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.

Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect ofDRD2variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of theDRD2locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studiedDRD2variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproducedin vitroby using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatoryDRD2polymorphisms that modify mRNA expression and splicing and working memory pathways.

The cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control (AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase (COMT). A functional polymorphism (val¹⁵⁸met) in the COMT gene accounts for some of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMTval¹⁵⁸metpolymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine (“val”) allele show greater activity and poorer performance than val/methionine (“met”) heterozygotes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activitymetallele, and these effects are most evident at the highest demand for AC. These results indicate thatmetallele load and presumably enhanced dopaminergic tone improve the “efficiency” of local circuit processing within the cingulate cortex and thereby its function during AC.