to reactive aggression (Ficks & Waldman, 2014; Nelson & Trainor, 2007; Siever, 2008). The study that produced very robust findings in that area and has later proven seminal was conducted by Caspi and colleagues (2002). This study was the first to look at the effects of MAOA activity in combination with childhood maltreatment on reactive aggression in adulthood. Indeed, adverse childhood experiences were found to affect the development and functioning of neural pathways involving the neurotransmitters metabolised by MAOA which can potentially result in increased aggression (Caspi, et al., 2002). Thus, Caspi and colleagues (2002) hypothesised that childhood maltreatment can predict reactive aggression in adulthood, and that this relationship is moderated by levels of MAOA expression.
Results of this study demonstrated the dose-response effect of childhood maltreatment on the aggressive behaviour in adulthood, which was consistent with prior findings. However, this effect was much smaller in participants with the high-activity version of the MAOA gene as compared to men with low MAOA activity, suggesting the protective property of MAOA-H (Caspi et al, 2002). Moreover, as levels of maltreatment increased, so did the protective effect of the MAOA-H variant. A low-activity MAOA gene combined with a history of childhood maltreatment increased the risk of aggressive behaviour in adulthood sevenfold. These results supported the predicted hypothesis that MAOA activity would act as a moderator of the effects of childhood maltreatment on antisocial outcomes in adulthood.
This study paved the way to a number of subsequent studies looking at gene and environment interaction. A recently published meta-analysis, which looked at 27 peer-reviewed studies on adverse childhood experiences, MAOA genotype, and aggressive and antisocial behaviour showed that results across 20 male cohorts (11064 participants) were largely consistent with findings from the original study by Caspi and colleagues (2002) (Byrd & Manuck, 2014). These findings remained robust even after removing each study individually.
However, the question remains, how does low activity MAOA gene in combination with childhood stressors translate to antisocial behaviours in adulthood? Several theories have been proposed to answer this question. On one hand, the association between low activity MAOA gene and aggression appears paradoxical, since MAOA-L leads to increased levels of serotonin, which has been found to be positively correlated with impulse control and negatively correlated with aggression (Manuch, Flory, Ferrell, Mann, & Muldoon, 2000; Siever, 2008). However, MAOA also plays a role in regulating dopamine and norepinephrine, which were shown to lower thresholds for violent response to perceived threat (Manuch, et al., 2000). High levels of DA and NE, resulting from MAOA dysfunction, would activate a fight or flight response, and indirectly enhance aggression (Volavka, Bilder, & Nolan, 2004). Indeed, previous studies showed a similar association between COMT gene (also responsible for breakdown of NE and DA) and aggression (Siever, 2007; Volavka, et al., 2004). Therefore the elevated levels of NE and DA, due to low expression of MAOA, would be consistent with the results of previous studies, showing an association between low activity MAOA gene and aggression. Nevertheless, this theory does not account for the role of childhood maltreatment on aggression, and as it was mentioned previously, results of studies looking solely at MAOA activity and aggression are mixed and inconclusive, showing both high and low activity MAOA gene being associated with impulsive aggression (Ficks & Waldman, 2014; Nelson & Trainor, 2007; Siever, 2008).
Another theory that sheds more light on the mechanism through which MAOA deficiency in combination with childhood maltreatment influences aggression in adulthood relies on the findings that high concentrations of intracellular serotonin have been associated with increased reactivity to stress and elevated anxiety (Seif & De Maeyer, 1999, Viding & Frith, 2006). Therefore, it is possible that MAOA deficiency might predispose individuals to neural hyper-reactivity to a threat (maltreatment). While genetic predisposition alone rarely results in adverse outcomes in adulthood, when combined with childhood stressors, it might potentially have consequences on brain function (Meyer-Lindenberg, Buckholtz, Kolachana, Hariri, Pezawas, Blasi, Wabnitz, et al., 2006). Previous findings in populations prone to impulsive violence demonstrated functional and structural abnormalities in brain areas associated with perception and regulation of emotions, particularly in the amygdala, orbitofrontal cortex, and the interconnected regions (Davidson, Putnam, Larson, 2000). Neuropsychological functions associated with these brain regions were also compromised in the aforementioned populations (Blair, Peschardt, Budhani, Mitchell, Pine, 2006). Previous work using animal models and clinic samples seems to suggest that maltreatment negatively affects the functioning of the neural structures involved during an individual’s reaction to threat (i.e., pariaquaductal gray and amygdala) and the regulation of the triggered threat response (i.e., orbitofrontal cortex and anterior cingulate). Therefore, the genetic risk (MAOA-L) along with childhood maltreatment may result in changes to brain function, and subsequently increases the risk of impulsive aggression (Viding & Frith, 2006).
