(A)

Main effect of 5-HTTLPR. (B) Main effect of BDNF Val66Met. (C) Interaction effect of 5-HTTLPR × BDNF Val66Met, demonstrating epistasis. Red dots, S and Met group; Yellow … Table 2 Peak rACC and AMY activation to emotional stimuli for 5-HTTLPR × BDNF Enzastaurin research buy Val66Met groupings IAPS ratings and BOLD activation In order to examine the relationship between subjective ratings of emotion processing and BOLD activation during emotion processing, a multiple regression of the IAPS ratings and the distribution Inhibitors,research,lifescience,medical of rACC BOLD activation was conducted. The IAPS ratings significantly predicted 43% of the variance (adjusted R2 = 0.268) in BOLD activation of the rACC, F(6, 21) = 2.645, P = 0.045. Ratings of both valence (interesting) and arousal (negative) were significant predictors. Discussion The aim of this study was to determine the functional effects of 5-HTTLPR, BDNF Val66Met, and whether their epistasis impacts on emotion processing. Building on previous research (Wang

et al. 2012), the 5-HTTLPR and BDNF Val66Met polymorphisms were found to Inhibitors,research,lifescience,medical interact in the Inhibitors,research,lifescience,medical rACC and the AMY during overt emotion processing in a homogenous, healthy sample of Caucasian females. The effect of the BDNF Met66 allele was moderated by the 5-HTTLPR alleles such that S and Met carriers displayed the greatest activation of the rACC and AMY in response to emotional images, while L/L and Met carriers had the least. Therefore, the epistasis of 5-HTTLPR and BDNF Val66Met is not only related to structural variation of the rACC, as reported previously (Pezawas et al. 2008), it is also associated with functional variation. Relative to all other groups, participants with S and Met alleles are more reactive to emotional stimuli generally. Findings such as these may have implications Inhibitors,research,lifescience,medical for the understanding of affective disorder Inhibitors,research,lifescience,medical development and maintenance (Martinowich and Lu 2008; Grabe et al. 2012). A particularly novel finding obtained in the present study is the observation of a potential epistatic relationship of the 5-HTTLPR and BDNF Val66Met polymorphisms during emotion processing. Our data indicate that the vulnerable effects of the Met66 allele are

– at least – partially dependent on 5-HTTLPR polymorphisms, such that the S allele in combination with the PD184352 (CI-1040) Met66 allele is associated with the greatest activation, while the L allele in combination with the Met66 allele is associated with reduced activity (Fig. 1). Therefore, we suggest that the S and Met combination is the most vulnerable against all other combinations, while the L/L and Met may be the least vulnerable. Serotonergic activity is partly due to the modulatory effects on the serotonin transporter (Mössner et al. 2000). Low 5-HTT efficiency in S carriers may reduce BDNF Val66Met gene expression and the less efficient Met66 allele may magnify this effect (Mamounas et al. 2000; Murphy et al. 2003; Martinowich and Lu 2008).