DNA methylation partially mediates the relationship between 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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DNA METHYLATION PARTIALLY MEDIATES THE RELATIONSHIP BETWEEN TIME-DEPENDENT CHILDHOOD ADVERSITY AND DEPRESSIVE SYMPTOMS IN ADOLESCENCE

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.07.039 ◽

2021 ◽

Vol 51 ◽

pp. e15-e16

Author(s):

Brooke Smith ◽

Alexandre Lussier ◽

Janine Cerutti ◽

Esther Walton ◽

Andrew Simpkin ◽

...

Keyword(s):

Dna Methylation ◽

Depressive Symptoms ◽

Childhood Adversity ◽

Time Dependent ◽

The Relationship

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Childhood Material Hardship and Adolescent Mental Health

Youth & Society ◽

10.1177/0044118x211001896 ◽

2021 ◽

pp. 0044118X2110018

Author(s):

Chrisse Edmunds ◽

Melissa Alcaraz

Keyword(s):

Mental Health ◽

Adolescent Depression ◽

Adolescent Mental Health ◽

Anxiety And Depression ◽

Fragile Families ◽

Depression Symptoms ◽

Depression And Anxiety ◽

Material Hardship ◽

Critical Age ◽

The Relationship

Adolescent mental health has implications for current and future wellbeing. While a link exists between poverty and mental health, little is known about how experiencing material hardship, such as insecurity of food, housing, utilities, and medical care, throughout early childhood affects adolescent mental health. We examine the relationship between material hardship in childhood and adolescent mental health. We use Poisson regression to examine the effect of material hardship experienced at different stages of childhood on adolescent depression and anxiety outcomes at age 15. We use longitudinal data from the Fragile Families and Child Wellbeing Study ( N = 3,222). We find that recently experiencing material hardship during childhood is positively and significantly associated with anxiety and depression symptoms at age 15, even when controlling for material hardship at age 15. Additionally, we find that insecurity during mid-childhood and the stress of lacking basic needs during a critical age may influence mental health in adolescence.

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Methylome-wide change associated with response to electroconvulsive therapy in depressed patients

Translational Psychiatry ◽

10.1038/s41398-021-01474-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lea Sirignano ◽

Josef Frank ◽

Laura Kranaster ◽

Stephanie H. Witt ◽

Fabian Streit ◽

...

Keyword(s):

Electroconvulsive Therapy ◽

Rating Scale ◽

Antidepressant Treatment ◽

Cpg Sites ◽

Cpg Site ◽

Depressed Patients ◽

Resistant Depression ◽

Functional Pathway ◽

Regional Analyses ◽

The Relationship

AbstractElectroconvulsive therapy (ECT) is a quick-acting and powerful antidepressant treatment considered to be effective in treating severe and pharmacotherapy-resistant forms of depression. Recent studies have suggested that epigenetic mechanisms can mediate treatment response and investigations about the relationship between the effects of ECT and DNA methylation have so far largely taken candidate approaches. In the present study, we examined the effects of ECT on the methylome associated with response in depressed patients (n = 34), testing for differentially methylated CpG sites before the first and after the last ECT treatment. We identified one differentially methylated CpG site associated with the effect of ECT response (defined as >50% decrease in Hamilton Depression Rating Scale score, HDRS), TNKS (q < 0.05; p = 7.15 × 10−8). When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (p = 3.94 × 10−7). Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák’s p = 0.0031) and 20 (Šídák’s p = 4.2 × 10−5) associated with ΔHDRS. Functional pathway analysis did not identify any significant pathways. A confirmatory look at candidates previously proposed to be involved in ECT mechanisms found CpG sites associated with response only at the nominally significant level (p < 0.05). Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.

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What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: recency, accumulation, or sensitive periods?

Psychological Medicine ◽

10.1017/s0033291718000181 ◽

2018 ◽

Vol 48 (15) ◽

pp. 2562-2572 ◽

Cited By ~ 29

Author(s):

Erin C. Dunn ◽

Thomas W. Soare ◽

Miriam R. Raffeld ◽

Daniel S. Busso ◽

Katherine M. Crawford ◽

...

Keyword(s):

Theoretical Model ◽

Life Course ◽

Emotional Abuse ◽

Financial Stress ◽

Childhood Adversity ◽

Sensitive Period ◽

Sensitive Periods ◽

Legal Problems ◽

Best Fitting ◽

Psychopathology Symptoms

BackgroundAlthough childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.MethodsProspective data came from the Avon Longitudinal Study of Parents and Children (n= 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.ResultsRecencywas the best fitting theoretical model for the effect of physical/sexual abuse (girlsr2= 2.35%; boysr2= 1.68%). Bothrecency(girlsr2= 1.55%) andaccumulation(boysr2= 1.71%) were the best fitting models for caregiver physical/emotional abuse.Sensitive periodmodels were chosen alone (parent legal problems in boysr2= 0.29%) and withaccumulation(financial stress in girlsr2= 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22–1.18).ConclusionsChild psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.

