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
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Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved February 8, 2006 (received for review December 30, 2005)
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.
Footnotes
- §To whom correspondence should be addressed. E-mail: andreasml{at}nih.gov
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See Commentary on page 6085.
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↵ ¶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.
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↵ ‖Present address: Department of General Psychiatry, University Hospital of Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
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↵**Present address: Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy.
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↵ ††Present address: Merck & Co., Inc., BL2-6, P.O. Box 4, West Point, PA 19486.
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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.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- MAO-A,
- monoamine oxidase A;
- fMRI,
- functional MRI;
- BA,
- Brodmann’s area;
- OFC,
- orbitofrontal cortex;
- ROI,
- region of interest;
- VBM,
- voxel-based morphometry.
Abbreviations:
