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Association between child maltreatment and depressive symptoms in emerging adulthood: the mediating and moderating roles of DNA methylation

Published onJan 11, 2023
Association between child maltreatment and depressive symptoms in emerging adulthood: the mediating and moderating roles of DNA methylation
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Corresponding author

Isabelle Ouellet-Morin

E-mail: [email protected]

Abstract

Prospective studies suggest that child maltreatment substantially increases the risk for depression in adulthood. However, the mechanisms underlying this association require further elucidation. In recent years, DNA methylation has emerged as a potential mechanism by which maltreatment experiences (a) could partly explain the emergence or aggravation of depressive symptoms (i.e., mediation) and/or (b) could increase (or decrease) the risk for depressive symptoms (i.e., moderation). The present study tested whether the methylation levels of nine candidate genes mediated and/or moderated the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. The sample comprised 156 men aged between 18 and 35 years. Maltreatment experiences and depressive symptoms were assessed retrospectively using self-reported questionnaires. Methylation levels of nine candidate genes (COMT, FKBP5, IL6, IL10, MAOA, NR3C1, OXTR, SLC6A3 and SLC6A4), previously reported to be sensitive to early-life stress, were quantified from saliva samples. Maltreatment experiences in childhood were significantly associated with depressive symptoms in emerging adulthood. Both maltreatment experiences and depressive symptoms were associated with the methylation levels of two genomic sites, which cumulatively, but not individually, explained 16% of the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. Moreover, maltreatment experiences in childhood interacted with the methylation levels of fourteen genomic sites, which cumulatively, but not individually, modulated the level of depressive symptoms in young male adults who were maltreated as children. However, none of these effects survived multiple testing correction. These findings bring attention to the cumulative effects of DNA methylation measured in several candidate genes on the risk of reporting depressive symptoms following maltreatment experiences in childhood. Nonetheless, future studies need to clarify the robustness of these putative cumulative effects in larger samples and longitudinal cohorts.

Introduction

Prospective studies suggest that child maltreatment substantially increases the risk for depression in adulthood (M. Li, D’Arcy, and Meng 2016). Moreover, the global prevalence of self-reported maltreatment experiences are 12.7% for sexual abuse, 22.6% for physical abuse, 36.3% for emotional abuse, 16.3% for physical neglect, and 18.4% for emotional neglect [2]. Therefore, it is imperative to better understand how child maltreatment is associated with higher levels of depressive symptoms (i.e., mediating factors), as well as in which contexts or for whom these symptoms are more likely to arise following these experiences (i.e., moderating factors). In recent years, epigenetic marks have emerged as potential mediating and moderating factors of the association between early-life stress and psychopathology (Ladd-Acosta and Fallin 2016).

The most commonly studied epigenetic mark is DNA methylation (DNAm), which refers to the addition of a methyl group (-CH3) onto a cytosine base followed by a guanine base (i.e., CpG site) (Jones, Moore, and Kobor 2018). This epigenetic mark prevents gene transcription in two ways: (a) methylated CpG sites impede the binding of transcriptional activators and (b) methylated CpG sites promote the binding of transcriptional repressors (Bird 1986). In general, methylated CpG sites that are located within the promoter region of a gene are associated with decreased expression of that gene (Jjingo et al. 2012). Notably, these marks can be maintained through cell division, which may induce persistent changes in gene activity and, thus, may lead to stable alterations in biological processes. In addition to being responsive to the genome (Zhang et al. 2010), DNAm profiles are also responsive to environmental exposures, both physical and social (Feil and Fraga 2012).

A compelling body of theory and research suggests that exposure to stressful experiences, such as child maltreatment, may become ‘biologically embedded’. Biological embedding is the concept that the exposure to stressful experiences during sensitive periods of development engenders lasting biological changes, altering the development and functioning of stress-related neurobiological systems, and therefore contributing to the emergence of physical and mental health problems later in life (Hertzman 2012). This concept is supported, for example, by studies reporting atypical cortisol responses to stress in adults maltreated as children (Koss and Gunnar 2018; Ouellet-Morin et al. 2019)(Koss and Gunnar 2018; Ouellet-Morin et al. 2019). Despite increasing knowledge of the neurobiological consequences of early-life stress, the molecular mechanisms underlying the biological embedding of these experiences requires further elucidation. In recent years, DNAm has emerged as a promising mechanism driving biological embedding (Provençal and Binder 2015).

