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This study examined whether polymorphisms in the serotonin transporter (SLC6A4, 5-HTTLPR) and brain-derived neurotropic factor (BDNF Val66Met, rs6265) genes moderate the relationship between life stress and rumination. Participants were a large homogenous group of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N = 273). Results indicate that individuals with two short (S) alleles of the 5-HTTLPR polymorphism or two Met alleles of the BDNF Val66Met polymorphism ruminate more under conditions of life stress, compared to the other genotypes. Moreover, the accumulation of risk alleles (i.e. S and Met alleles) across genes is associated with significantly greater rumination in the context of life stress. These results suggest that both 5-HTTLPR and BDNF Val66Met moderate the relationship between life stress and rumination. These findings support the notion that variation in these genes is associated with biological sensitivity to the negative effects of stress.
A polymorphism in the serotonin transporter gene (5-HTT, SLC6A4) has been associated with individual differences in response to stress. Individuals carrying one or two copies of the relatively low-expressing short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) show more aversive responses to stressful events in field and laboratory studies (Caspi et al. 2010, for review) and are at greater risk for developing depression than long allele homozygotes (e.g., Karg et al. 2011; although see, Risch et al. 2009).
People who ruminate tend to believe that ruminative thinking helps them understand and solve problems (Papageorgiou & Wells 2001, 2003). Thus, adverse events may provide the fodder for rumination, and increases in adverse events are likely to increase rumination. In a small study (N = 21), Canli et al. (2006) found that S allele carriers reported higher levels of rumination than L allele homozygotes but only when they experienced current life stress. Similarly, individuals with two S alleles who experienced higher levels of emotional abuse in childhood report higher levels of rumination in adulthood than individuals carrying at least one copy of the high-expressing long (L) allele (Antypa & Van der Does 2010). These findings are consistent with the idea that the 5-HTTLPR polymorphism moderates the effect of current life stress on rumination.
Variation in a gene-regulating brain-derived neruotropic factor (BDNF) may also influence the effect of current adverse events on rumination. Brain-derived neurotropic factor is a protein involved in neuronal and synaptic development. An amino acid substitution (valine to methionine) at codon 66 (Val66Met, rs6265) of the BDNF gene results in two alleles: Val and Met. We recently reported that the Met allele was associated with increased levels of rumination in a sample of non-depressed adults (Beevers et al. 2009). Similar findings have been reported among women with adult onset depression (Hilt et al. 2007). It remains unclear whether BDNF Val66Met variation interacts with life stress to predict differences in rumination, although a growing animal literature indicates that Met homozygotes display more aversive responses to stress than animals carrying at least one Val allele (Chen et al. 2006; Spencer et al. 2010; Yu et al. 2009).
In summary, we hypothesized that individuals with genotypes associated with stress sensitivity (S 5-HTTLPR carriers or Met BDNF homozygotes) would report higher levels of rumination than L 5-HTTLPR and Val BDNF homozygotes when they experienced recent adverse events. Exploratory analyses investigated the aggregate effect of risk alleles across genes (i.e. S and Met alleles) on the relationship between life stress and rumination.
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The goal of this study was to examine whether 5-HTT and BDNF genes moderate the relationship between life stress and rumination. We tested the hypothesis that individual differences in 5-HTTLPR and BDNF Val66Met polymorphisms predict differences in the relationship between adverse events and ruminative thinking. Results suggest that individuals with two S′ alleles (5-HTTLPR) and individuals with two Met alleles (BDNF Val66Met) tend to ruminate more when they experience more adverse life events. Individuals with one S′ allele showed a similar pattern (although this effect fell just short of statistical significance, P = 0.054). Individuals with two L′ 5-HTTLPR alleles and individuals with at least one Val BDNF allele do not show increased rumination in the context of life stress. These results support the hypothesis that 5-HTT and BDNF genes moderate the relationship between life stress and rumination.
These findings are consistent with a growing body of research that indicating that the 5-HTTLPR polymorphism is associated with susceptibility to the negative effects of stress (Caspi et al. 2010). They are also consistent with evidence that 5-HTTLPR variation moderates the relationship between early life stress and rumination (Antypa & Van der Does 2010). Taken together, these results suggest individual differences in 5-HTTLPR genotype interact with life stress occurring across the life span to predict differences in ruminative thinking. Rumination represents an important cognitive vulnerability for depression (Nolen-Hoeksema et al. 2008); these results support the idea that rumination also represents an intermediary phenotype for depression vulnerability among S′ allele homozygotes who experience life stress.
Moreover, these results provide the first evidence that the BDNF Val66Met polymorphism interacts with life stress to predict rumination. Previous studies showed that the Met allele is associated with direct differences in ruminative thinking (Beevers et al. 2009; Hilt et al. 2007); however, these studies did not (1) investigate the influence of life stress and (2) did not include Met homozygous individuals as a separate group in the analysis. A growing literature suggests that Met homozygotes exhibit susceptibility to the negative effects of life stress (Gatt et al. 2009; Schüle et al. 2006; Vinberg et al. 2009). Results from this study are consistent with this evidence, as Met homozygotes were the only BDNF Val66Met genotype to show increased rumination when they experienced increased adverse events. These results highlight the importance of including this less common genotype in analyses, a demand that requires sampling a large number of participants in BDNF Val66Met association studies.
