DNA METHYLATION PARTIALLY MEDIATES THE RELATIONSHIP BETWEEN TIME-DEPENDENT CHILDHOOD ADVERSITY AND DEPRESSIVE SYMPTOMS IN ADOLESCENCE

Background: Exposure to adversity during childhood is estimated to at least double the risk of depression later in life. Some evidence suggests childhood adversity may have a greater impact on depression risk, if experienced during specific windows of development called sensitive periods. During these sensitive periods, there is evidence that adversity may leave behind biological memories, including changes in DNA methylation (DNAm). Here we ask if those changes play a role in the link between adversity and later adolescent depressive symptoms. Methods: We applied a method for high-dimensional mediation analysis using data from a subsample (n=627-675) of the Avon Longitudinal Study of Parents and Children. We first assessed the possibility of time-dependent relationships between seven types of childhood adversity (caregiver abuse, physical/sexual abuse, maternal psychopathology, one-adult household, family instability, financial stress, neighborhood disadvantage), measured on at least four occasions between ages 0-7 years, and adolescent depression at mean age 10.6. Specifically, we considered three types of life course hypotheses (sensitive periods, accumulation, and recency), and then evaluated which of these hypotheses had the strongest association in each adversity-adolescent depression relationship using the structured life course modeling approach (SLCMA; pronounced slick-mah). To conduct the mediation analyses, we used a combination of pruning and sure independence screening (a dimension reduction method) to reduce the number of methylated CpG sites under consideration to a viable subset for our sample size. We then applied a sparse group lasso penalized model to identify the top mediating loci from that subset using the combined strength of the coefficient measuring the relationship between the childhood adversity and a CpG site (α) and of the coefficient measuring the relationship between the CpG site and depressive symptoms (β) as a metric. Using a Monte Carlo method for assessing mediation (MCMAM), we assigned a significance level and confidence interval to each identified mediator. Results: Across all seven adversities, we identified a total of 70 CpG sites that showed evidence of mediating the relationship between adversity and adolescent depression symptoms. Of these 70 mediators, 37 were significant at the p < 0.05 level when applying the MCMAM, a method tailored to estimating the significance of SEM-derived mediation effects. These sites exhibited four different mediating patterns, differentiated by the direction of α and β. These patterns had signals that were: (1) both positive (19 loci), (2) both negative (18 loci), (3) positive α and negative β (23 loci) or (4) negative α and positive β (10 loci). Conclusion: Our results suggest that DNAm partially mediates the relationship between different types of childhood adversity and depressive symptoms in adolescence. These findings provide insight into the biological mechanisms that link childhood adversity to depression, which will ultimately help develop treatments to prevent depression in more vulnerable populations.

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A prospective study of time-dependent exposures to childhood adversity and DNA methylation in childhood and adolescence

10.1101/2021.06.28.21259423 ◽

2021 ◽

Author(s):

Alexandre A Lussier ◽

Yiwen Zhu ◽

Brooke J Smith ◽

Janine Cerutti ◽

Andrew Simpkin ◽

...

Keyword(s):

Dna Methylation ◽

Childhood Adversity ◽

Time Dependent ◽

Childhood And Adolescence ◽

Parents And Children ◽

Genome Wide ◽

Latent Effects ◽

Underlying Mechanisms ◽

A Prospective Study ◽

The Relationship

Background: Childhood adversity influences long-term health, particularly if experienced during sensitive periods in development when physiological systems are more responsive to environmental influences. Although the underlying mechanisms remain unclear, prior studies suggest that DNA methylation (DNAm) may capture these time-dependent effects of childhood adversity. However, it remains unknown whether DNAm alterations persist into adolescence and how the timing of adversity might influence DNAm trajectories across development. Methods: We examined the relationship between time-dependent adversity and genome-wide DNAm measured at three waves from birth to adolescence using prospective data from the Avon Longitudinal Study of Parents and Children. We first assessed the relationship between the timing of exposure to seven types of adversity (measured 5-8 times between ages 0-11) and DNAm at age 15 using a structured life course modeling approach. We also characterized the persistence into adolescence of associations identified from age 7 DNAm, as well as the influence of adversity on DNAm trajectories from ages 0-15. Results: Adversity was associated with differences in age 15 DNAm at 24 loci (FDR<0.05). Most loci (19 of 24) were associated with adversity (i.e., physical/sexual abuse, one-adult households, caregiver abuse) that occurred between ages 3-5. Although no DNAm differences present at age 7 persisted into adolescence, we identified seven unique types of DNAm trajectories across development, which highlighted diverse effects of childhood adversity on DNAm. Conclusions: Our results suggest that childhood adversity, particularly between ages 3-5, can influence the trajectories of DNAm across development, exerting both immediate and latent effects on the epigenome.