Although epigenome-wide association studies (i.e., EWAS) are now preferred, many studies investigating the associations between maltreatment experiences, DNAm levels and depressive symptoms employed a candidate gene approach, whereby genes are pre-selected on the basis of prior knowledge regarding their neurobiological functions in terms of sensitivity to stress and/or the pathogenesis of depression, such as genes involved in neuroendocrine (FKBP5, NR3C1, OXTR), neurotransmitters (COMT, MAOA, SLC6A3, SLC6A4) and inflammatory pathways (IL6, IL10). Cecil et al. (Cecil, Zhang, and Nolte 2020) and Parade et al. (Parade et al. 2021) reported that although maltreatment experiences were associated with DNAm levels, the results were often mixed between studies targeting a same gene. To date, the most solid evidence emerges for the NR3C1 gene, which encodes glucocorticoid receptors, with most studies reporting higher DNAm levels in participants with a history of child maltreatment (Cecil, Zhang, and Nolte 2020; Parade et al. 2021; Turecki and Meaney 2016)(Cecil, Zhang, and Nolte 2020; Parade et al. 2021; Turecki and Meaney 2016)(Cecil, Zhang, and Nolte 2020; Parade et al. 2021; Turecki and Meaney 2016). The robustness of this association is noteworthy; as noted across species (e.g., (Suderman et al. 2012)), developmental stages (childhood [e.g., (Parade et al. 2016)], adolescence [e.g., (van der Knaap et al. 2014)], adulthood [e.g., (Perroud et al. 2011)]), samples (clinical [e.g., (Martín-Blanco et al. 2014)], community [e.g., (Tyrka et al. 2012)]), tissues (blood [e.g., (Bustamante et al. 2016)], brain [e.g., (Labonte et al. 2012; McGowan et al. 2009)(Labonte et al. 2012; McGowan et al. 2009)], saliva [e.g., (Tyrka et al. 2015)]), maltreatment measures (self-report [e.g., (Farrell et al. 2018)], official records [e.g., (Cicchetti and Handley 2017)]), designs (retrospective [e.g., (Radtke et al. 2015)], prospective [e.g., (Parent et al. 2017)] and approaches (EWAS [e.g., (Weder et al. 2014)]). However, this has not been the case for other candidate genes involved in the neuroendocrine response to stress. Studies on FKBP5, which encodes proteins that regulate the sensitivity of glucocorticoid receptors to cortisol, reported either negative (e.g., (Klengel et al. 2013)) or no association (e.g., (Bustamante et al. 2018)) between child maltreatment and DNAm levels, while studies on OXTR, which encodes oxytocin receptors, reported no overall association (e.g., (Gouin et al. 2017)). The maltreatment literature also focused on genes involved in the serotoninergic and dopaminergic pathways, such as SLC6A4, which encodes serotonin transporters responsible for serotonin reuptake, and MAOA, which encodes enzymes involved in the degradation of dopamine and serotonin. Studies on SLC6A4 reported positive (e.g., (Booij et al. 2015)) or no associations (e.g., (Wankerl et al. 2014)) between maltreatment experiences and DNAm levels, while studies on MAOA reported positive associations (e.g., (Checknita et al. 2018)) or no associations (e.g., (Peng et al. 2018)). That is, important methodological constraints currently limit the conclusions that can be drawn from existing DNAm studies in the context of maltreatment, such as the lack of control for well-known DNAm confounders and multiple testing [13, 14]. Cecil et al. [13] also suggested to use continuous assessments of child maltreatment to capture a wide range of exposures and to increase statistical power, as well as to measure all types of maltreatment to account for their potential cumulative effects.

Regarding the depression literature, Li et al. (Muzi Li et al. 2019) reported in their recent systematic review that although depressive symptoms were associated with DNAm levels, the strength and/or direction of this association varied dramatically across studies. To date, however, and despite considerable differences in study designs (e.g., sample size, sample characteristics, biological samples), laboratory techniques (e.g., DNA extraction methods/kits, DNA methylation methods/kits) and statistical analyses (e.g., parametric models, non-parametric models), the most solid evidence points to the SLC6A4 gene, for which most studies reported higher DNAm levels in depressed participants compared to their healthy counterparts (Muzi Li et al. 2019). However, conflicting results (i.e., both higher and lower DNAm levels or non-significant differences) were reported in the few studies that focused on the FKBP5, MAOA, NR3C1 and OXTR genes (Muzi Li et al. 2019). For example, in adult samples, Melas et al. (Melas et al. 2013) detected higher NR3C1 DNAm levels in saliva samples, while Na et al. (Na et al. 2014) detected lower NR3C1 DNAm levels in blood samples levels, whereas Alt et al. (Alt et al. 2010) reported no differences in brain samples. Although most studies focused on case-control differences, depression is a continuous measure that captures both clinical and sub-clinical depressive symptoms, for which associated DNAm signatures may signal a risk for or a consequence of a depressive symptomatology (Starnawska et al. 2019).

