Role of variation in the serotonin transporter protein gene (SLC6A4) in trait disturbances in the ventral anterior cingulate in bipolar disorder

Maulik P. Shah, Fei Wang, Jessica H. Kalmar, Lara G. Chepenik, Karen Tie, Brian Pittman, Monique M. Jones, R. Todd Constable, Joel Gelernter, Hilary P. Blumberg

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Bipolar disorder (BD) is associated with abnormalities of the ventral anterior cingulate cortex (vACC) and its connection sites, including the amygdala, which are key components of a corticolimbic neural system that subserves emotional regulation. Decreased functional connectivity from the vACC to the amygdala in healthy individuals is associated with the short 's' allele - as opposed to the long 'l' allele - of a well-known serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4), as are features of BD. This study tests the hypothesis that the s allele influences dysfunction in the vACC-amygdala neural system in BD. A total of 30 euthymic individuals with BD (20 s carriers, 10 ll) and 48 healthy comparison (HC) participants (34 s, 14 ll) participated in an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, vACC activation was significantly lower in the BD compared to the HC group, and in s carriers compared to ll individuals within both the HC and BD groups, such that BD s carriers exhibited the greatest magnitude of vACC dysfunction. No significant differences were detected in amygdala activation. The findings suggest that the 5-HTTLPR s allele may contribute to a trait-related, genetically derived, neurobiological subgroup within BD characterized by prominent vACC dysfunction. Future treatment may be optimized for this BD subgroup by targeting the serotonergic system and the vACC.

Original languageEnglish (US)
Pages (from-to)1301-1310
Number of pages10
Issue number5
StatePublished - Apr 2009
Externally publishedYes


  • Bipolar disorder
  • Genetic polymorphism
  • Gyrus cinguli
  • Magnetic resonance imaging
  • Serotonin
  • Serotonin transporter promoter polymorphism

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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