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Objective and design: Inflammatory processes are an important part of the etiology of many chronic diseases across various medical domains, including neurodegeneration. Understanding their regulation on the molecular level represents a major challenge. Regulatory microRNAs (miRNAs), have been recognized for their role in post-transcriptionally modulating immune-related pathways serving as biomarkers for numerous diseases. Subjects and Methods: This study aims to investigate the association between 176 plasma-circulating miRNAs and the blood-based immune markers C-reactive protein and fibrinogen within the general population-based SHIP-TREND-0 cohort (N = 801) and assess their impact on neurodegeneration in linear regression and moderation analyses. Results: We provide strong evidence for miRNA-mediated regulation, particularly in relation to fibrinogen, identifying 48 significant miRNAs with a pronounced over-representation in chronic inflammatory and neurological diseases. Additional moderation analyses explored the influence of the APOE ε4 genotype and brain white matter neurodegeneration on the association between miRNAs and inflammation. Again, significant associations were observed for fibrinogen with special emphasize on hsa -miR-148a-3p, known to impact on neuroinflammation. Conclusions: Our study suggests the involvement of several plasma-circulating miRNAs in regulating immunological markers while also being linked to neurodegeneration. The strong interplay between miRNAs and inflammation holds promising potential for clinical application in many immune-related neurodegenerative diseases. • First study on the association between CRP and fibrinogen as markers of low-grade inflammation and circulating microRNAs. • Large sample size of N = 801 subjects from the general population. • Strong signal of fibrinogen on miRNAs. • Moderating effect of APOE e4 carrier status reveals the link toward neurodegeneration. • Supported by moderating effects between fibrinogen and the main target miRNA has-miR-148a-3p on white matter lesions. [ABSTRACT FROM AUTHOR]

Background: Alexithymia ("no word for feelings") is a personality feature that is common in patients with psychiatric disorders. However, little is known about biological causes and mechanism behind. Research so far focusses on genetic risk variants primary associated with depression, but analyses on epigenetic mechanisms are still missing.Methods: In a sample of n = 813 subjects from the "Study of Health in Pomerania" we analyzed the association between alexithymia and plasma circulating micro RNAs (miRNA). Significant miRNAs were compared to associations regarding depression and pathway analyses were performed.Results: Two miRNAs were significantly associated with at least one of the alexithymia scores (hsa-miR-324-3p, hsa-miR-33a-5p) and three miRNAs additionally revealed a strong association pattern to alexithymia (hsa-miR-106b-5p, hsa-miR-484, hsa-miR-25-3p). None of these miRNAs was significantly associated with depressive symptoms in our sample. Literature research showed that all of the miRNAs have been found in association with several neuropsychiatric phenotypes.Limitations: Main limitations are the lack of a replication sample as well as the limited number of miRNAs analyzed.Conclusions: This is the first analysis investigating the association between miRNAs and alexithymia. Results indicate that miRNAs are not specific for one psychiatric disorder but may influence biological mechanisms that are involved in various psychiatric conditions which might be relevant for future treatment options and improve the biological understanding of psychiatric conditions. [ABSTRACT FROM AUTHOR]

As an epigenetic regulator micro-RNAs (miRNAs) have gained increasing attention in biomarker research for diseases. Many studies point towards an involvement of miRNAs in neuropsychiatric disorders such as Alzheimer's Disease, schizophrenia or depression. In a recent study we identified a possible relationship between childhood traumatization and miRNAs associated with Alzheimer's Disease in the general population as well as in a small psychiatric clinical sample. In this study we aimed to confirm this biological link in an independent psychiatric clinical sample (N = 104) and to also explore the impact of different childhood trauma dimensions (sum score, abuse dimension and neglect dimension). Analyses revealed their different impact on disease in the combined sample (N = 154; N = 50 from the recent study). We could confirm associations for all of the four recently identified miRNAs in the replication sample (N = 104) on a suggested significance level of p < 0.08 (two with p < 0.05). In the combined sample (N = 154) fifteen miRNAs were significantly associated with the childhood trauma sum score after correction for multiple testing. Most of them showed recently significant associations for Alzheimer's Disease. For the subscores of abuse and neglect only one miRNA was identified in addition, associated with childhood neglect. Bioinformatics analysis identified significant brain-related pathways regulated by the respective miRNAs. At the time of publication our study is the largest study of the association between childhood trauma and miRNAs in a clinical psychiatric sample. The confirmation of our previous results supports the relevance of the association between childhood traumatization and Alzheimer's Disease through miRNA regulation of brain-related pathways. • Three miRNAs associated with childhood traumatization from a recent paper were replicated. • In our clinical psychiatric samples miRNAs were associated with childhood traumatization. • The same miRNAs are also associated with Alzheimer's Disease in previous studies. • Different miRNAs are associated with childhood abuse and neglect. [ABSTRACT FROM AUTHOR]