Altogether, existing studies seem to support the hypothesis that DNAm may partly explain the association between maltreatment experiences in childhood and depressive symptoms in adulthood. However, to this day, very few studies have formally tested the presumed mediating role of DNAm, which requires going beyond the investigation of the bivariate associations between maltreatment experiences, methylation levels, and depressive symptoms, and to directly estimate the significance of the indirect effect of DNAm linking maltreatment experiences to depressive symptoms. For instance, Bustamante et al. (Bustamante et al. 2018) found that FKBP5 methylation levels did not explain the association between child maltreatment and the severity of depressive symptoms among adults. Similarly, Smearman et al. (Smearman et al. 2016) found that OXTR methylation levels did not mediate the association between child maltreatment and depression and anxiety symptoms in adulthood. In contrast, Checknita et al. (Checknita et al. 2018) found that MAOA methylation levels mediated the association between sexual abuse and depression. Interestingly, Peng et al. (Peng et al. 2018) found that the methylation levels of two CpG sites in BDNF and NR3C1 explained about 20% of the association between traumatic experiences in childhood and depressive symptoms in adulthood. In sum, although theoretical frameworks suggest that DNAm could partially explain higher risk of depressive symptoms following maltreatment experiences, empirical evidence is still limited, and so far, rather inconsistent.

DNAm has also been hypothesized to modulate the influence that social environments may exert on the development of mental health problems (Bush et al. 2018). This hypothesis is consistent with the idea that the extent to which child maltreatment is associated with depressive symptoms may differ across individuals and contexts, which is shared by several stress models, such as the diathesis-stress (Monroe and Simons 1991) and the differential susceptibility (J. Belsky and Pluess 2009) models. However, to this day, very few studies have formally tested the presumed moderating role of DNAm. For instance, Radtke et al. (Radtke et al. 2015) found that the methylation levels of nine CpG sites in NR3C1 moderated the association between maltreatment experiences in childhood and psychopathological symptoms in adulthood, but the direction of the interaction is not specified. Similarly, Smearman et al. (Smearman et al. 2016) found that the methylation levels of three CpG sites in the OXTR gene moderated the association between experiences of physical abuse in childhood and symptoms of depression or anxiety in adulthood. Interestingly, the direction of these interactions varied between these CpG sites. For example, for the CpG site located within OXTR promoter region, participants with lower methylation levels reported higher depression and anxiety levels if they reported experiences of physical abuse. Taken together, these findings provide preliminary evidence for epigenome-environment interactions. Differences in DNAm levels may thus help explain why some adults are more likely to suffer from depressive symptoms following maltreatment experiences in childhood and adolescence, while others do not (or less so).

The present study aimed to extend current evidence suggesting that DNAm may play a role in the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. Specifically, we tested the putative mediating and moderating roles of DNAm. First, we expected that individual differences in DNAm levels of nine genes involved in the regulation of stress, emotions and behaviors (COMT, FKBP5, IL6, IL10, MAOA, NR3C1, OXTR, SLC6A3, and SLC6A4) would partly mediate (or explain) the association between maltreatment experiences in childhood and depressive symptoms in early adulthood. Second, we expected that DNAm of these candidate genes would also moderate (or modulate) the strength and/or direction of the maltreatment-depression association, whereby the strength of this association is expected to be stronger in participants with a high-risk DNAm profile (either high or low DNAm levels depending on the targeted gene) than in participants with a low-risk DNAm profile (either high or low DNAm levels depending on the targeted gene). In addition, as each CpG site usually exert a small effects in the prediction of complex phenotypes, such as depressive symptoms, we expected that the cumulative effect of all significant individual CpG sites would yield stronger mediating and moderating effects than their individual effects (Peng et al. 2018).

Materials and methods

Participants

The sample includes 160 men aged from 18 to 35 years recruited from the general population (M = 24.06, SD = 3.70). Participants were selected from a larger study whose general objective was to investigate the mechanisms by which victimization experiences (e.g., maltreatment, bullying) in childhood and adolescence are linked to higher levels of aggression in emerging adulthood. This group was targeted for three reasons. First, the prevalence of aggressive behaviors is higher in males than in females (Archer 2004) and as DNAm profiles appear to differ according to participants’ biological sex (Yousefi et al. 2015), only men were initially investigated. Second, emerging adulthood represents a transitional stage from dependency (i.e., adolescence) to autonomy (i.e., adulthood), a stressful period in which young adults are at heightened risk to develop mental health problems (Hagan et al. 2014). Third, the biological and psychological consequences of child maltreatment are rarely investigated in this age group (Toth and Cicchetti 2013). Of the 160 participants, four were removed because they had previously participated to a standardized stress test, resulting in a final sample of 156 participants.

