Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken. METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates. RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain. CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Stability and durability of salivary alpha-amylase across different storage conditions.

Data collection in remote and field settings gains importance and popularity in stress research. Accordingly, existing stress induction paradigms have been successfully adapted to remote and field settings. However, guidelines for the comprehensive assessment of biomarkers such as salivary alpha-amylase (sAA) have yet to be sufficiently established for such contexts. In remote and field settings, swift freezing of saliva samples is not always possible, and samples must be returned to the laboratory for further processing. The current study investigated the robustness of sAA activity against external factors that may affect measurements obtained from saliva samples collected in field and remote settings. We compared sAA activity of samples that were stored in different vials (Salivettes® and Eppendorf® vials) and that were exposed to (1) up to three cycles of freezing and thawing, (2) different temperatures (4 °C, 20 °C, 30 °C, and 40 °C) for 3, 7, 14, or 28 days, or that were (3) sent via postal delivery. Results indicate sAA activity to be susceptible across different temperatures, different time intervals, and different vials. As a systematic pattern, sAA activity seems to decrease in treated samples with this effect being potentiated by more extreme conditions such as higher temperatures and longer time intervals. To conclude, sAA data collected in remote or field settings could be affected systematically by various external variables. Future studies collecting sAA should take factors influencing the durability and stability of sAA into account to ensure reliable and valid measurements of salivary data.

DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.

Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.

The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites.

MicroRNA-Related Polymorphism and Their Association with Fibromyalgia.

MicroRNAs are tissue-specific expressed short RNAs that serve post-transcriptional gene regulation. A specific microRNA can bind to mRNAs of different genes and thereby suppress their protein production. In the context of the complex phenotype of fibromyalgia, we used the Axiom miRNA Target Site Genotyping Array to search genome-wide for DNA variations in microRNA genes, their regulatory regions, and in the 3'UTR of protein-coding genes. To identify disease-relevant DNA polymorphisms, a cohort of 176 female fibromyalgia patients was studied in comparison to a cohort of 162 healthy women. The association between 48,329 markers and fibromyalgia was investigated using logistic regression adjusted for population stratification. Results show that 29 markers had p-values < 1 × 10-3, and the strongest association was observed for rs758459 (p-value of 0.0001), located in the Neurogenin 1 gene which is targeted by hsa-miR-130a-3p. Furthermore, variant rs2295963 is predicted to affect binding of hsa-miR-1-3p. Both microRNAs were previously reported to be differentially expressed in fibromyalgia patients. Despite its limited statistical power, this study reports two microRNA-related polymorphisms which may play a functional role in the pathogenesis of fibromyalgia. For a better understanding of the disease pattern, further functional analyses on the biological significance of microRNAs and microRNA-related polymorphisms are required.

Treatment-associated mRNA co-expression changes in monocytes of patients with posttraumatic stress disorder.

PTSD is a prevalent mental disorder that results from exposure to extreme and stressful life events and comes at high costs for both the individual and society. Therapeutic treatment presents the best way to deal with PTSD-the mechanisms underlying change after treatment, however, remain poorly understood. While stress and immune associated gene expression changes have been associated with PTSD development, studies investigating treatment effects at the molecular level so far tended to focus on DNA methylation. Here we use gene-network analysis on whole-transcriptome RNA-Seq data isolated from CD14+ monocytes of female PTSD patients (N = 51) to study pre-treatment signatures of therapy response and therapy-related changes at the level of gene expression. Patients who exhibited significant symptom improvement after therapy showed higher baseline expression in two modules involved in inflammatory processes (including notable examples IL1R2 and FKBP5) and blood coagulation. After therapy, expression of an inflammatory module was increased, and expression of a wound healing module was decreased. This supports findings reporting an association between PTSD and dysregulations of the inflammatory and the hemostatic system and mark both as potentially treatment sensitive.

Interactive teaching enhances students' physiological arousal during online learning.

