Dataset Information

Childhood Adversity Moderates the Effects of HTR2A Epigenetic Regulatory Polymorphisms on Rumination.

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.

SUBMITTER: Eszlari N

PROVIDER: S-EPMC6588047 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Childhood Adversity Moderates the Effects of <i>HTR2A</i> Epigenetic Regulatory Polymorphisms on Rumination.

Eszlari Nora N Petschner Peter P Gonda Xenia X Baksa Daniel D Elliott Rebecca R Anderson Ian Muir IM Deakin John Francis William JFW Bagdy Gyorgy G Juhasz Gabriella G

Frontiers in psychiatry 20190614

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 <i>HTR2A</i> serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived f ...[more]

PMID: 31258491

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Project description:BackgroundSensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods.MethodsGenome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes = 15), closing (ngenes = 36), and expression (ngenes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences.ResultsSuggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction.ConclusionsOur gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

Project description:Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR(*)D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR(*)D (rs1954787, p=0.076, p(corrected)=0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR(*)D (rs7997012, allelic, p=0.043, p(corrected)=0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p=0.0019, p(corrected)=0.12) and the HTR2A SNP (rs17288723, genotypic, p=0.0011, p(corrected)=0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p=0.022) or HTR2A (genotypic, p=0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p=0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p=0.002) and cortisol (p=0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR(*)D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

Dataset Information

Childhood Adversity Moderates the Effects of HTR2A Epigenetic Regulatory Polymorphisms on Rumination.

Publications

Childhood Adversity Moderates the Effects of <i>HTR2A</i> Epigenetic Regulatory Polymorphisms on Rumination.

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