These speculations imply that there is no one clear explanation for the findings we currently have regarding genetic variation and its effect on aggression. The human brain and the effects of genetic and environmental factors on its development are too complex to assume that one specific gene, or neurotransmitter levels are responsible for aggression. More likely, it is the gradual change in neural pathways that regulate aggression. As of this moment, it still remains unclear if aggression in adulthood that is observed in many of the aforementioned studies is due to developmental change in neural circuits or to a change in neurotransmitter function. Moreover, the effects of these changes for adults are very different than for children. Therefore, it is possible that low MAOA activity resulted in compensatory changes which transformed the organisation of the nervous system in children during the sensitive period of brain development, and was later reflected in antisocial outcomes in adulthood (Lesch & Merschdorf, 2000).
Attempts to replicate Caspi et. al. (2002) findings in female populations yielded significantly different results. Recent meta-analysis that looked at 11 studies with female samples produced inconclusive results: even though MAOA activity had a significant association with adverse childhood events, high, as opposed to low, MAOA activity in combination with childhood maltreatment was associated with antisocial behaviour in adulthood. Moreover, this interaction was weaker, and after removing a few individual studies, it lost its significance (Byrd & Manuck, 2014). Replicating Caspi and colleagues’ study using female cohorts has proven to be significantly more complicated for two main reasons. First of all, dividing females into two groups based on MAOA activity is challenging due to uncertain inactivation of heterozygous alleles. Secondly, severe personality disorders and antisocial outcomes are quite rare in women, thus it is difficult to get a large enough sample to demonstrate dose-response relationships. In sum, taking into account findings from previous studies it is unclear what relationship MAOA activity plays in antisocial outcomes in women, and calls for further investigation (Caspi, et al., 2002; Byrd & Manuck, 2014).
In attempts to understand the relationship between genes, environment, and aggression, the study by Caspi and colleagues (2002), as well as numerous studies that came out afterward, certainly advanced our understanding in the field. However, it is important to point out the limitations that characterise many of the research studies investigating the relationship between gene-environment interaction and adult antisocial behaviour. First of all, lack of published articles reporting null findings due to publication bias still remains a big problem in the field. As a result, published findings seem more robust than they actually are (Duncane & Keller, 2011). Secondly, the samples of many studies, primarily those with female subjects, are often too small resulting in inadequate statistical power (Byrk & Manuck, 2014). Indeed, negative findings had larger sample sizes compared to positive ones. These limitations make it difficult to correct for potential false-positive results (Duncan & Keller, 2011). This is especially the case in replication attempts using female populations, and in neuroimaging studies. Finally, due to the difficulty recruiting participants for these studies, samples are often not easily comparable and consist of individuals with many comorbid psychiatric conditions, making it difficult to tease apart effects of certain genetic variations and maltreatment on specific psychopathology (McCrory, DeBrito, Viding, 2010).
While there is strong evidence to suggest that genotype, particularly variants of the Monoamine Oxidase A gene, in combination with childhood maltreatment, plays an important role in reactive aggression in human adulthood, the exact underlying mechanism remains unclear. The aforementioned controversies call for caution when making any strong conclusions regarding the effects of genetic variation on antisocial outcomes. Further research, including longitudinal studies, genome-wide association studies, gene-environment-sex and gene-gene interaction studies, and neuroimaging studies, is necessary to better understand the underlying neurobiological mechanisms which underpin reactive aggression in humans.
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