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Intensity-Specific Differential Leukocyte DNA Methylation in Physical (In)Activity: An Exploratory Approach

Twin Research and Human Genetics ◽

10.1017/thg.2018.10 ◽

2018 ◽

Vol 21 (2) ◽

pp. 101-111 ◽

Cited By ~ 3

Author(s):

Maarten Caspers ◽

Sara Blocquiaux ◽

Ruben Charlier ◽

Sara Knaeps ◽

Johan Lefevre ◽

...

Keyword(s):

Dna Methylation ◽

Correlation Coefficients ◽

Global Dna Methylation ◽

Site Specific ◽

Cpg Sites ◽

Cpg Site ◽

Biological Pathway Analysis ◽

Exploratory Approach ◽

Health Related ◽

Related Pathway

The aim of this exploratory study was to investigate how sedentary behavior (SB) and physical activity (PA) influence DNA methylation at a global, gene-specific, and health-related pathway level. SB, light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed objectively for 41 Flemish men using the SenseWear Pro 3 Armband. CpG site-specific methylation in leukocytes was determined using the Illumina HumanMethylation 450 BeadChip. Correlations were calculated between time spent on the three PA intensity levels and global DNA methylation, using a z-score-based method to determine global DNA methylation levels. To determine whether CpG site-specific methylation can be predicted by these three PA intensity levels, linear regression analyses were performed. Based on the significantly associated CpG sites at α = 0.005, lists were created including all genes with a promoter region overlapping these CpG sites. A biological pathway analysis determined to what extent these genes are overrepresented within several pathways. No significant associations were observed between global DNA methylation and SB (r = 0.084), LPA (r = -0.168), or MVPA (r = -0.125), although the direction of the correlation coefficients is opposite to what is generally reported in literature. SB has a different impact on global and gene-specific methylation than PA, but also LPA and MVPA affect separate genes and pathways. Furthermore, the function of a pathway seems to determine its association with SB, LPA, or MVPA. Multiple PA intensity levels, including SB, should be taken into account in future studies investigating the effect of physical (in)activity on human health through epigenetic mechanisms.

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THE RELATIONSHIP BETWEEN MARITAL STATUS, COHORT, AND DEPRESSION SYMPTOMS IN TAIWAN

Innovation in Aging ◽

10.1093/geroni/igz038.1140 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S311-S312

Author(s):

Fang-Yi Huang ◽

Min Li

Keyword(s):

Depressive Symptoms ◽

Marital Status ◽

Baby Boom ◽

Depression Symptoms ◽

Depression Symptom ◽

Economic Decline ◽

Logistic Regression Models ◽

Financial Decline ◽

Married Female ◽

The Relationship

Abstract Objectives: The relationship between marital status and depression symptoms is well documented. However, how the negative economic shock affect relationship differ by gender and cohort is still indecisive. The dataset “2011 wave of the Taiwan Longitudinal Study in Aging” and logistic regression models were used in the study. The results: Marital status is related to depression symptoms, but it differs by gendered cohort. With considering financial shock, there is no difference of depressive symptom between divorced and married female. The divorced and widowed have 4.81 and 2.47 times higher of getting depression symptom than the married for baby boom female. Being divorced is 3.67 times higher of getting depressive symptoms than being married for baby boom male. For WWII female, the widows are 1.78 times higher to have depressive symptoms than the married. being divorced, widowers, and single are 3.32, 2.21 and 2.90 times higher of getting depressive symptoms than being married for WWII male. Being divorced is 3.67 times higher of getting depressive symptoms than being married for baby boom male. In conclusions, people with unstable marital statuses are more depressed than the married. In particular, the effect of unstable marital statuses on depression could be account for by financial decline for women but not men. Given the policy emphasis on those with unstable marital status and economic decline, divorce female and single baby boom female may represent particular groups in whom interventions designed to financially support.

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Romantic Acts and Depression

Psychological Reports ◽

10.2466/pr0.2000.86.1.260 ◽

2000 ◽

Vol 86 (1) ◽

pp. 260-262 ◽

Cited By ~ 2

Author(s):

John Maltby ◽

Liza Day

Keyword(s):

Depressive Symptoms ◽

Beck Depression Inventory ◽

Undergraduate Students ◽

General Health ◽

General Health Questionnaire ◽

Depression Symptoms ◽

Health Questionnaire ◽

The Relationship

The aim of the present study was to provide an examination of the relationship between the importance individuals attach to romantic acts and depressive symptoms. Among 140 male and 160 female English undergraduate students, the importance individuals attach to romantic acts is significantly negatively correlated with higher scores on the Beck Depression Inventory and the Depression symptoms subscale of the General Health Questionnaire among the men only.

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Expanding our understanding of the relationship between negative life events and depressive symptoms in black and white adolescent girls

Psychological Medicine ◽

10.1017/s0033291704003186 ◽

2004 ◽

Vol 34 (7) ◽

pp. 1319-1330 ◽

Cited By ~ 47

Author(s):

DEBRA L. FRANKO ◽

RUTH H. STRIEGEL-MOORE ◽

KATHLEEN M. BROWN ◽

BRUCE A. BARTON ◽

ROBERT P. McMAHON ◽

...

