The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent ...studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.
Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels.
Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of ...clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. RESULTS: We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. CONCLUSIONS: Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles.
In view of the potential effects of psychiatric drugs on DNA methylation, we investigated whether medication use in bipolar disorder is associated with DNA methylation signatures.
Blood-based DNA ...methylation patterns of six frequently used psychotropic drugs (lithium, quetiapine, olanzapine, lamotrigine, carbamazepine, and valproic acid) were examined in 172 bipolar disorder patients. After adjustment for cell type composition, we investigated gene networks, principal components, hypothesis-driven genes and epigenome-wide individual loci.
Valproic acid and quetiapine were significantly associated with altered methylation signatures after adjustment for drug-related changes on celltype composition.
Psychiatric drugs influence DNA methylation patterns over and above cell type composition in bipolar disorder. Drug-related changes in DNA methylation are therefore not only an important confounder in psychiatric epigenetics but may also inform on the biological mechanisms underlying drug efficacy.
Animal studies have identified persistent and functional effects of traumatic stress on the epigenome. This review discusses the clinical evidence for trauma-induced changes in DNA methylation across ...the life span in humans. Studies are reviewed based on reports of trauma exposure during the prenatal period (13 studies), early life (20 studies), and adulthood (ten studies). Even though it is apparent that traumatic stress influences the human epigenome, there are significant drawbacks in the existing human literature. These include a lack of longitudinal studies, methodological heterogeneity, selection of tissue type, and the influence of developmental stage and trauma type on methylation outcomes. These issues are discussed in order to present a way in which future studies can gain more insight into the functional relevance of trauma-related DNA methylation changes. Epigenetic studies investigating the detrimental effects of traumatic stress have great potential for an improved detection and treatment of trauma-related psychiatric disorders.
Background
Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in ...vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism.
Methods
We investigated the effect of childhood maltreatment, major life events, daily hassles, and a composite index thereof (cumulative stress index) on depressive symptoms and major depressive disorder (MDD) including the possible moderating role of neuroticism in a discovery sample from the general population (N = 563) and an independent replication sample from the Netherlands Study of Depression and Anxiety (N = 2,274).
Results
All stress domains were independently associated with depressive symptoms in the discovery sample. In the replication sample, we confirmed these findings for childhood maltreatment and daily hassles but not for major life events with depressive symptoms as outcome. Nevertheless, all stress domains significantly contributed to the presence of MDD in the replication sample. The cumulative stress index was significantly associated with depression in the discovery (β = 1.42, P < .001) and replication sample (β = 3.79, P < .001), especially in those individuals with high levels of trait neuroticism (discovery: β = 0.013, P < .001; replication: β = 0.367, P < .001).
Conclusions
This is the first study to show that cumulative stress exposure across different stress domains contributes to depressive symptoms and MDD in adulthood. Moreover, we show that increased exposure to stress
across the life span has more impact on vulnerable individuals with high levels of trait neuroticism.
Summary Decisions are rarely made in social isolation. One phenomenon often observed in social interactions is altruistic punishment, i.e. the punishment of unfair behavior by others at a personal ...cost. The tendency for altruistic punishment is altered by affective states including those induced by stress exposure. Stress is thought to exert bi-directional effects on behavior: immediately after stress, reflex-like and habitual behavior is promoted while later on more far-sighted, flexible and goal-directed behavior is enhanced. We hypothesized that such time-dependent effects of stress would also be present in the context of altruistic punishment behavior. Healthy male participants ( N = 80) were exposed to either a grouped stress test or a control condition. Participants were tested in prosocial decision making tasks either directly after stress or 75 min later. Altruistic punishment was assessed using the Ultimatum Game. General altruism was assessed with a one-shot version of the Dictator Game in which an anonymous donation could be offered to a charitable organization. We found that stress caused a bi-directional effect on altruistic punishment, with decreased rejection rates in the late aftermath of stress in response to ambiguous 30% offers. In the Dictator Game, stressed participants were less generous than controls, but no time-dependent effect was observed, indicating that the general reward sensitivity remained unchanged at various time-points after stress. Overall, during the late aftermath after acute stress exposure (i.e. 75 min later), participants acted more consistent with their own material self-interest, and had a lower propensity for altruistic punishment, possibly through upregulation of cognitive self-control mechanisms. Thus, our findings underscore the importance of time as a factor in simple, real-life economic decisions in a stressful social context.
The Psychiatric Case Register Middle Netherlands (PCR-MN) registers the mental healthcare consumption of over Dutch 760,000 inhabitants in the centre of the Netherlands. In 2010 the follow-up period ...was over ten years. In this paper we describe the content, aims and research potential of this case register.
All mental healthcare institutions in the middle-western part of the province of Utrecht participate in the PCR-MN case register. All in- and out-patients treated in these institutions have been included in the database from the period 2000 to 2010. Diagnosis according to DSM-IV on axis I to IV, visits to in- and out-patient clinics and basic demographics are recorded. A major advantage of this register is the possibility to link patients anonymously from the PCR-MN cohort to other databases to analyze relationships with determinants and outcomes, such as somatic healthcare consumption, mortality, and demographics, which further increases the research potential
The PCR-MN database has a large potential for scientific research because of its size, duration of follow-up and ability to link with additional databases, and is accessible for academic researchers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Cardiac surgery patients are at risk for post-traumatic stress disorder (PTSD) and depression, which might hamper recovery.•Factors associated with the development of PTSD and depression are ...variable.•Linear backwards regression identified higher trait anxiety to affect the occurrence of PTSD and depression significantly.•In this setting, female patients potentially benefit from intraoperative dexamethasone administration.
Cardiac surgery patients are at risk for psychopathology. Symptoms of post-traumatic stress disorder (PTSD) and depression occur in 10–20% of these patients and affect their quality of life. The aim of this study was to assess factors associated with psychopathology after cardiac surgery.
We followed participants of the multi-center randomized clinical trial Dexamethasone for Cardiac Surgery (DECS), on a single, intravenous dose of dexamethasone (1 mg/kg) or placebo during cardiac surgery, using validated questionnaires to assess PTSD and depressive symptoms after 1.5 to 4 years, as well as childhood trauma, trait anxiety, pre-existing psychopathology, and substance use. Saliva was used for genotyping of the hypothalamic-pituitary-adrenal-axis (HPA axis) glucocorticoid receptor gene. Linear backward regression analysis was performed with these factors, including pre-specified interaction terms of dexamethasone with sex and genotype.
Complete data was available for 90% of cases (n = 1111). The model including trait anxiety and the dexamethasone x female sex interaction explained 57% of variance in PTSD symptoms (Model fit F (2;4.817)=643.043, p<.001; R2=0 0.57). Similar explained variance was seen for depressive symptoms, where age, trait anxiety and the dexamethasone x female sex interaction provided the optimal model (Model fit F (3;4.261)=435,960, p<.001; R2=0.58).
In this study psychopathology was assessed through validated questionnaires. Variability in data collection detail was present.
This study suggests that the occurrence of psychopathology after cardiac surgery is influenced by higher trait anxiety. Female cardiac surgery patients may benefit from intra-operative dexamethasone administration.
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