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

Roy H. Perlis, Daphne J. Holt, Jordan W. Smoller, Anne J. Blood, Sang Lee, Byoung Woo Kim, Myung Joo Lee, Mei Sun, Nikos Makris, David K. Kennedy, Kathryn Rooney, Darin D. Dougherty, Rick Hoge, Jerrold F. Rosenbaum, Maurizio Fava, James Gusella, Gregory P. Gasic, Hans C. Breiter

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)882-892
Number of pages11
JournalArchives of general psychiatry
Issue number8
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

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