Neural mechanisms of genetic risk for impulsivity and violence in humans

Abstract

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.aggression ͉ antisocial ͉ functional MRI ͉ monoamine oxidase A ͉ serotonin

Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women

“…Similarly to our finding, the functional response of heterozygous women carrying both high-and low-expressing allele was intermediate between homozygous female subjects. 41 This finding is consistent with a codominant effect of the alleles not only on neurobiology but on complex behavior and might be seen as supportive of a recent study showing that MAOA is among those genes that escape X inactivation. 43 Alternatively, in brain, the clonality of MAOA allele inactivation is such that mosaicism of allele expression of the heterozygotes is relatively fine-grained and the neurobehavioral phenotypes of heterozygotes are therefore intermediate.…”

“…42,43 Our results showed that heterozygous individuals displayed a risk, which was intermediate between the homozygote, echoing the neuroimaging findings of Meyer-Lindenberg et al 41 Meyer-Lindenberg et al found that the genotype conferring low MAOA activity predicted amygdala hypereactivity during emotional arousal in both male subjects and female subjects. Similarly to our finding, the functional response of heterozygous women carrying both high-and low-expressing allele was intermediate between homozygous female subjects.…”

“…Carriers of the low activity variant of MAOA-LPR display hyperactivation of the hippocampus and amygdala during the retrieval of negatively valenced emotional material. 41 Therefore, the heightened sensitivity to adverse experiences of carriers of the low activity MAOA genotype might be due to their impaired ability to extinct adverse memories and conditioned fears.…”

MAOA, maltreatment, and gene–environment interaction predicting children's mental health: new evidence and a meta-analysis

“…67 A statistical G Â E involving MAOA thus represents an important launching pad for developmental neuroscience research into the underlying causal mechanisms involved in the etiology of psychopathology. 10,64,[68][69][70] Moreover, it is possible that the MAOA gene may simply be a marker for a behavioral trait, which itself moderates the association between maltreatment and children's mental health.…”

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

“…A recent fMRI study shed some light on possible neurobiological underpinnings of MAOA genotype on aggressive behavior, demonstrating that the at-risk genotype results in amygdalar hyperreactivity in response to emotional arousal, paralleled by impaired response of prefrontal brain regions including the anterior cingulate cortex (Meyer-Lindenberg et al, 2006). Considering the data on reduced 5HTT availability in this structure in aggressive subjects (Frankle et al, 2005), serotonin metabolism in the cingulate gyrus seems to be a crucial determinant of disposition toward violent behavior.…”