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Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies

10.1101/2021.04.23.441014 ◽

2021 ◽

Author(s):

Alexandre A. Lussier ◽

Yiwen Zhu ◽

Brooke J. Smith ◽

Andrew J. Simpkin ◽

Andrew D.A.C. Smith ◽

...

Keyword(s):

Dna Methylation ◽

Association Studies ◽

Childhood Adversity ◽

Reference Points ◽

Time Dependent ◽

P Value ◽

Prenatal Smoking ◽

Parents And Children ◽

Successful Replication ◽

The Impact

ABSTRACTIntroductionBiomedical research has grown increasingly cooperative, with several large consortia compiling and sharing epigenomic data. Since data are typically preprocessed by consortia prior to distribution, the implementation of new pipelines can lead to different versions of the same dataset. Analytic frameworks also constantly evolve to incorporate cutting-edge methods and shifting best practices. However, it remains unknown how differences in data and analytic versions alter the results of epigenome-wide analyses, which has broad implications for the replicability of epigenetic associations. Thus, we assessed the impact of these changes using a subsample of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.MethodsWe analyzed two versions of DNA methylation data, processed using separate preprocessing and analytic pipelines, to examine associations between childhood adversity and prenatal smoking exposure on DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modeling Approach (SLCMA), a two-stage method that models time-dependent effects. We also compared results from the SLCMA using more recent methodological recommendations.ResultsDifferences between ALSPAC data versions impacted both EWAS and SLCMA analyses, yielding different sets of associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of significance thresholds. Updating the SLCMA analytic version similarly altered top associations, but time-dependent effects remained concordant.ConclusionsChanges to data and analytic versions influenced the results of epigenome-wide studies, particularly when using p-value thresholds as reference points for successful replication and stability.

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Poor Acceptance of the Past is Related to Depressive Symptoms in Older Adults

GeroPsych ◽

10.1024/1662-9647/a000227 ◽

2020 ◽

Vol 33 (4) ◽

pp. 246-251

Author(s):

Gozde Cetinkol ◽

Gulbahar Bastug ◽

E. Tugba Ozel Kizil

Keyword(s):

Older Adults ◽

Regression Analysis ◽

Depressive Symptoms ◽

Death Anxiety ◽

Geriatric Depression ◽

Ego Integrity ◽

The Past ◽

Depressed Group ◽

Total Death ◽

The Relationship

Abstract. Depression in older adults can be explained by Erikson’s theory on the conflict of ego integrity versus hopelessness. The study investigated the relationship between past acceptance, hopelessness, death anxiety, and depressive symptoms in 100 older (≥50 years) adults. The total Beck Hopelessness (BHS), Geriatric Depression (GDS), and Accepting the Past (ACPAST) subscale scores of the depressed group were higher, while the total Death Anxiety (DAS) and Reminiscing the Past (REM) subscale scores of both groups were similar. A regression analysis revealed that the BHS, DAS, and ACPAST predicted the GDS. Past acceptance seems to be important for ego integrity in older adults.

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Symptoms of Alcohol Dependence Predict Suicide Ideation Among Alaskan Undergraduates

Crisis ◽

10.1027/0227-5910/a000373 ◽

2016 ◽

Vol 37 (3) ◽

pp. 232-235 ◽

Cited By ~ 3

Author(s):

Christopher R. DeCou ◽

Monica C. Skewes

Keyword(s):

Depressive Symptoms ◽

Alcohol Consumption ◽

Alcohol Dependence ◽

Suicide Ideation ◽

Alcohol Problems ◽

Future Research ◽

Causal Mechanism ◽

Students At Risk ◽

The Relationship ◽

Alcohol Related Problems

Abstract. Background: Previous research has demonstrated an association between alcohol-related problems and suicidal ideation (SI). Aims: The present study evaluated, simultaneously, alcohol consequences and symptoms of alcohol dependence as predictors of SI after adjusting for depressive symptoms and alcohol consumption. Method: A sample of 298 Alaskan undergraduates completed survey measures, including the Young Adult Alcohol Consequences Questionnaire, the Short Alcohol Dependence Data Questionnaire, and the Beck Depression Inventory – II. The association between alcohol problems and SI status was evaluated using sequential logistic regression. Results: Symptoms of alcohol dependence (OR = 1.88, p < .05), but not alcohol-related consequences (OR = 1.01, p = .95), emerged as an independent predictor of SI status above and beyond depressive symptoms (OR = 2.39, p < .001) and alcohol consumption (OR = 1.08, p = .39). Conclusion: Alcohol dependence symptoms represented a unique risk for SI relative to alcohol-related consequences and alcohol consumption. Future research should examine the causal mechanism behind the relationship between alcohol dependence and suicidality among university students. Assessing the presence of dependence symptoms may improve the accuracy of identifying students at risk of SI.