• Main and interactive effects of childhood trauma and FKBP5 on resilience were tested in a general-population sample. • Childhood trauma and all subscales were negatively associated with trait resilience. • Rs1360780 showed no main effects on resilience. • Childhood trauma and rs1360780 interacted such that the T-allele enhanced effects of childhood trauma on resilience. • Effects remained stable even after adjusting for depression and PTSD. [ABSTRACT FROM AUTHOR]

Background The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. Methods Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. Results MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10 −5 , R 2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10 −18 and OR = 2.62, p = 1.4 ×10 −5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). Conclusions No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT. [ABSTRACT FROM AUTHOR]

Traumatizing events are known to have consequences for the victim which may lead to the development of several well-known mental disorders. Recent research has shown that traumatic events may affect not only the victims' lives, but also that of their progeny. It is generally accepted that this transmission of trauma occurs through parental behavior; however as has been recently discovered, the effects of trauma may also be inherited due to induced alterations in gene expression. These changes, so called epigenetic modifications, illuminate the interaction between genes and the environment. In contrast to mutations, epigenetic alterations do not change the DNA code, but rather modify the DNA structure, thus being capable of regulating gene expression and in turn making it possible for an individual to genetically respond to environmental changes. There are four possible epigenetic mechanisms: paramutation, DNA methylation, posttranslational modification of histones, and non-coding RNA. All of these mechanisms can be found both in somatic cells and in germ cells, leading to the putative transmission of alterations upon fertilization. To date, little is known regarding the epigenetic inheritance of trauma in humans. In this review, we elucidate the hypothesis that males may transmit biological correlates of traumatization through the germline to their offspring. This model of epigenetic inheritance has been supported by some evidence from animal studies. Overall, by considering findings on the epigenetic inheritance of traumatizing events in other mammals as well as findings on epigenetic transmission of acquired traits in humans, it should be possible through future research to confirm the transmission of traumatic effects in humans. By doing so, new possibilities of trauma treatment through modulation of epigenetic pathways might arise. [ABSTRACT FROM AUTHOR]

Previous studies suggested that childhood maltreatment is associated with altered memory performance in adulthood. Deficits in identifying and describing feelings as captured by the alexithymia construct are strongly linked with childhood trauma and may mediate the associations with memory function. To investigate the associations of childhood trauma with verbal declarative memory performance and the putative mediating role of alexithymia. Associations of the different dimensions of childhood trauma with adult declarative memory performance were tested in two large, independent general population samples comprising a total of N = 5574 participants. Moreover, we tested whether associations were mediated by alexithymia. In both samples, childhood emotional neglect, but not abuse emerged as a negative statistical predictor of early (sample 1: β=-1.79; p < 0.001, sample 2: β=-0.26; p < 0.001) as well as delayed recall (β=-0.78; p < 0.001; β=-0.24; p < 0.05). Likewise, childhood emotional neglect was the strongest predictor for alexithymia (β = 3.2; p < 0.001; β = 3.54; p < 0.001). Finally, the association between childhood emotional neglect and early (Total Mediated Effect (TME): 13.2, CI: 0.087-0.302; TME: 20.1; CI: 0.123-0.619) as well as late recall (TME: 13.2, CI: 0.086-0.301; TME: 9; CI: -0.442-0.699) was significantly mediated by alexithymia. Our findings suggest that childhood emotional neglect is particularly detrimental to memory functioning in adulthood. In comparison, childhood abuse was not associated with reduced declarative memory capacity. Our results contribute to explain the mechanism underlying the relation of childhood trauma and memory deficits: Finding specific associations with emotional neglect and a mediating role of alexithymia highlights the relevance of emotion processing capacities for memory functioning. [ABSTRACT FROM AUTHOR]