Procedure

Participants were recruited for a study about early life experiences via advertisements displayed on public billboards and posted online on the Center for Studies on Human Stress’s website. In order to recruit enough participants with a history of child maltreatment, the advertisements insisted on memories of childhood and adolescence. Trained research assistants conducted a short phone interview with interested individuals, in which the questions regarding child maltreatment experiences were asked in the context of ‘when you were growing up’. Eligible participants were invited to a single laboratory session at the Center for Studies on Human Stress, which lasted about three hours and a half. The sampling strategy was blind in regards to depressive symptoms. Upon their arrival at the laboratory, participants were once again informed about the study procedures and provided written consent. All participants provided saliva samples for DNA extraction approximately two hours after they took part into a standardized stress test. Participants completed a questionnaire measuring depressive symptoms at the end of the visit. This study was approved by the Ethics Committee of the Research Center of the Montreal Mental Health University Institute (Project no. 2014-146, 2013-014). Data collection took place between July 2013 and December 2014.

Measures

Child maltreatment

Maltreatment experiences in childhood and adolescence were assessed retrospectively using the Childhood Trauma Questionnaire – Short form (CTQ-SF) (Bernstein et al. 2003), which measures five types of traumatic experiences, including emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Participants rated the extent to which each of the 28 items (25 clinical items and 3 validity items) corresponded to past experiences on a five-point Likert scale ranging from 1 = “never true” to 5 = “very often true”, leading to total scores 5 to 25 on each subscale. The severity of maltreatment experiences was calculated by summing up all 25 items. In this sample, participants’ scores varied from 25 to 76 (M = 37.43, SD = 11.04). Of note, the scores of three participants were winsorized by setting them to the highest value within three standard deviations from the sample’s mean to avoid the disproportional weight of these extreme scores in subsequent analyses.

Depressive symptoms

Current depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II) (Beck, Steer, and Brown 1996). Participants rated each of the 21 items according to their severity in the past two weeks using a four-point Likert scale ranging from 0 = “not present” to 3 = “severe”. The severity of depressive symptoms was calculated by summing up all 21 items. In this sample, participants’ scores varied from 0 to 44 (M = 10.48, SD = 8.79). The score of three participants were winsorized according to the aforementioned strategy.

DNA methylation

Saliva samples were collected between July 2013 and December 2014 using the Oragene® Self-Collection Kit (DNA Genotek, Ontario, Canada). DNA extraction and DNAm analysis were performed by Génome Québec (Québec, Canada) in July 2015, less than two years after saliva collection. Because of the proprietary reagents present in these kits, saliva samples can be stored up to five years at room temperature without significant DNA degradation (Iwasiow, Desbois, and Birnboim 2011). Genomic DNA was extracted manually using the QIAamp® DNA Blood Mini Kit (QIAGEN, Hilden, Germany). Genomic DNA was then treated with bisulfite using the EZ-DNA Methylation Gold Kit (Zymo Research, California, United States) according to the manufacturer’s protocol. DNAm levels of 442 CpG sites previously investigated within nine candidate genes (COMT, FKBP5, IL6, IL10, MAOA, NR3C1, OXTR, SLC6A3 and SLC6A4, see S1 Table for detailed locations) were quantified using the EpiTYPER MassARRAY technology (Agena Bioscience, California, United States). DNAm levels at each CpG site were calculated as the percentage of the surface area of the peak representing the methylated fragment by the total surface area of the peaks of both methylated and unmethylated fragments. Methylation values varied from 0 % (unmethylated) to 100 % (fully methylated). CpG sites with high mass or low mass as well as duplicates were removed (n = 116). CpG sites with greater than 20% missing values were removed (n = 6) as well as the CpG sites with greater than 80% of zeros (n = 14). Finally, CpG sites within the same gene that were positively and perfectly correlated (r = 1.00) have been grouped into a single variable, resulting in a final sample of 191 CpG sites.

Potential confounding variables

Information about the sociodemographic (e.g., age, civil status, education), health (e.g., height, weight, physical and/or mental health problems), medication intake (e.g., antidepressants, anxiolytics, antipsychotics), and lifestyle characteristics (e.g., tobacco, alcohol, and/or drug consumption) were enquired during the phone interview. The Body Mass Index (BMI) was calculated for each participant by dividing their body weight (in kilograms) by the square of their body height (in meters).

Statistical analyses

All statistical analyses were performed using R 3.6.0 (Team 2019). We first tested the bivariate associations between maltreatment experiences, depressive symptoms and DNAm levels using a series of linear regressions in which DNAm level at each CpG site was the dependent variable and maltreatment experiences or depressive symptoms were included in the model as an independent variable. We also examined these associations within specific genomic regions, where the CpG sites of the same gene that were correlated at r ≥ 0.50 and located within 500 base pairs of each other were grouped. The mean scores of the designated CpG sites were then used.