Keyword(s):

Depressive Symptoms ◽

Life Events ◽

Adolescent Girls ◽

Negative Life Events ◽

White Female ◽

Depression Symptoms ◽

Black And White ◽

Domains Of Life ◽

Diverse Groups ◽

The Relationship

Background. Little is known about the extent to which negative life events predict depressive symptoms in ethnically diverse groups or whether this relationship is proximal or enduring.Method. The relationship between negative life events in adolescence and depressive symptoms in young adulthood was studied in a sample of over 1300 black and white female adolescents. Five domains of life events were assessed at age 16 years and depressive symptoms were measured at age 18 and again at age 21 years. Questions of interest included whether the association continued over time and whether there were specific domains of life events that predicted symptoms better than others.Results. The total number of negative life events at time 1 predicted depressive symptoms at both time 2 and time 3. Interpersonal loss events and other adversities, however, predicted depressive symptoms only at time 2, whereas at time 3, only interpersonal trauma was a significant predictor. No ethnic differences were found, indicating that the relationship between life events and depressive symptoms appears to be similar for black and white adolescent girls.Conclusions. The results suggest that negative life events and some specific type of stressors increase the likelihood of the onset of depression symptoms in future years, for both black and white girls. Early preventive efforts should be directed at adolescents who experience loss due to death of a significant other, traumatic events, and psychosocial adversities to forestall the development of depressive symptoms.

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Virtual Reality and Web-Based Growth Mindset Interventions for Adolescent Depression: Protocol for a Three-Arm Randomized Trial (Preprint)

10.2196/preprints.13368 ◽

2019 ◽

Author(s):

Jessica Lee Schleider ◽

Michael C Mullarkey ◽

John R Weisz

Keyword(s):

Virtual Reality ◽

Depressive Symptoms ◽

Perceived Control ◽

Adolescent Depression ◽

Growth Mindset ◽

Depression Symptoms ◽

Single Session ◽

Post Intervention ◽

Web Based ◽

The Web

BACKGROUND Depression is the leading cause of disability in youth, with a global economic burden of US >$210 billion annually. However, up to 70% of youth with depression do not receive services. Even among those who do access treatment, 30% to 65% fail to respond and many dropout prematurely, demonstrating a need for more potent, accessible interventions. In a previous trial, a single-session Web-based growth mindset (GM) intervention significantly reduced depressive symptoms in high-symptom adolescents; however, this intervention did not benefit adolescents uniformly. For instance, the intervention reduced depression in adolescents who reported post intervention increases in perceived control, but it did not lead to significant depression reductions in adolescents who reported no significant post intervention increases in perceived control. OBJECTIVE The goal of this project is to test the acceptability and efficacy of a novel, single-session, virtual reality (VR) depression intervention—the VR Personality Project—teaching GM, the belief that personal attributes are malleable rather than fixed. The VR Personality Project was designed to systematically target and increase adolescents’ perceived control by offering a more immersive, engaging, user-directed intervention experience than the Web-based intervention can provide. By targeting an identified predictor of intervention response, the VR Personality Project may lead to larger reductions in depressive symptoms than existing Web-based mindset interventions. METHODS Adolescents with elevated depressive symptoms or a recent history of depression (N=159; ages 12 to 16 years) will be randomized to one of 3 intervention conditions: the VR Personality Project; the Web-based GM intervention tested previously; or an active, Web-based control. Adolescents and their parents will report on the adolescents’ depression symptoms, perceived control, and related domains of functioning at preintervention, postintervention, and at 3- and 9-month follow-up assessments. RESULTS We predict that the VR and Web-based mindset interventions will both lead to larger reductions in adolescent symptoms than the control intervention. Additionally, we predict that the VR-based single session intervention will lead to larger reductions in depression than the online mindset intervention and that these symptom reductions will be mediated by increases in adolescents’ perceived control from pre- to postintervention. CONCLUSIONS The results may suggest an efficient strategy for reducing adolescent depressive symptoms: One that is mechanism-targeted, relatively affordable (less than US $200 for a commercially available VR headset, a fraction of the cost of long-term psychotherapy) and potentially engaging to adolescents experiencing mood-related distress. CLINICALTRIAL ClinicalTrials.gov NCT0385881; https://clinicaltrials.gov/ct2/show/NCT03858881 (Archived by WebCite at http://www.webcitation.org/78C3roDgA). INTERNATIONAL REGISTERED REPOR DERR1-10.2196/13368

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Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD

Clinical Epigenetics ◽

10.1186/s13148-021-01129-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Nicholas D. Johnson ◽

Xiumei Wu ◽

Christopher D. Still ◽

Xin Chu ◽

Anthony T. Petrick ◽

...

Keyword(s):

Dna Methylation ◽

Cell Types ◽

Disease Stage ◽

Rna Seq ◽

Cell Type ◽

Alcoholic Fatty Liver ◽

Cell Composition ◽

Cpg Sites ◽

Plausible Mechanism ◽

The Relationship

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. Results Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p < 5.96 × 10–8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. Conclusion These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.

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