Neural mechanisms of genetic risk for impulsivity and violence in humans
Andreas Meyer-Lindenberg,*†‡§ Joshua W. Buckholtz,†‡ Bhaskar Kolachana,‡ Ahmad R. Hariri,†‡¶ Lukas Pezawas,†‡‖ Giuseppe Blasi,†‡** Ashley Wabnitz,†‡ Robyn Honea,†‡ Beth Verchinski,†‡ Joseph H. Callicott,†‡ Michael Egan,‡†† Venkata Mattay,†‡ and Daniel R. Weinberger‡
*Unit for Systems Neuroscience in Psychiatry,
†Neuroimaging Core Facility, and
‡Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 9000 Rockville Pike, Bethesda, MD 20892-1365
§To whom correspondence should be addressed. E-mail: email@example.com
Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved February 8, 2006
¶Present address: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, E-729, Pittsburgh, PA 15213.
‖Present address: Department of General Psychiatry, University Hospital of Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
**Present address: Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy.
††Present address: Merck & Co., Inc., BL2-6, P.O. Box 4, West Point, PA 19486.
Author contributions: A.M.-L., J.W.B., and D.R.W. designed research; A.M.-L., J.W.B., B.K., J.H.C., M.E., V.M., and D.R.W. performed research; A.M.-L., B.K., A.R.H., L.P., and G.B. contributed new reagents/analytic tools; A.M.-L., J.W.B., B.K., A.W., R.H., and B.V. analyzed data; and A.M.-L., J.W.B., and D.R.W. wrote the paper.
Received December 30, 2005.
Proc Natl Acad Sci U S A. 2006 April 18; 103(16): 6269–6274. [Open Access article]
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.
Keywords: aggression, antisocial, functional MRI, monoamine oxidase A, serotonin
Violent and criminal behavior are likely related to complex environmental and social circumstances, but heritable factors also have been implicated (1, 2). The specific neural mechanisms leading to delinquency and impulsive aggression are poorly understood, although they have been the subject of spirited speculation and debate for literally centuries (2–4). Arguably, the clearest link between genetic variation and aggression exists for monoamine oxidase A (MAO-A, MIM 309850), a key enzyme in the catabolism of monoamines, especially serotonin. The serotonergic system has been implicated in impulsivity and manifest violent behavior in animals and both auto- and heteroaggression in humans (2). MAOA and -B genes, likely derived from the same ancestral gene, are both located on the X chromosome (Xp11.23), comprising 15 exons with identical intron–exon organization (5). MAO-A provides the major enzymatic clearing step for serotonin and norepinephrine during brain development, whereas MAO-B activity increases dramatically after birth (5). Mouse knockouts for MAOA, but not MAOB, have elevated brain levels of serotonin, norepinephrine, and dopamine. They show enhanced amygdala-dependent emotional, but not motor, learning (6), and males exhibit dramatically increased aggressive behavior (7). In humans, a Dutch kindred with a missense mutation in the MAOA gene has been described (8): hemizygous males, representing functional gene knockouts, exhibited a pattern of impulsively violent criminal behavior for generations.
Although functionally disabling variants of the gene are rarities outside of the laboratory setting, a common variable number of tandem repeats polymorphism of the MAOA gene has been described that strongly impacts transcriptional efficiency: enzyme expression is relatively high for carriers of 3.5 or 4 repeats (MAOA-H) and lower for carriers of 2, 3, or 5 repeats (MAOA-L) (9). Although conflicting evidence exists for the association of genotype with trait impulsivity in human cross-sectional studies, a clear and pronounced gene-by-environment interaction was found in a large longitudinal study of children followed for 25 years in which MAOA-L predicted violent offenses in males with adverse early experience (maltreatment) (10). This finding, replicated in the majority of further studies (11–13), but not all (14), suggests a deficiency in the neural systems for emotional regulation and memory as possible substrates for the observed gene-environment interaction, because they are essential for the encoding, retrieval, and extinction of negative emotional information expected to be associated with maltreatment during childhood. This finding agrees with current proposals linking brain structures involved in emotional control, such as amygdala and medial prefrontal and orbitofrontal cortices, to the emergence of violent behavior (3, 4). However, whereas two previous functional MRI (fMRI) studies suggested an effect of MAOA genotype during a cognitive task in small samples (15, 16), no data related to emotion processing or brain structure are available.
In the present study, we examined a large sample of healthy volunteers (Table 1, which is published as supporting information on the PNAS web site) using a multimodal imaging approach that we have shown previously to be sensitive to genetic variation affecting the serotonergic system (17). Because our sample was nonviolent, we are not studying the relationship of MAOA and violence per se, but rather the effects of one specific genetic factor on relevant aspects of brain circuitry without contamination by other interacting genetic and epidemiological risk factors that may be implicated in the emergence of this complex behavior and that could obscure or exaggerate the genetic effect (e.g., drug or alcohol use or maltreatment) (1, 2). Voxel-based morphometry was used to canvass the brain for regional volume changes related to genotype (17), previously seen in genetic variation related to serotonin (17), a major modulator of neurodevelopment (18, 19). Three functional magnetic resonance paradigms were used to assess aspects of emotional and cognitive control, subserved by limbic circuitry and conceptually linked to impulse control. To probe circuits of emotional arousal, we used affectively salient social stimuli (angry and fearful faces) previously shown to reliably activate amygdala (17). To examine the neural circuitry engaged by emotional memory, we used incidental encoding and retrieval of neutral and aversive visual scenes. Finally, because cognitive inhibitory processing has also been implicated as a substrate of impulsivity (4), we studied cognitive inhibitory control using a no-go variant of the “flanker” task (20). We hypothesized that carriers of MAOA-L would exhibit structural and functional changes in brain circuitry subserving these various regulatory functions related to emotion and inhibitory control. Because the behavioral effects of MAOA variation have been consistently more penetrant in males in both animal (7) and human (8) studies, we also expected that some physiological and structural differences would be more pronounced in males than females.