The pure transfer of face-to-face teaching to a digital learning environment can be accompanied by a significant reduction in the physiological arousal of students, which in turn can be associated with passivity during the learning process, often linked to insufficient levels of concentration and engagement in the course work. Therefore, the aim of this study was to investigate whether students' psychobiological stress responses can be enhanced in the context of anatomical online learning and how increased physiological parameters correlate with characteristics of learning experiences in a digital learning environment. Healthy first-year medical students (n = 104) experienced a regular practical course in Microscopic Anatomy either in face-to-face learning, in passive online learning or in an interaction-enhanced version of online learning. Compared to passive online learning, students engaged in the interaction-enhanced version of online learning displayed a significantly reduced Heart Rate Variability (P 0.001, partial η2 = 0.381) along with a strong increase in salivary cortisol (P 0.001, partial η2 = 0.179) and salivary alpha-amylase activity (P 0.001, partial η2 = 0.195). These results demonstrated that the physiological arousal of students engaged in online learning can be enhanced via interactive teaching methods and pointed towards clear correlations between higher physiological responses and elementary criteria of learning experience such as engagement and attention.

Proteome analysis of monocytes implicates altered mitochondrial biology in adults reporting adverse childhood experiences.

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14+ monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology.

Circulating inflammatory markers, cell-free mitochondrial DNA, cortisol, endocannabinoids, and N-acylethanolamines in female depressed outpatients.

OBJECTIVES: Major depressive disorder (MDD) involves peripheral low-grade pro-inflammatory activity. This multi-biomarker case-control study characterises the proinflammatory status in MDD beyond C-reactive protein (CRP) and Interleukin (IL)-6 levels through investigating concomitant alterations of immunoregulatory biomolecules. METHODS: In 20 female MDD patients and 24 non-depressed women, circulating levels of CRP, IL-6, cortisol, selected endocannabinoids (ECs; anandamide [AEA], 2-arachidonylglycerol [2-AG]), and N-acylethanolamines (NAEs), as well as circulating cell-free mitochondrial DNA (ccf-mtDNA) were measured. RESULTS: We found higher serum CRP and plasma AEA levels in MDD and a positive association of CRP and AEA levels with current depressive symptoms. Blood levels of cortisol, ccf-mtDNA, 2-AG, and NAEs did depend on MDD diagnosis nor correlated with the severity of current depressive symptoms. CRP correlated positively with AEA, and AEA showed positive associations with 2-AG and NAE levels. CONCLUSIONS: In this study, female MDD outpatients with mild to moderate disorder severity did not substantially differ from non-depressed controls in the resting levels of multiple immunoregulatory markers in peripheral blood. Instead of investigating resting levels, future research on the role of inflammatory activity in MDD should focus on investigating the reactivity of pathways modulating the immune system upon exposure to physical and psychosocial stressors.

No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder.

DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD.

No long-term effects of antenatal synthetic glucocorticoid exposure on epigenetic regulation of stress-related genes.

Antenatal synthetic glucocorticoid (sGC) treatment is a potent modifier of the hypothalamic-pituitary-adrenal (HPA) axis. In this context, epigenetic modifications are discussed as potential regulators explaining how prenatal exposure to GCs might translate into persistent changes of HPA axis "functioning". The purpose of this study was to investigate whether DNA methylation and gene expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) may mediate the persistent effects of sGC on cortisol stress reactivity that have been previously observed. In addition, hair cortisol concentrations (hairC) were investigated as a valid biomarker of long-term HPA axis activity. This cross-sectional study comprised 108 term-born children and adolescents, including individuals with antenatal GC treatment and controls. From whole blood, DNA methylation was analyzed by targeted deep bisulfite sequencing. Relative mRNA expression was determined by RT-qPCR experiments and qBase analysis. Acute stress reactivity was assessed by the Trier Social Stress Test (TSST) measuring salivary cortisol by ELISA and hairC concentrations were determined from hair samples by liquid chromatography coupled with tandem mass spectrometry. First, no differences in DNA methylation and mRNA expression levels of the stress-associated genes between individuals treated with antenatal sGC compared to controls were found. Second, DNA methylation and mRNA expression levels were neither associated with cortisol stress reactivity nor with hairC. These findings do not corroborate the belief that DNA methylation and mRNA expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) play a key mediating role of the persistent effects of sGC on HPA axis functioning.

Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood.

Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population. In 142 mother-infant pairs from the Duisburg Birth Cohort Study, PCBs and PCDD/Fs levels were quantified from maternal blood during late pregnancy and associated with DNAm levels in cord blood using the Illumina EPIC beadchip. The epigenome-wide association studies (EWAS) identified 32 significantly differentially methylated positions (DMPs) and eight differentially methylated regions (DMRs) associated with six congeners of PCB and PCDD in females or males (FDRs < 0.05). DMPs and DMRs mapped to genes involved in neurodevelopment, gene regulation, and immune functioning. Weighted gene correlation network analysis (WGCNA) showed 31 co-methylated modules (FDRs < 0.05) associated with one congener of PCDF levels in females. Results of both analytical strategies indicate that prenatal exposure to PCBs and PCDD/Fs is associated with altered DNAm of genes involved in neurodevelopment, gene expression and immune functioning. DNAm and gene expression levels of several of these genes were previously associated with EDC exposure in rodent models. Follow-up studies will clarify whether these epigenetic changes might contribute to the origin for adverse mental and health outcomes.

Integrated microRNA and mRNA gene expression in peripheral blood mononuclear cells in response to acute psychosocial stress: a repeated-measures within-subject pilot study.

OBJECTIVE: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with current research efforts directed at possible mechanisms. Here, we focused on a potential mechanism involving differential expression of mRNA and microRNA in response to acute psychosocial stress. We utilized a validated behavioral paradigm, the Trier Social Stress Test (TSST), to induce acute psychosocial stress in a cohort of volunteers. Stress reactivity was assessed repeatedly during the TSST using saliva samples that were analyzed for levels of cortisol. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. Total RNA was extracted, and mRNA and microRNA microarrays were utilized to assess within-subject changes in gene expression between baseline and the two post-stressor time points. RESULTS: For microarray gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, as an indicator of robust HPA-axis activation. We discovered a set of mRNAs and miRNAs that exhibited dynamic expression change in response to the TSST in peripheral blood mononuclear cells, further characterizing the link between psychosocial stress and cellular response mechanisms.

Genes in treatment: Polygenic risk scores for different psychopathologies, neuroticism, educational attainment and IQ and the outcome of two different exposure-based fear treatments.

OBJECTIVES: Evidence for a genetic influence on psychological treatment outcome so far has been inconsistent, likely due to the focus on candidate genes and the heterogeneity of the disorders treated. Using polygenic risk scores (PRS) in homogenous patient samples may increase the chance of detecting genetic influences. METHODS: A sample of 342 phobic patients treated either for clinically relevant dental fear (n = 189) or other (mixed) phobic fears (n = 153) underwent highly standardised exposure-based CBT. A brief five-session format was used to treat dental fear, whereas longer multi-session treatments were used with the mixed-fear cohort. PRS were calculated based on large genetic studies of Neuroticism, Educational Attainment (EA), Intelligence, and four psychopathology domains. We compared PRS of post-treatment and follow-up remitters and non-remitters and regressed PRS on fear reduction percentages. RESULTS: In the dental fear cohort, EA PRS were associated with treatment outcomes, i.e. drop-out, short- and long-term remission state, fear reduction, and attendance of subsequent dental appointments. In the mixed fear treatment cohort, no gene effects were observable. CONCLUSIONS: Results indicate the importance of EA-related traits for outcomes following brief, but not long, standardised exposure-based CBT. Such use of PRS may help inform selection and tailoring of treatments.

Stress and circulating cell-free mitochondrial DNA: A systematic review of human studies, physiological considerations, and technical recommendations.