Objective Data suggests that traumatic experiences at early age contribute to the onset of major depressive disorder (MDD) in later life. This study aims at investigating the influence of dispositional resilience on this relationship. Methods Two thousand and forty-six subjects aged 29-89 (SD=13.9) from a community based sample who were free of MDD during the last 12months prior to data collection were diagnosed for Lifetime diagnosis of MDD by the Munich-Composite International Diagnostic Interview (M-CIDI) according to DSM-IV criteria. Childhood maltreatment (CM) and resilience were assessed with the Childhood Trauma Questionnaire (CTQ) and the Resilience-Scale (RS-25). Results Both CM (OR=1.03, 95% CI [1.02, 1.04], P <.000) and resilience (OR=0.98, 95% CI [0.98, 0.99], P <.000) were associated with MDD later in life. The detrimental effects of low resilience on MDD were not only especially prominent in subjects with a history of CM (OR=3.18, 95% CI [1.84, 5.50], P<.000), but also effective in subjects without CM (OR=2.62, 95% CI [1.41, 4.88], P=.002). Conclusions The findings support the clinical assumption that resilient subjects may be partly protected against the detrimental long-term effects of child abuse and neglect. [ABSTRACT FROM AUTHOR]

Low levels of vitamin D were found to be associated with different mental disorders. However, the role of vitamin D in the pathogenesis of PTSD is unclear. In this study, we aimed at investigating whether PTSD is linked to reduced vitamin D levels and vitamin D deficiency. Moreover, we sought to investigate the role of the vitamin D-binding protein (also group-specific component or Gc) by testing if two functional polymorphisms (rs4588 and rs7041) were associated with vitamin D levels and PTSD. Serum levels of total 25(OH)D were measured in a general-population sample of the Study of Health in Pomerania (SHIP-1). The number of traumatic events and status of PTSD were assessed using the PTSD module of the Structured Clinical Interview for the DSM-IV. Study participants were genotyped for rs4588 and rs7041. Associations of 25(OH)D levels and the genotypes with PTSD were tested in subjects with at least one traumatic event (n = 1653). 25(OH)D levels were inversely (OR: 0.96; p = 0.044) and vitamin D deficiency was positively (OR = 2.02; p = 0.028) associated with PTSD. Both polymorphisms of the Gc were associated with 25(OH)D levels and PTSD: Carriers of the CC-genotype of rs4588 showed significantly higher 25(OH)D levels (ß = 0.179, p < 0.001) and lower odds for PTSD (OR = 0.35; p = 0.023) compared to the AA-genotype. Likewise, carriers of the TT-allele of rs7041 showed lower 25(OH)D levels (−0.122; p < 0.001) and increased odds for PTSD (OR = 2.80; p = 0.015) compared to the GG-genotype. Our results suggest that an altered vitamin D metabolism may be involved in the pathophysiology of PTSD. Also, genotypes of the Gc and thus Gc serum levels may impact on PTSD development over and above the effects of 25(OH)D. Our findings contribute to explain the associations of PTSD with different mental and physical disorders. • PTSD is associated with reduced vitamin D levels and vitamin D deficiency. • rs4588 and rs7041 of the vitamin D-binding protein are associated with vitamin D levels. • rs4588 and rs7041 are associated with PTSD, even after adjusting for vitamin D levels. • Homozygous carriers of the Gc2 genotype showed an increased risk for PTSD. [ABSTRACT FROM AUTHOR]

