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Original Article
August 4, 2008

Association of a Polymorphism Near CREB1 With Differential Aversion Processing in the Insula of Healthy Participants

Author Affiliations

Author Affiliations: Department of Psychiatry (Drs Perlis, Holt, Smoller, Blood, Makris, Dougherty, Rosenbaum, Fava, and Breiter and Ms Rooney), Neurodevelopmental Genetics Unit of the Center for Human Genetic Research (Drs Perlis and Smoller), Depression Clinic and Research Program (Drs Perlis and Fava and Ms Rooney), Athinoula A. Martinos Center and Department of Radiology (Drs Holt, Blood, Makris, Kennedy, Hoge, Gasic, and Breiter, Messrs Lee and Kim, and Ms Lee), Motivation and Emotion Neuroscience Collaboration (Drs Blood, Hoge, Gasic, and Breiter, Messrs Lee and Kim, and Ms Lee), Addiction Research Program (Mr Lee), Neurogenetics Unit of the Center for Human Genetic Research (Drs Sun and Gusella), Center for Morphometric Analysis (Drs Makris and Kennedy), and Department of Neurology (Dr Kennedy), Massachusetts General Hospital and Harvard Medical School, Boston; and the University of Montreal (Dr Hoge), Quebec, Canada.Group Information: A list of the Phenotype Genotype Project on Addiction and Mood Disorders Investigators appears at http://pgp.mgh.harvard.edu/PGP/People.html.

Arch Gen Psychiatry. 2008;65(8):882-892. doi:10.1001/archgenpsychiatry.2008.3

Context  Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment–emergent suicidality in men with major depressive disorder, but its functional effects have not been studied.

Objective  To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions.

Design and Participants  A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1.

Main Outcome Measures  Blood oxygenation level–dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions.

Results  The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces.

Conclusions  A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.