Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Perlis
Roy H
RH
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Holt
Daphne J
DJ
Smoller
Jordan W
JW
Blood
Anne J
AJ
Lee
Sang
S
Kim
Byoung Woo
BW
Lee
Myung Joo
MJ
Sun
Mei
M
Makris
Nikos
N
Kennedy
David K
DK
Rooney
Kathryn
K
Dougherty
Darin D
DD
Hoge
Rick
R
Rosenbaum
Jerrold F
JF
Fava
Maurizio
M
Gusella
James
J
Gasic
Gregory P
GP
Breiter
Hans C
HC
D000328:Adult; D000483:Alleles; D000786:Anger / Q000502:physiology*; D001143:Arousal / Q000235:genetics* / Q000502:physiology; D001362:Avoidance Learning / Q000502:physiology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D002755:Choice Behavior / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D004292:Dominance, Cerebral / Q000235:genetics; D005149:Facial Expression; D005260:Female; D005838:Genotype; D006791:Hostility; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D009415:Nerve Net / Q000503:physiopathology*; D010100:Oxygen / Q000097:blood; D010364:Pattern Recognition, Visual / Q000502:physiology*; D010555:Personality Inventory; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D010100:Oxygen