To examine the mediating role of DNAm in the association between maltreatment experiences and depressive symptoms, we performed a mediation analysis, using the mediation package in R (Tingley et al. 2014). This method uses information from two linear regression models: (1) DNAm as the dependent variable and child maltreatment as the independent variable and (2) depressive symptoms as the dependent variable and child maltreatment and DNAm as independent variables. The mediating effect is considered statistically significant when the lower and the upper bounds of the 95% confidence interval of the indirect effect do not include zero. Confidence intervals were estimated by using 1,000 Monte Carlo simulations. To avoid unnecessary tests and thus minimize the likelihood of identifying false positives, the mediation analyses were only conducted for CpG sites with significant associations with both maltreatment experiences and depressive symptoms. The methylation levels of these CpG sites were then summed up to derive a cumulative index of methylation and included as a potential mediator in the linear regression model.

To examine the moderating role of DNAm, we performed a moderation analysis, using the interactions package. This method uses information from a linear regression model: child maltreatment, DNAm and their interaction term as independent variables and depressive symptoms as the independent variable. All independent variables were mean-centered prior to analyses. The moderating effect was considered statistically significant when the estimate of the interaction term between child maltreatment and DNAm had an observed p < 0.05. Significant interactions were decomposed and illustrated by using the simple slopes analysis, which depicts the association between child maltreatment and depressive symptoms at one standard deviation above and below the mean methylation level of the identified CpG sites. The methylation levels of all CpG sites that modified the strength of the association between maltreatment experiences and depressive symptoms were grouped into tertiles and given a score of -1, 0 or 1 depending on the direction of associations. These scores were then summed up to derive a cumulative index of methylation and included as a potential moderator in the linear regression model.‬‬‬‬‬‬‬‬

Significant associations were rerun with confounding variables for which a unique association of p < 0.10 was detected between child maltreatment, DNAm or depressive symptoms. To do so, we tested, in preliminary analyses, the associations between these three variables and a wide range of individual characteristics known to covary with child maltreatment and depressive symptoms or affecting DNAm profiles, including age, smoking, drug consumption, alcohol consumption, and BMI. Only age and drug consumption were associated with the methylation level of several CpG sites as well as with depressive symptoms. These variables were then controlled for in the aforementioned linear models, mediation models and moderation models.

Correction for multiple testing was performed using the false discovery rate (FDR). As none of the results were significant after this correction at FDR < 0.20 and given the exploratory nature of this study, all results nominally significant at p < 0.05 were deemed of interest and discussed accordingly.

Results

Association between child maltreatment and depressive symptoms

Child maltreatment was significantly associated with depressive symptoms (B = 0.25, p < 0.001), whereby child maltreatment explained 10% of the variance of depressive symptoms (R2 = 0.10, F(1, 154) = 17.39, p = < 0.001).

Associations between child maltreatment and DNA methylation

Child maltreatment was significantly associated with the methylation levels of 9 CpG sites, namely 1 site in the MAOA gene, 2 sites in the NR3C1 gene, 4 sites in the SLC6A3 gene, and 2 sites in the SLC6A4 gene (see Unadjusted Models in Table 1). Estimates of explained variance varied between 2.51% to 4.82%. After adjusting for age and drug consumption, only 8 CpG sites remained significant (see Adjusted Models in Table 1). None of these associations survived multiple testing correction. In addition, grouping the CpG sites per regions did not yield additional significant findings.

Table 1. Significant Associations Between Child Maltreatment and DNA methylation.

CpG name

Position

DNA methylation

Unadjusted Models

Adjusted Models

B

SE

p

R2

B

SE

p

R2

MAOA

MAOA_2_CpG_12and13

chrX:43515458

chrX:43515468

-0.029

0.015

0.048

0.025

-0.026

0.015

0.074

0.052

NR3C1

NR3C1_1_CpG_9

chr5:142784413

0.030

0.013

0.021

0.034

0.029

0.013

0.022

0.065

NR3C1_2_CpG_49to52

chr5:142783299

chr5:142783303

chr5:142783310

chr5:142783314

0.041

0.015

0.006

0.048

0.040

0.015

0.008

0.052

SLC6A3

SLC6A3_1_CpG_4

chr5:1446537

0.079

0.031

0.012

0.040

0.080

0.032

0.012

0.041

SLC6A3_1_CpG_8to11

chr5:1446488

chr5:1446485

chr5:1446478

chr5:1446474

-0.022

0.010

0.031

0.030

-0.024

0.010

0.016

0.068

SLC6A3_1_CpG_16

chr5:1446430

-0.050

0.021

0.018

0.036

-0.053

0.021

0.015

0.043

SLC6A3_2_CpG_2to4

chr5:1446371

chr5:1446369

chr5:1446367

0.026

0.011

0.019

0.035

0.027

0.011

0.016

0.043

SLC6A4

SLC6A4_2_CpG_28and29

chr17:28562786

chr17:28562783

-0.010

0.005

0.034

0.029

-0.010

0.005

0.038

0.066

SLC6A4_3_CpG_36

chr17:28562435

-0.029

0.015

0.046

0.026

-0.032

0.015

0.027

0.060

Note. Based on GRCh37/hg19 coordinates.

