Abstract
The serotonin system has been suggested to moderate the association between childhood maltreatment and rumination, with the latter in its turn reported to be a mediator in the depressogenic effect of childhood maltreatment. Therefore, we investigated whether the associations of two epigenetic regulatory polymorphisms in the HTR2A serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived from the Childhood Trauma Questionnaire) among 1,501 European white adults. We tested post hoc whether the significant associations are due to depression. We also tested the replicability of the significant results within the two subsamples of Budapest and Manchester. We revealed two significant models: both the association of methylation site rs6311 with rumination and that of miRNA binding site rs3125 (supposed to bind miR-1270, miR-1304, miR-202, miR-539 and miR-620) with brooding were a function of childhood adversity, and both interaction findings were significantly present both in the never-depressed and in the ever-depressed group. Moreover, the association of rs3125 with brooding could be replicated across the separate subsamples, and remained significant even when controlling for lifetime depression and the Brief Symptom Inventory depression score. These findings indicate the crucial importance of involving stress factors when considering endophenotypes and suggest that brooding is a more promising endophenotype than a broader measure of rumination. Transdiagnostic relevance of the brooding endophenotype and the potential of targeting epigenetic regulatory polymorphisms of HTR2A in primary and secondary prevention of depression and possibly of other disorders are also discussed.
Highlights
Ruminative response style is a passive and repetitive way of responding to distress and depressed mood, and it predicts future depression [1]
We have demonstrated that both of two HTR2A polymorphisms related to two distinct epigenetic regulatory mechanisms exert a significant effect on current adult rumination as a function of childhood stress, independently of current and lifetime depression status
Both the methylation site rs6311 and the miRNA binding site rs3125 appear to contribute to the endophenotypic manifestation of rumination, and these findings support the need to consider the role of childhood stress when considering endophenotypes
Summary
Ruminative response style (rumination) is a passive and repetitive way of responding to distress and depressed mood, and it predicts future depression [1]. It has two subtypes: the more maladaptive brooding and the less maladaptive reflection [2]. It has been suggested that the depressogenic effect of childhood maltreatment is partly mediated by rumination [3] Both retrospective studies [4, 5] and a longitudinal one [6] indicates that this mediatory effect is carried by the brooding but not the reflection subtype of rumination, one study found no evidence on the mediating effect of brooding between childhood maltreatment and adolescent internalizing or externalizing psychopathology [7]. Brooding level is consistently predicted by childhood maltreatment [4, 6] and its all forms except for physical neglect [5]
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