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Science 297 (5580): 400-403

Copyright © 2002 by the American Association for the Advancement of Science

Serotonin Transporter Genetic Variation and the Response of the Human Amygdala

Ahmad R. Hariri,1 Venkata S. Mattay,1 Alessandro Tessitore,1 Bhaskar Kolachana,1 Francesco Fera,1 David Goldman,2 Michael F. Egan,1 Daniel R. Weinberger1*

A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

1 Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
2 Laboratory of Neurogenetics, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed at Clinical Brain Disorders Branch, National Institute of Mental Health, 10 Center Drive, Room 4S235, Bethesda, MD 20892-1384, USA. E-mail: weinberd{at}

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