Cell-free mitochondrial DNA (cf-mtDNA) is a marker of inflammatory disease and a predictor of mortality, but little is known about cf-mtDNA in relation to psychobiology. A systematic review of the literature reveals that blood cf-mtDNA varies in response to common real-world stressors including psychopathology, acute psychological stress, and exercise. Moreover, cf-mtDNA is inducible within minutes and exhibits high intra-individual day-to-day variation, highlighting the dynamic regulation of cf-mtDNA levels. We discuss current knowledge on the mechanisms of cf-mtDNA release, its forms of transport ("cell-free" does not mean "membrane-free"), potential physiological functions, putative cellular and neuroendocrine triggers, and factors that may contribute to cf-mtDNA removal from the circulation. A review of in vitro, pre-clinical, and clinical studies shows conflicting results around the dogma that physiological forms of cf-mtDNA are pro-inflammatory, opening the possibility of other physiological functions, including the cell-to-cell transfer of whole mitochondria. Finally, to enhance the reproducibility and biological interpretation of human cf-mtDNA research, we propose guidelines for blood collection, cf-mtDNA isolation, quantification, and reporting standards, which can promote concerted advances by the community. Defining the mechanistic basis for cf-mtDNA signaling is an opportunity to elucidate the role of mitochondria in brain-body interactions and psychopathology.

Event-related functional MRI of awake behaving pigeons at 7T.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds-a vertebrate class of which some clades are cognitively on par with primates.

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218.

Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twenty postmortem samples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA-protein-miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed that SV2A is associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278). Postmortem amygdala expression profiling implicated three putative regulatory miRNAs to target SV2A: miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from the SV2A dual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenous SV2A mRNA and protein levels, confirming miRNA targeting of the SV2A gene. This study illustrates the utility of combining postmortem gene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology.

Highs and lows: Genetic susceptibility to daily events.

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.

The role of the 5-HTTLPR polymorphism in acquired capability for suicide.

OBJECTIVE: According to the Interpersonal Psychological Theory of Suicide, capability for suicide comprises two dimensions: fearlessness about death and elevated pain tolerance. The short (S) allelic variant of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has repeatedly been associated with more violent and lethal suicide methods and lethality of suicide attempts. The current study aimed to investigate whether 5-HTTLPR allelic variants are associated with fearlessness about death and pain tolerance/persistence and whether it moderates the relationship between childhood maltreatment and acquired capability for suicide. METHOD: A cohort of 208 inpatients hospitalized due to a recent suicide attempt or severe suicidal ideation was genotyped for the 5-HTTLPR and assessed for childhood maltreatment. Subjective pain tolerance and fearlessness about death as well as objective pain persistence was assessed using a pressure algometer. RESULTS: Fearlessness about death, pain tolerance, and pain persistence did not differ between 5-HTTLPR genotypes. However, there was a significant correlation between self-reported childhood maltreatment and fearlessness about death that emerged exclusively in homozygous S-allele carriers. CONCLUSION: Results suggest that there are no "high-risk"-alleles that generally increase capability for suicide. However, in terms of future suicide-related behaviors exposure to childhood maltreatment events could exert a particularly negative influence on homozygous S-allele carriers by increasing their fearlessness about death.

Oxytocin and the stress buffering effect of social company: a genetic study in daily life.

Social relationships are a crucial determinant of both mental and physical health. This effect is partly due to social buffering of stress. Animal studies suggest that social buffering is mediated via the oxytocin system, while studies in humans are sparse and limited by the low ecological validity of laboratory settings. In the present study, participants (N = 326) completed smartphone questionnaires four times a day over 4 to 5 days, measuring stressors, negative affect, and social context to assess social buffering. We found that under stress, participants reported a higher need for social company. Further, the impact of prior stressful events on momentary negative affect was attenuated by the perceived pleasantness of current social company. This social buffering effect was moderated by haplotypes of the oxytocin receptor gene, based on two well-described single nucleotide polymorphisms (rs2268498, rs53576). Effects were robust when controlling for gender and age, applying different data quality criteria, and even apparent in genotype-based analyses. Our findings demonstrate that social buffering and its modulation by oxytocin system characteristics have implications for life as lived outside the laboratory.