• Levels of renin and aldosterone were altered in relation to childhood and adulthood trauma in the general population. • Exposure to and severity of childhood trauma were associated with increased levels of aldosterone. • This association was carried by all dimensions of childhood abuse, but not neglect. • Adulthood trauma and PTSD were associated with enhanced renin levels. • Renin and aldosterone were increased in subjects with exposure to childhood and adulthood. Previous evidence suggested lasting and cumulative effects of traumatization on the renin-angiotensin-aldosterone-system (RAAS). However, it is unclear whether traumas during childhood and those experienced in adulthood differentially impact the RAAS. In this study, we sought to investigate main and putative interactive effects of childhood and adulthood trauma on RAAS functioning. Plasma concentrations of renin and aldosterone were measured in a general population sample (n = 2016). Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ), adulthood trauma was measured using the PTSD module of the Structured Clinical Interview of the DSM-IV. Linear regression models were calculated to assess the relations between childhood or adulthood traumatization with renin and aldosterone concentrations. Exposure to (ß = 0.094; p = 0.01), severity of childhood trauma (ß = 0.004; p = 0.01) were associated with increased aldosterone, but not renin levels. Results were carried by all dimensions of abuse, while childhood neglect was not associated with altered RAAS activity. In contrast, adulthood traumas (ß = 0.113; p < 0.01) were significantly associated with increased renin concentrations. Subjects with PTSD (renin: ß = 0.345; p = 0.01; aldosterone: ß = 0.232; p = 0.04) and those who had been exposed to both childhood and adulthood trauma showed increases in renin (ß = 0.180; p < 0.01) and aldosterone (ß = 0.340; p < 0.01) levels. These findings indicate that trauma is associated with differential alterations of the RAAS depending on the time of traumatization. Moreover, exposure to childhood or adulthood trauma may act synergistically on the RAAS, resulting in severe dysregulation of the RAAS. The results contribute to explain associations between trauma and enhanced risk for physical disease. [ABSTRACT FROM AUTHOR]

Objective: Alexithymia, neuroticism, and extraversion have been described as relevant predictors of mental and physical health conditions, but their putative interactive effects remain poorly understood and their prospective effects are not well studied. The present study has investigated the differential contributions of distinct personality traits in predicting mental and somatic health symptoms in cross-sectional and longitudinal analyses.Methods: Additive and interactive effects of neuroticism and extraversion (NEO-FFI), the TAS-20 total score (20-Item Toronto Alexithymia Scale) and its factors (Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF) and External Oriented Thinking (EOT)) have been investigated on depressive symptoms, the number of chronic diseases, somatic and mental subjective health complaints. Analyses have been based on data from the population-based "Study of Health in Pomerania" (SHIP) in cross-sectional (N = 1704) and longitudinal (N = 1244) analyses.Results: In cross-sectional and longitudinal analyses, additive associations of the TAS-20 total score and neuroticism on somatic and mental health complaints have been observed. The effects of the TAS-20 total score have been mainly carried by DIF. Further, in interaction effetcs extraversion has attenuated the negative impact of neuroticism, whereas DIF has augmented it.Conclusion: The present study is the first demonstrating longitudinal effects of alexithymia, particularly DIF, neuroticism, and extraversion in predicting mental and somatic health symptoms. Associations between DIF, neuroticism, and extraversion have been additive and interactive. Hence, subjects high in neuroticism and DIF but low in extraversion have reported most health symptoms and thus might be in need for prevention strategies. Treatments chould be adapted to the associated combination of the personality characteristics. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms affecting depressive disorders. GWAS results support the heterogeneity of depression as a disorder affected by a large number of genetic variants with mainly small effect sizes. However, not much is known about the interplay of different genetic risk factors. Moreover, recent studies are questioning the role of common candidate genes in the development of depressive disorders. One such candidate variant is the serotonin-transporter-promoter-polymorphism 5-HTTLPR in the SLC6A4 gene. We hypothesize that 5-HTTLPR exerts its effect on depressive disorders in interaction with other genetic variants. In the present study we test this hypothesis using a genome-wide gene-gene interaction approach on a large sample from the UK Biobank (N = 127,558). We identified a region in the DPF1 gene that displayed a genome-wide significant (p = 3.31 × 10−7) interaction effect with the biallelic version of 5-HTTLPR on lifetime depression. DPF1 has not previously been described as risk factor for depressive disorders but is exclusively expressed in the brain as a major regulator of neuronal development and neuroplasticity. This study stresses the need for further analyses that take into consideration the fact that genetic variants do operate in biological networks. • Biallelic 5-HTTLPR variant interacts with DPF1 gene on depression. • DPF1 new risk factor for depression; regulator of neurodevelopment, −plasticity. • Interaction analyses important in the quest to understand disease development. [ABSTRACT FROM AUTHOR]