Associations between DNA methylation and depressive symptoms

Depressive symptoms were significantly associated with the methylation levels of 14 CpG sites, namely, 1 site in the IL6 gene, 1 site in the IL10 gene, 2 sites in the NR3C1 gene, 1 site in the OXTR gene, 3 sites in the SLC6A3 gene, and 6 sites in the SLC6A4 gene (see Unadjusted Models in Table 2). Estimates of explained variance varied between 2.54% to 4.96%. Of these, 3 CpG sites (1 site in the NR3C1 gene, 1 site in SLC6A3 gene, and 1 site SLC6A4 gene) were also associated with child maltreatment. After adjusting for age and drug consumption, only 8 CpG sites remained significant, including the 2 of the 3 sites also associated with child maltreatment (see Adjusted Models in Table 2). None of these associations survived multiple testing correction. Once again, grouping the CpG sites per regions did not yield additional significant findings.

Table 2. Significant Associations Between Depressive Symptoms and DNA methylation.

CpG names

Position

DNA methylation

Unadjusted Models

Adjusted Models

B

SE

p

R2

B

SE

p

R2

IL6

IL6_2_CpG_3and4

chr7:22764029

chr7:22764031

-0.082

0.037

0.028

0.033

-0.093

0.384

0.015

0.046

IL10

IL10_2_CpG_4

chr1:206940003

0.110

0.053

0.040

0.027

0.084

0.054

0.119

0.082

NR3C1

NR3C1_2_CpG_49to52

chr5:142783299

chr5:142783303

chr5:142783310

chr5:142783314

0.043

0.019

0.027

0.031

0.048

0.020

0.016

0.044

NR3C1_2_CpG_61to63

chr5:142783380

chr5:142783384

chr5:142783386

0.099

0.039

0.013

0.039

0.107

0.041

0.009

0.048

OXTR

OXTR_2_CpG_11

chr3:8810699

-0.046

0.021

0.032

0.029

-0.035

0.022

0.107

0.058

SLC6A3

SLC6A3_1_CpG_7

chr5:1446498

-0.033

0.016

0.041

0.027

-0.035

0.016

0.033

0.044

SLC6A3_1_CpG_12

chr5:1446462

-0.061

0.029

0.035

0.028

-0.054

0.029

0.064

0.055

SLC6A3_1_CpG_16

chr5:1446430

-0.065

0.027

0.018

0.036

-0.064

0.028

0.023

0.038

SLC6A4

SLC6A4_2_CpG_26

chr17:28562826

-0.014

0.006

0.033

0.029

-0.009

0.006

0.154

0.090

SLC6A4_2_CpG_28and29

chr17:28562786

chr17:28562783

-0.013

0.006

0.024

0.033

-0.011

0.006

0.069

0.060

SLC6A4_3_CpG_1and2

chr17:28562751

chr17:28562749

-0.021

0.010

0.048

0.025

-0.022

0.011

0.039

0.031

SLC6A4_3_CpG_9to12

chr17:28562706

chr17:28562703

chr17:28562700

chr17:28562691

-0.050

0.018

0.005

0.050

-0.042

0.018

0.020

0.111

SLC6A4_3_CpG_22

chr17:28562596

-0.066

0.029

0.022

0.034

-0.065

0.030

0.030

0.038

SLC6A4_3_CpG31to33

chr17:28562499

chr17:28562492

chr17:28562489

-0.041

0.018

0.021

0.034

-0.034

0.018

0.058

0.061

Note. Based on GRCh37/hg19 coordinates.

Mediation Analyses

The mediation analyses focused on the CpG sites associated with both child maltreatment and depressive symptoms after controlling for age and drug consumption. The methylation level of NR3C1_2_CpG_49to52 did not mediate the association between maltreatment and depressive symptoms (Fig 1A). While the association between maltreatment experiences and the methylation level of NR3C1_2_CpG_49to52 was still significant (B = 0.04, p = 0.01), the association between the methylation level of NR3C1_2_CpG_49to52 and depressive symptoms was no longer significant when controlling for maltreatment experiences (B = 0.47, p = 0.15). The bootstrapped unstandardized coefficient representing the indirect effect was 0.02, for which the 95% confidence interval ranged from -0.006 to 0.050, indicating a non-significant indirect effect (p = 0.15). After adjusting for age and drug consumption, the bootstrapped unstandardized indirect effect was practically unchanged (B = 0.02, 95% CI = -0.003 to 0.060, p = 0.13).

