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P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms.

ABSTRACT: The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

SUBMITTER: Kristof Z

PROVIDER: S-EPMC8191953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Women experience dramatic physiological changes during pregnancy, including changes in the production of the “stress hormone,” cortisol. Evidence has been mixed regarding whether hair cortisol concentration (HCC) can be used to accurately capture the trajectory of cortisol during this period and whether factors related to psychosocial stress are related to HCC in pregnant and postpartum women. In the current study, we collected hair samples from 85 individuals during the peripartum period (with collection occasions in pregnancy [12–37 weeks], at 3–8 weeks postpartum, and at 5–8 months postpartum) from which we derived 783 monthly observations of HCC. In addition, at each assessment individuals reported their current depressive symptoms and experiences of recent psychosocial adversity. Using piecewise mixed effects modeling, we identified significant increases in HCC across pregnancy (approximately a 2-fold rise) followed by significant decreases in HCC postpartum. Beyond these effects, however, there was substantial within-individual variability in HCC. Disaggregating between- from within-individual associations of depressive symptoms and adversity with HCC, we found that within-individual fluctuations in adversity were positively coupled with levels of HCC. Overall, the current findings suggest that measurement of cortisol in human hair captures its trajectory from conception through six months postpartum, including prenatal increases and gradual recovery of typical levels following childbirth. In addition to the overall severity of psychosocial adversity, change in women's experiences of adversity during the peripartum period merit attention. Highlights • We analyzed monthly estimates of hair cortisol concentration (HCC) across the peripartum period.• HCC increased across pregnancy and decreased through six months postpartum.• There was substantial within-person variability in HCC.• Within-person fluctuations in recent adversity were positively coupled with HCC.• Depressive symptoms were not significantly associated with HCC.

Project description:Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = -0.057 to -0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = -0.059, P = 0.043; nucleus accumbens: β = -0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

Project description:Background: Early adversity (EA) can contribute to the onset, manifestation, and course of various mental disorders. Measuring EA is still conceptually and psychometrically challenging due to issues such as content coverage, item-wording, scaling methods, and validation procedures. Further, despite research demonstrating the importance of the severity of EA, most EA scales solely focused on the 'presence-versus-absence' indicator of adverse events.Objective: To address these potentially relevant gaps, we have developed a 13-item measure of EA, the Youth and Childhood Adversity Scale (YCAS). Beyond a dichotomous assessment of whether a set of adverse events have been experienced, this scale also assesses the respective severity of these events.Methods: We evaluated the YCAS in a sample of 596 adolescent students (ages 16-19) and a second sample of 451 medical students (ages 18-30+). Exploratory factor analysis was used to determine the underlying structure as proposed by the data, which was then tested with confirmatory factor analysis. We psychometrically assessed both factor scores and sum scores.Results: In both samples, a one-factorial solution was found for both responses to dichotomous items and severity items. Item loadings had a broad range, with minimum loadings of .1-.2 and maximum loadings of .7-.9. Irrespective of the response type, this factor exhibited good reliability (omega total, range: .80 - .89) and was associated with a range of mental-health outcomes, self-esteem, and childhood maltreatment. The fit of the model resembling sum scores was not satisfactory, but the sum score reliability (coefficient alpha, range: .78 - .89) was acceptable and most of the associations with the validation measures held.Conclusions: The YCAS allows an efficient, reliable, and valid assessment of EA and its severity. It covers a reasonable breadth of events, whilst simultaneously being parsimonious. We discuss next steps of how to improve this measure to fully capture the complexity of EA.

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P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms.

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