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The neuropeptide oxytocin has played an essential role in the regulation of social behavior and attachment throughout mammalian evolution. Because recent studies in humans have shown that oxytocin administration reduces stress responses and increases prosocial behavior, we investigated whether a common single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) might interact with stress-protective effects of social support. Salivary cortisol samples and subjective stress ratings were obtained from 194 healthy male participants before, during, and after a standardized psychosocial laboratory stress procedure. Participants were randomly assigned either to prepare alone or to receive social support from their female partner or close female friend while preparing for the stressful task. Differential stress responses between the genotype groups were observed depending on the presence or absence of social support. Only individuals with one or two copies of the G allele of rs53576 showed lower cortisol responses to stress after social support, compared with individuals with the same genotype receiving no social support. These results indicate that genetic variation of the oxytocin system modulates the effectiveness of positive social interaction as a protective buffer against a stressful experience.

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT , and catechol-O-methyltransferase, COMT ) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents.

Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults' exposure to ELA influences neuroendocrine and inflammatory responses to acute stress. Participants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ('ELA group'), and half who confirmed zero ('controls'). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test. In this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups. Overall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.

Yoga is associated with reduced stress and increased well-being, although the molecular basis for these benefits is not clear. Mounting evidence implicates the immune response, with current studies focused on protein immune markers (such as cytokines) in clinical populations. To explore the molecular impact, this pilot study uses a subsample ( n =28) from a randomised waitlist control trial investigating the impact of an 8-week yoga intervention in a community population of women reporting psychological distress ( N =116). We measured interleukin-6 (IL-6), tumour necrosis factor (TNF) and C-reactive protein (CRP) protein levels, and the DNA methylation of these genes and the global indicator, LINE-1 . Correlations between these and psychological variables were explored, identifying moderate correlations with CRP protein levels, and methylation of IL-6 , CRP and LINE-1 . Many cytokine samples were below detection, however a Mann–Whitney U demonstrated a trend of moderate between-group effect for elevated IL-6 in the yoga group. Methylation analyses applied cross-sectional and non-controlled longitudinal analyses. Waist-to-height ratio and age were covaried. We demonstrated reduced methylation of the TNF region in the yoga group relative to the waitlist control group. No other genes demonstrated a significant difference. Longitudinal analysis further supported these results. This study is one of the first to explore yoga and immunological markers in a non-clinical population, and is the first study to explore DNA methylation. These findings indicate that further research into molecular impact of yoga on markers of immune function is warranted, with larger studies required.

Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene–environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene–environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F=6.6; df=3, 671; P <0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene–environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.

IntroductionNeurodevelopmental disability (ND) represents an adverse condition for infants’ socio-emotional and behavioural development as well as for caregiving (eg, parental sensitivity) and mother-infant interaction. Adverse exposures are associated with altered neuroendocrine hormones concentrations (eg, oxytocin and cortisol) and epigenetic regulation (eg, methylation of stress-related genes), which in turn may contribute to less-than-optimal mother-infant interaction. Parental sensitivity is a protective factor for childrens’ development and early parental interventions (eg, video-feedback intervention) can promote parental caregiving and better developmental outcomes in children. The present multi-centric and longitudinal randomised controlled trial aims to assess if and to which extent early VFI could benefit both infants and mothers in terms of behavioural outcomes as well as neuroendocrine and epigenetic regulation.Methods and analysisDyads will be randomly assigned to the video-feedback Intervention Group or Control Group (‘dummy’ intervention: telephone calls). Infants with ND aged 3 to 18 months will be recruited from three major child neuropsychiatric units in northern Italy. A multi-layer approach to intervention effects will include videotapes of mother-infant interaction, maternal reports as well as saliva samples for hormones concentrations and target-gene methylation analysis (eg, BDNF, NR3C1, OXTR and SCL6A4) that will be obtained at each of the four assessment sessions: T0, baseline; T1, post-intervention; T2, short-term follow-up (3 month); T3, long-term follow-up (6 month). Primary effectiveness measures will be infant socio-emotional behaviour and maternal sensitivity. Neuroendocrine hormones concentrations and DNA methylation status of target genes will be secondary outcomes. Feasibility, moderation and confounding variables will be measured and controlled between the two groups.Ethics and disseminationEthics approval has been obtained in all three participating units. Results of the main trial and each of the secondary endpoints will be submitted for publication in peer-reviewed journals and international conferences.Trial registration numberNCT03853564; Pre-results.