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Coping Style as a Mediator of the Relationship Between Depressive Symptoms and Deliberate Self-Harm

Crisis ◽

10.1027/0227-5910/a000083 ◽

2011 ◽

Vol 32 (5) ◽

pp. 272-279 ◽

Cited By ~ 9

Author(s):

Allison S. Christian ◽

Kristen M. McCabe

Keyword(s):

Depressive Symptoms ◽

Undergraduate Students ◽

Cross Sectional Study ◽

Self Report ◽

Hierarchical Regression ◽

Cross Sectional ◽

Deliberate Self Harm ◽

Self Blame ◽

Self Harm ◽

The Relationship

Background: Deliberate self-harm (DSH) occurs with high frequency among clinical and nonclinical youth populations. Although depression has been consistently linked with the behavior, not all depressed individuals engage in DSH. Aims: The current study examined maladaptive coping strategies (i.e., self-blame, distancing, and self-isolation) as mediators between depression and DSH among undergraduate students. Methods: 202 students from undergraduate psychology courses at a private university in Southern California (77.7% women) completed anonymous self-report measures. Results: A hierarchical regression model found no differences in DSH history across demographic variables. Among coping variables, self-isolation alone was significantly related to DSH. A full meditational model was supported: Depressive symptoms were significantly related to DSH, but adding self-isolation to the model rendered the relationship nonsignificant. Limitations: The cross-sectional study design prevents determination of whether a casual relation exists between self-isolation and DSH, and obscures the direction of that relationship. Conclusions: Results suggest targeting self-isolation as a means of DSH prevention and intervention among nonclinical, youth populations.

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Interpersonal Stress and Poor Health

European Psychologist ◽

10.1027/1016-9040/a000003 ◽

2010 ◽

Vol 15 (1) ◽

pp. 3-11 ◽

Cited By ~ 32

Author(s):

Mette M. Aanes ◽

Maurice B. Mittelmark ◽

Jørn Hetland

Keyword(s):

Psychological Distress ◽

Depressive Symptoms ◽

Social Relationships ◽

Indirect Effects ◽

Social Connectedness ◽

Somatic Symptoms ◽

Total Effect ◽

Subjective Feeling ◽

Interpersonal Stress ◽

The Relationship

This paper investigated whether the lack of social connectedness, as measured by the subjective feeling of loneliness, mediates the well-known relationship between interpersonal stress and psychological distress. Furthermore, a relationship between interpersonal stress and somatic symptoms was hypothesized. The study sample included 3,268 women and 3,220 men in Western Norway. The main findings were that interpersonal stress was significantly related to psychological distress as well as to somatic symptoms, both directly and indirectly via paths mediated by loneliness. The size of the indirect effects varied, suggesting that the importance of loneliness as a possible mediator differs for depressive symptoms, anxiety symptoms, and somatic symptoms. In the case of depressive symptoms, more than 75% of the total effect was mediated through loneliness, while in the case of somatic symptoms just over 40% of the total effect was mediated through loneliness. This study supports the hypotheses that social connectedness mediates a relationship between interpersonal stress and psychological distress. The study also provides the first link between interpersonal stress, as measured by the Bergen Social Relationships Scale, and somatic symptoms, extending earlier research on the relationship between interpersonal stress and psychological distress.

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Plasminogen Depletion during Streptokinase Treatment or Two-Chain Urokinase Incubation Correlates with Decreased Clot Lysability Ex Vivo and In Vitro

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649714 ◽

1993 ◽

Vol 70 (06) ◽

pp. 0998-1004 ◽

Cited By ~ 13

Author(s):

Páll T Önundarson ◽

H Magnús Haraldsson ◽

Lena Bergmann ◽

Charles W Francis ◽

Victor J Marder

Keyword(s):

Myocardial Infarction ◽

Ex Vivo ◽

Time Dependent ◽

State Variables ◽

Thrombolytic Treatment ◽

Direct Proportion ◽

Plasmin Activity ◽

Plasma Exposure ◽

The Relationship

SummaryThe relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/1. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 ± 8% after 5 min to 21 ± 8% at 10 min and was significantly lower (8 ± 9%, p <0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p <0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

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