Influence of a Serotonin Transporter Promoter Polymorphism (5-HTTLPR) on Corticolimbic Abnormalities in Bipolar Disorder An Integrated Genetics and Functional MRI Study

INFLUENCE OF A SEROTONIN TRANSPORTER PROMOTER POLYMORPHISM ON CORTICOLIMBIC ABNORMALITIES IN BIPOLAR DISORDER Maulik P. Shah, and Hilary P. Blumberg. Department of Psychiatry, Yale University School of Medicine, New Haven, CT. Bipolar disorder (BD) is associated with abnormalities of the subgenual anterior cingulate cortex (sgACC) and the amygdala, components of a corticolimbic neural system that subserves emotional regulation. The short s allele—as opposed to the long l allele—of a serotonin transporter promoter (5-HTTLPR) polymorphism is associated with more severe course features of BD and impaired functional connectivity between the sgACC and amygdala in healthy control (HC) individuals. This study tests the hypothesis that the s allele influences the dysfunction in the sgACC-amygdala neural system in BD. Twenty-six euthymic BD participants (17 s carriers, 9 ll) and 43 HC participants (31 s, 12 ll) completed an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, sgACC activation was significantly lower (p < 0.05) in the BD versus the HC group, and in HC and BD s carriers compared to HC and BD ll individuals respectively. In the sgACC region where BD activation was less than HC, response to emotional faces was lowest in the BD s group, suggesting that the s allele may contribute to more severe sgACC dysfunction in a subset of individuals that represent a distinct genetically-derived subtype within the heterogeneous BD clinical phenotype. Thus, sgACC dysfunction may be an endophenotype of BD, and the s allele appears to influence this dysfunction in a subset of BD individuals. Future treatment may be optimized for this subset, by targeting treatments to affect this system, and by further study of treatment response amongst those who carry the s allele.