The methylation level of SLC6A3_1_CpG_16 did not either mediate the association between child maltreatment and depressive symptoms (Fig 1B). Once more, while the association between maltreatment experiences and the methylation level of SLC6A3_1_CpG_16 was significant (B = -0.05, p = 0.02), the association between the methylation level of SLC6A3_1_CpG_16 and depressive symptoms was no longer significant when controlling for maltreatment experiences (B = -0.39, p = 0.08). The bootstrapped unstandardized indirect effect was 0.02, and the 95% confidence interval ranged from -0.003 to 0.060, suggesting a non-significant indirect effect (p = 0.11). After adjusting for age and drug consumption, the bootstrapped unstandardized indirect effect was practically unchanged (B = 0.02, 95% CI = -0.003 to 0.050, p = 0.11).

Interestingly, these 2 CpG sites cumulatively mediated the association between maltreatment experiences and depressive symptoms, and this, even after controlling for age and drug consumption (Fig 1C). The bootstrapped unstandardized coefficient of the indirect effect was 0.04, with 95% confidence intervals ranged from 0.008 to 0.091 indicating a significant indirect effect. That is, maltreatment experiences were associated with higher levels of the index of cumulative methylation (B = 0.04, p < 0.001), which was, in turn, associated to higher depressive symptoms (B = 1.12, p = 0.02). Nevertheless, after accounting for the indirect effect of the index of cumulative methylation, maltreatment experiences were still significantly associated with depressive symptoms (B = 0.25, p < 0.001), suggesting a partial mediation. The index of cumulative methylation mediated approximately 16% of the association between maltreatment experiences and depressive symptoms (B = 0.16, 95% CI = 0.03 to 0.41, p = 0.02).

Fig 1. Mediation analyses.

(A) Adjusted model for NR3C1_2_CpG_49to52. (B) Adjusted model for SLC6A3_1_CpG_16. (C) Adjusted model for the index of cumulative methylation.

Moderation Analyses

A total of 12 CpG sites significantly moderated the association between maltreatment experiences and depressive symptoms, including 1 site in the FKBP5 gene, 3 sites in the MAOA gene, 3 sites in the NR3C1 gene, 2 sites in the SLC6A3 gene, and 3 sites in the SLC6A4 gene (see Unadjusted Models in Table 3). Estimates of explained variance varied between 12.4% and 18.4%. Once age and drug consumption were included in the models, the methylation levels of 14 CpG sites significantly moderated the association between maltreatment experiences and depressive symptoms, namely 2 sites in the FKBP5 gene, 2 sites in the IL10 gene, 1 site in the MAOA gene, 3 sites in the NR3C1 gene, 3 sites in the SLC6A3 gene, and 3 sites in the SLC6A4 gene (see Adjusted Models in Table 3). The interactions between maltreatment experiences and the methylation levels of each of these 14 CpG sites are depicted in S1 Figure. However, none of these interactions survived multiple testing correction. Grouping the CpG sites per regions did not yield additional significant findings.

Table 3. Significant Interactions Between Child Maltreatment and DNA Methylation Predicting Depressive Symptoms

