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 interact in the 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 for the understanding of affective disorder 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 Met66 allele is associated with the greatest activation, while the L allele in combination with the Met66 allele is associated with reduced activity (). 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
). This effect may result from impaired neurogenesis of serotonergic neurons (Ren-Patterson et al. 2005
) supporting the circuitry underlying emotional experiences (Mukherjee et al. 2011
). In contrast, our data suggest that the more efficient L/L genotype may compensate for the effects of the Met66 allele. Our findings further highlight the need for future neurocellular research to consider the impact of 5-HTTLPR and BDNF Val66Met epistasis on the neurogenesis of emotion circuitry.
Our findings indicated that participants with a combination of 5-HTTLPR S and BDNF Met66 alleles display the greatest activity in rACC and AMY in response to high-arousal emotional images relative to nonemotional landscape images. We also found that participant ratings of emotional stimuli were strongly associated with rACC activation during the presentation of the stimuli. This finding further supports the notion that differential rACC activity may be associated with individual differences in adaptive emotion regulation and response preparation (e.g., Roiser et al. 2012
). Prior studies have reported that harm avoidance and neuroticism – well-validated, heritable personality measures linked to the risk of affective disorders – are also associated with the S allele of 5-HTTLPR gene (Lesch et al. 1996
; Reif and Lesch 2003
; Sen and Burmeister 2004
), the Met66 allele of the BDNF Val66Met gene (Gatt et al. 2009
), and heightened rACC and AMY activity in response to emotional stimuli (Keightley et al. 2003
; Bertolino et al. 2005
; Pezawas et al. 2005
). The epistasis of 5-HTTLPR and BDNF Val66Met influences susceptibility for dysfunctional affective disorder-related personality characteristics (Lang et al. 2005
; Ren-Patterson et al. 2005
). For instance, the number of risk alleles increases susceptibility for rumination, with those of the S/S and Met/Met genotype at the most risk (Clasen et al. 2011
). Our results suggest that individual differences in emotional reactivity may be underpinned, in part, by the epistasis of BDNF Val66Met and 5-HTTLPR polymorphism variants. Future examination of the 5-HTTLPR and BDNF Val66Met epistasis on emotion processing also should consider associated risk factors such as personality traits. This line of enquiry may provide further insights into the development and maintenance of affective disorders.
Our finding that the S and Met group was the most reactive to emotional stimuli – suggesting that it is the most vulnerable group – is consistent with that of Wang and colleagues (2012
). Although they did not test for an epistatic relationship or interaction between 5-HTTLPR and BDNF Val66Met, they also found the S and Met group to be the most vulnerable genetic grouping against a combined non-S and Met group. While an earlier structural MRI study (Pezawas et al. 2008
) reported the S and Val combination to be the most vulnerable against other combinations, a more recent study (Carballedo et al. 2012
) reported the structural connectivity of the ACC and the AMY to be reduced in Met carriers. Within a multimodal MRI framework, future research should integrate the structural and functional lines of enquiry by examining the impact of the epistasis of 5-HTTLPR and BDNF Val66Met polymorphisms on the relationship between the structure and structural connections of regions involved in emotion processing as well as their function and functional connections.
A main effect for 5-HTTLPR was observed for emotional stimuli such that S carriers had greater activation in the rACC and AMY than L/L homozygotes. Together with the extant literature (see Murphy et al. 2012
for a meta-analysis), S carriers are more reactive to emotional stimuli. While there is debate as to the magnitude of the effect of the 5-HTTLPR polymorphism function on AMY function – Murphy et al. (2012
) suggest the effect is smaller in magnitude than previously thought (Munafò et al. 2008
) – our data demonstrate a moderate effect of this polymorphism on the AMY and a large effect on the rACC. These findings suggest that the effects of 5-HTTLPR may be stronger in the rACC than in the AMY, which in turn impact on AMY reactivity via reentrant feedback.
We also observed a main effect of BDNF Val66Met in the rACC and AMY, with Met66 carriers showing greater reactivity to emotional stimuli than Val/Val homozygotes; a finding consistent with previous fMRI research on emotion processing (Montag et al. 2008
; Mukherjee et al. 2011
). Additionally, previous behavioral (Beevers et al. 2009
; Terracciano et al. 2010
), structural (Pezawas et al. 2004
; Carballedo et al. 2012
), molecular (Chen et al. 2006
), and fMRI memory consolidation (Egan et al. 2003
) studies have identified Met66 carriers as being more at risk for affective disorders and related traits. Due to the lower neural plasticity associated with lower BDNF levels and impaired memory consolidation processes, it has been suggested that the BDNF Met66 allele reduces capacity for the retrieval of emotional memories (Mukherjee et al. 2011
). This impairment consequently impacts the ability to process the present emotional context, and thus to respond to it adaptively (Mukherjee et al. 2011
). The overreactivity displayed in BDNF Met66 allele carriers may be also associated with hyperactivity of neurovisceral networks (including the rACC; Lane et al. 2009
) involved in the activation and regulation of the autonomic nervous system (Thayer 2006
; Gatt et al. 2009
), and our results suggest that these networks may be further and partially moderated by 5-HTTLPR status. Therefore, those carrying the BDNF Met66 allele may have a reduced capacity to strengthen networks that regulate reactivity to emotional stimuli through learning in previous emotional contexts.
Due to the infancy of research in this area (Martinowich and Lu 2008
), a limitation that is faced by researchers is small sample size, which is then magnified when attempting to examine epistatic interactions. However, the large effects and clear differences between groups at the individual subject level within a homogenous sample are reassuring. Indeed, significant and strong fMRI findings obtained from smaller samples with conservative correction procedures may be true, rather than false, positives and consistent with findings from larger samples (Murphy and Garavan 2004
), particularly within the imaging genetics paradigm (Meyer-Lindenberg et al. 2008
). As there are known modulatory effects of hormone status (e.g., Felmingham et al. 2012
) and sex on gene–brain (e.g., Everaerd et al. 2012
) and gene-affective disorder vulnerability (e.g., Sjöberg et al. 2006
), our findings are limited to the female sex only. Future studies employing emotion processing paradigms and recruiting larger, homogenous samples of females and males will broaden and increase confidence in findings on the impact of the functional epistasis of 5-HTTLPR and BDNF Val66Met on brain-behavioral correlates of emotion processing.
In conclusion, our preliminary study demonstrates a role for 5-HTTLPR, BDNF Val66Met, and their epistasis on emotion processing. Building on previous findings, our novel contribution to the literature is an illustration of a potential functional epistasis of 5-HTTLPR and BDNF Val66Met polymorphisms on emotion processing. The functional impact of the BDNF Val66Met allele may be partially dependent on 5-HTTLPR alleles, with the emotional reactivity of the rACC and AMY being implicated in this epistasis. Both Wang et al. (2012
) and our findings, in independent samples and tasks, provide support for S and Met as a vulnerable genetic grouping. Future research on the epistasis of 5-HTTLPR and BDNF Val66Met should consider both its structural and functional impacts, employing large, homogenous samples of females and males. Working within a gene–brain–behavior framework, future clinical research should consider the potential for a structural–functional epistasis of 5-HTTLPR and BDNF Val66Met that may underpin vulnerability for affective disorders.