Background Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic–pituitary–adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic–pituitary–adrenal axis-related genes FKBP5 and NR3C1 . We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation. Methods This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N  = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation. Results Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels. Conclusions Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up. Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.

Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption. Data from 90 108 participants in the Copenhagen General Population Study was used. Exposures included self-reported cigarettes/day and pack years and the CHRNA3 rs1051730 genotype as instrumental variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status. Self-reported amount of smoking was associated with all three dimensions of psychological distress. For instance among participants smoking 30 cigarettes/day or more, the odds ratio (OR) for stress was 1.67 (95% confidence interval [CI] 1.47-1.89) compared to never-smokers. Corresponding ORs for fatigue and hopelessness were 2.18 (95% CI 1.92-2.47) and 3.08 (95% CI 2.62-3.62). Among current smokers, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0.91-1.15) among homozygotes compared to noncarriers of the CHRNA3 genotype. Though a strong association between tobacco consumption and psychological distress was found, there was no clear evidence that high tobacco consumption was causally related to psychological distress. Smoking is associated with several mental health outcomes and smoking cessation is associated with improved mental health. Causality in the association between smoking and mental health is difficult to establish using observational data. Using a genotype known to influence tobacco consumption as instrumental variable for amount of smoking, we found no clear evidence of a direct causal path between high tobacco consumption and psychological distress. Whatever causes the strong association between tobacco consumption and psychological distress, the co-occurrence is important to consider both in interventions for smoking prevention and cessation.

Background Gender, genetic makeup, and prior experience interact to determine physiological responses to an external perceived stressor. Here, we investigated the contribution of both genetic variants and promoter methylation of the NR3C1 (glucocorticoid receptor) gene to the cardiovascular and hypothalamus-pituitary-adrenal (HPA) axis response to the socially evaluated cold pressor test (seCPT). Results Two hundred thirty-two healthy participants were recruited and underwent the experiment. They were randomly assigned to either the seCPT group (cold water) or a control group (warm water). The seCPT group had a clear stress reaction; salivary cortisol levels and peak systolic and diastolic blood pressure all increased significantly compared to the control group. GR genotype ( TthIII I, NR3C1-I, 1H, E22E, R23K, Bcl I and 9beta) and methylation data were obtained from 218 participants. Haplotypes were built from the GR genotypes, and haplotype 2 (minor allele of Bcl I) carriers had a higher cortisol response to the seCPT in comparison to non-carriers (20.77 ± 13.22; 14.99 ± 8.42; p  = 0.034), as well as independently of the experimental manipulation, higher baseline heart rate (72.44 ± 10.99; 68.74 ± 9.79; p  = 0.022) and blood pressure (115.81 ± 10.47; 111.61 ± 10.74; p  = 0.048). Average methylation levels throughout promoter 1F and 1H were low (2.76 and 1.69 %, respectively), but there was a strong correlation between individual CpGs and the distance separating them (Pearson’s correlation r  = 0.725, p  = 3.03 × 10 −26 ). Higher promoter-wide methylation levels were associated with decreased baseline blood pressure, and when incorporated into a linear mixed effect model significantly predicted lower systolic and diastolic blood pressure evolution over time in response to the experimental manipulation. The underlying genotype significantly predicted methylation levels; particularly, the homozygous Bcl I minor allele was associated with higher methylation in promoter 1H ( p  = 0.042). Conclusions This is one of the first studies linking epigenetic modifications of the GR promoter, receptor genotype and physiological measures of the stress response. At baseline, there were clear genetic and epigenetic effects on blood pressure. The seCPT induced a strong cardiovascular and HPA axis response, and both systems were affected by the functional genetic variants, although methylation also predicted blood pressure reactivity. The return to baseline was predominantly influenced by the genomic sequence. Overall, the physiological response to the seCPT is controlled by an exquisite mix of genetic and epigenetic factors.

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence ( P =0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T− and TCE+ patients; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology ( P =0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.