Hypothesis & findings regarding genes involved in stress & stress-related affective disorders –> serotonergic system
- SLC6A4 gene: encoding the serotonin transporter (SERT)
- polymorphism in promotor region (5-HTTLPR): short (S) & long (L) repeats
- S allele leading to decreased SERT expression compared to the L allele
- S allele is associated with increased stress sensitivity & more likely to develop MDD
- association of the S allele with stress sensitivity & depression in maltreated children
==> S allele carriers are more likely to develop stress-related psychiatric disorders, such as PTSD & MDD, which may be due to lower resilience in S allele carriers
Hypothesis regarding genes involved in stress & stress-related affective disorders–> 5-HTTLPR x Environment interaction on
depression ==> Bleys et al (2018)
- meta-analysis
- investigated the influence of dimensional versus categorical assessment of depression & stress, self-report versus interview-based assessment of depression & stress & the timing of stress (i.e., early life stress versus stress in adulthood) as potential moderators of the interaction between 5- HTTLPR & stress in prediction of depression
Findings regarding genes involved in stress & stress-related affective disorders–> 5-HTTLPR x Environment interaction on
depression ==> Bleys et al (2018)
-overall effect size across all included studies significant
o effect size: small
o maybe effect significant since more studies included (than in meta-analyses with non-significant results that investigated less studies)
-very little evidence that way depression & stress were assessed, or the timing of stress, influenced findings concerning interactions between 5HTTLPR and stress in the prediction of depression
-some evidence that studies using a categorical & interview approach to the assessment of stress yielded larger effect sizes –> effect was driven by a small number of effect sizes & included effect sizes that were previously identified as outliers
Limitations of Bleys et al.’s (2018) study
- could not control for gender, ethnicity& twin status or include the biallelic 5-HTTLPR in all studies
- although the 95%CI of the overall GxE effect was comparatively small, the majority of the individual studies showed a large 95%CI that included OR = 1 (NON-significant)
- ratio of included studies to eligible studies was about 48%
Hypothesis regarding genes involved in stress & stress-related affective disorders –> 5-HTTLPR x Environment interaction on
depression ==> Sharpley et al., 2017
- investigated the associations between (i) the 5-HTTLPR & depression; (ii) between the 5-HTTLPR & PR (=psychological resilience) & (iii) between PR & depression
- old men (above 50) that have prostate cancer
Findings regarding genes involved in stress & stress-related affective disorders –> 5-HTTLPR x Environment interaction on
depression ==> Sharpley et al., 2017
- no significant difference in the depression scores of ss vs ll carriers of the 5-HTTLPR after a major stressor (cancer)
- patients with higher PR scores had significantly lower depression scores –> significant inverse correlation between total PR score & depression score
- carriers of the ss allele had significantly higher CDRISC (HIGHER PR) but did not have significantly lower PHQ9 scores (DEPRESSION)
==> PR protected ss allele carriers from the depressive effects of major stress
Under which environmental circumstances is 5HTTLPR suggested to increase the risk for depression?
- childhood maltreatment & stressful life events (Caspi et al., 2003)
- high-impact events & high trait neuroticism (Markus, 2013)
Via what process/ mechanism? (By what process/ vulnerability is 5HTTLPR assumed to contribute to negative emotionality/ depression?)
-due to higher neuroticism (personality) & environment (high impactful events)
What has stress to do with it?
- S allele is associated with increased stress sensitivity & more likely to develop MDD (Maul et al, 2020)
- S allele carriers are more likely to develop stress-related psychiatric disorders, such as PTSD & MDD, which may be due to lower resilience in S allele carriers (Maul et al, 2020)
Markus (2013): What does this illustrated three-way interaction on depression (BDI) implicate?
-3 way interaction of: impact of life events, neuroticism (high vs low) & allele combinations
==> High impact of life events on depression becomes most profound under high neuroticism when at least one S allele (SS or LS) (but not for LL)
==> only S allele carriers showed vulnerability to depression exclusively when reporting exposure to high-impact events & high trait neuroticism
Markus (2013): What do the findings mean for the assumed gene (5HTTLPR) x Environment interaction on depression?
- main effect of neuroticism
- main effect of impact of life events
- NO main effect of 5-HTTLPR genotype
- -> no differences in depression scores between S & L allele carriers
(NO interaction between gene& neuroticism)
Markus (2013): Are there additional factors mediating the suggested link between genes, environment & risk for depression? (e.g. personal psychological resilience)
–> PR (=psychological resilience) protected ss allele carriers from the depressive effects of major stress (cancer) (Sharpley et al., 2017)
Might there be benefits of having the ss allele? (McGuffin & Rivera, 2015)
preliminary evidence that children with anxiety or depression respond
more positively to psychological treatments if they carry the 5-HTTLPR s allele (30)