It is interesting to note that Val/Met individuals reported higher levels for rumination than Val homozygotes in this study, independent of the effects of life stress. This result is consistent with our previous research (Beevers et al. 2009). BDNF Val66Met variation, therefore, appears to influence rumination via two pathways: (1) moderating stable differences in the tendency to ruminate among Val/Met individuals and (2) moderating susceptibility to rumination under conditions of stress among Met homozygous individuals. More work is needed to replicate these initial findings. However, the notion that a gene can influence vulnerability for rumination via different mechanisms has important implications for understanding the etiology of rumination.
Consistent with this idea, future work should also examine whether these genotypes influence sensitivity to both positive and negative environmental contexts (Ellis & Boyce 2008). This model, which is routed in evolutionary-developmental biology, suggests that selection pressures favor adaptive phenotypic plasticity – the capacity for a genotype to flexibly influence behavior depending on environmental context (Boyce & Ellis 2005). The 5-HTTLPR appears to fit this model (Belsky & Pluess 2009). In this study, Met/Met carriers and individuals with four risk alleles reported the lowest levels of rumination in the absence of life stress. This may be evidence for differential susceptibility to context – the BDNF genotypes may increase vulnerability to rumination in stressful environments but lead to lowered rumination in low stress (or more supportive) environments. Future should measure directly positive and negative environmental contexts to test this intriguing possibility.
Finally, our results suggest that susceptibility accumulates across polymorphisms associated with rumination. Previous research has documented evidence of epistatic interactions between 5-HTTLPR and BDNF Val66Met polymorphisms predicting differences in response to adversity (Dourghty et al. 2010) and mood challenges (Wells et al. 2010). This is the first study, to our knowledge, that shows that the accumulation of risk alleles (i.e. S′ and Met alleles) across these polymorphisms is associated with greater susceptibility for ruminative thinking in the context of adverse events. These findings require replication; however, they suggest that susceptibility to stress is not only moderated by epistatic interactions, but can also accumulate across combinations of risk alleles from different genes. Future work should consider including a larger number of single-nucleotide polymorphisms that might influence rumination in the aggregate genetic risk score (De Jager et al. 2009). Doing so may increase the power of genetic models to predict individual differences in rumination.
There are two important limitations to this study. First, the correlational research design prevents conclusions about causal relationships. We assume that adverse events are capable of causing increases in rumination among individuals with certain genetic profiles. Creating adverse events in the laboratory and measuring rumination across genetic profiles would allow us to better understand these relationships. Longitudinal studies would allow us to better explore the temporal relations between stress and rumination among different genetic profiles across the life span. This is particularly important given ambiguity about the nature of BDNF Val66Met associations with rumination at different stages of development (Hilt et al. 2007). Hilt et al. (2007) have reported that an association between the Val/Val genotype and rumination in daughters of women with adult onset depression; but among their mothers, there was an association between the Met allele and rumination. Future longitudinal research, including measures of life stress, may help to better characterize these associations across stages of development.
Second, this research does not identify mediating mechanisms. It is likely that genetic effects on biological systems underlying stress response, affect and cognition mediate genetic influences on the relationship between life stress and rumination. There is growing evidence that both 5-HTTLPR and BDNF polymorphisms are associated with individual differences in stress reactivity, neural function and brain development (Alexander et al. 2009; Canli et al. 2005; Dougherty et al. 2010; Hariri & Holmes 2006; Lau et al. 2010; Montag et al. 2008). Future work integrating functional and structural neuroimaging, for example, may help to identify mechanisms that mediate observed genetic differences in the relationship between life stress and rumination (Canli & Lesch 2007; Canli et al. 2006).
One of these mechanisms may include cognitive control. There is emerging evidence that 5-HTTLPR variation moderates inhibition of emotional stimuli following a laboratory stressor (Markus & De Raedt 2011). Deficits in cognitive control have been associated with rumination (Joormann 2006; Koster et al. 2011; De Lissynder et al. 2010). Together, these results suggest that cognitive control represents an important mediating mechanism for the relationship between genes and rumination in the context of life stress. Future work is required to further examine this hypothesis and explore these relationships in other candidate genes (e.g. BDNF).
Despite these limitations, this research provides important insight into who is most likely to ruminate and when rumination is most likely to occur. Individual differences in the 5-HTT and BDNF genes moderate the relationship between adverse events and rumination among healthy adults. Individuals with two S′ alleles of the 5-HTTLPR polymorphism or two Met alleles of the BDNF Val66Met polymorphism reported higher levels of rumination as adverse events increased. This susceptibility to rumination accumulates across genes, as individuals with the greatest number of summed risk alleles (i.e. S′ and Met alleles) showed the strongest relationship between adverse events and rumination. More work is needed to examine the causal nature of these relationships and to uncover mediating mechanisms that link genetic variation to broad cognitive thinking styles like rumination. This work requires an integrated approach across levels of analyses (i.e. genetic, neural, cognitive, environmental) that will facilitate more comprehensive models of how genes confer susceptibility to the negative effects of stress.