CpG names

Position

DNA methylation

Unadjusted Models

Adjusted Models

B

SE

p

R2

B

SE

p

R2

FKBP5

FKBP5_1_CpG_3

chr6:35558489

0.022

0.011

0.047

0.126

0.022

0.011

0.043

0.182

FKBP5_1_CpG_4

chr6:35558514

0.020

0.011

0.071

0.124

0.024

0.011

0.026

0.187

IL10

IL10_2_CpG_5

chr1:206939984

-0.034

0.019

0.075

0.124

-0.043

0.019

0.022

0.189

IL10_2_CpG_6

chr1:206939954

-0.025

0.014

0.066

0.137

-0.032

0.014

0.021

0.195

MAOA

MAOA_2_CpG_7to9

chrX:43515403

chrX:43515413

chrX:43515419

-0.075

0.035

0.035

0.131

-0.056

0.035

0.115

0.179

MAOA_2_CpG_27

chrX:43515647

-0.022

0.009

0.016

0.168

-0.015

0.009

0.101

0.214

MAOA_3_CpG_1

chrX:43515676

0.025

0.012

0.033

0.184

0.025

0.011

0.031

0.245

NR3C1

NR3C1_1_CpG_5

chr5:142784370

-0.096

0.050

0.055

0.124

-0.098

0.048

0.045

0.184

NR3C1_2_CpG_23and24

chr5:142783121

chr5:142783129

-0.095

0.047

0.043

0.127

-0.085

0.046

0.067

0.179

NR3C1_2_CpG_60

chr5:142783361

-0.200

0.096

0.039

0.136

-0.191

0.094

0.044

0.189

NR3C1_3_CpG_8

chr5:142782723

0.265

0.012

0.024

0.137

0.270

0.113

0.019

0.194

SLC6A3

SLC6A3_1_CpG_7

chr5:1446498

-0.072

0.042

0.086

0.135

-0.085

0.041

0.037

0.199

SLC6A3_2_CpG_28to30

chr5:1446121

chr5:1446119

chr5:1446113

-0.081

0.037

0.029

0.130

-0.083

0.036

0.023

0.188

SLC6A3_2_CpG_35to37

chr5:1446079

chr5:1446076

chr5:1446068

-0.089

0.038

0.021

0.135

-0.097

0.037

0.010

0.196

SLC6A4

SLC6A4_3_CpG_13and14

chr17:28562685

chr17:28562683

0.082

0.038

0.036

0.129

0.079

0.037

0.036

0.186

SLC6A4_3_CpG_23and24

chr17:28562572

chr17:28562567

0.069

0.034

0.042

0.126

0.070

0.033

0.035

0.186

SLC6A4_3_CpG_36

chr17:28562435

0.084

0.033

0.013

0.140

0.085

0.032

0.009

0.197

Note. Based on GRCh37/hg19 coordinates. Estimates (B) represent the coefficient of the interaction between maltreatment experiences and DNAm levels.

Interestingly, these 14 CpG sites cumulatively moderated the association between maltreatment experiences and depressive symptoms (B = 0.04, p < 0.01), while still controlling for age and drug consumption. Specifically, stronger associations between maltreatment experiences and depressive symptoms were noted as the cumulative index of methylation, derived from the methylation levels of the 14 CpG sites previously identified to independently moderate this association, increased. While no association was detected for participants with lower scores in this cumulative index (B = 0.12, p = 0.11), significant effects emerged for those who had moderate (B = 0.30, p < 0.01) to higher scores (B = 0.49, < 0.01; see Fig 2). This interactive model explained 28% of the variance of depressive symptoms (R2 = 0.28, F(5, 136) = 10.35, p = < 0.001).

Fig 2. A visual representation of the association between child maltreatment and depressive symptoms according to a cumulative index of methylation.

Fig 2 depicts the conditional association between maltreatment experiences and depressive symptoms according to increasing DNAm levels, depicted in three equal groups.

Discussion

In the present study, we aimed to extend preliminary reports suggesting that DNAm may play a role in the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. Specifically, we examined whether this association could be explained, in part, by the DNAm levels of nine candidate genes involved in the regulation of stress, emotions and behaviors (i.e., mediation) and whether the strength and/or direction of this association could be modulated by individual differences in DNAm levels (i.e., moderation). Consistent with a previous study on this sample (Cantave et al. 2019), we observed a positive association between maltreatment experiences and depressive symptoms. Four observations are worth highlighting.

First, we found that maltreatment experiences were associated with DNAm levels of eight CpG sites (out of 191). In line with previous studies [57,58], the effect sizes of the uncovered associations between child maltreatment and salivary DNAm were relatively small (B < 8%). Unfortunately, none of the CpG sites deemed nominally significant (p < 0.05) survived multiple testing correction. Nonetheless, these signals remain of interest for future investigations and contribute to foster a greater collective knowledge about the expected role of DNAm in the association between maltreatment experiences and depressive symptoms. Specifically, our results indicate that adults who reported higher levels of maltreatment experiences exhibited higher levels of methylation at two CpG sites across NR3C1 promoter region (out of 34), including one CpG site within the exon 1B and one CpG site within the exon 1C. Labonté et al. (Labonte et al. 2012) previously found that men who died by suicide and who had a history of child abuse showed differential methylation levels in NR3C1 promoter region in the hippocampus, namely two CpG sites within the exon 1C (out of 18) and three CpG sites within the exon 1H (out of 13) compared to men who died by suicide without such a history. Contrary to our findings, Labonté et al. (Labonte et al. 2012) did not observed differential methylation levels at any of the 12 CpG sites investigated within the exon 1B. In addition, the two CpG sites that we found to be associated with maltreatment experiences in our study did not correspond to those reported by Labonté et al. (Labonte et al. 2012) Although the majority of studies found a positive association between child maltreatment and NR3C1 methylation levels (Cecil, Zhang, and Nolte 2020), inconsistencies exist, especially when focusing on specific (individual) CpG sites. These inconsistencies may be partly due to the use of different biological tissues to measure DNAm. Indeed, as DNAm plays an important role in cell differentiation (Farré et al. 2015), it is unclear whether the observed inter-individual differences in DNAm levels are attributable to the exposure to maltreatment experiences or tissue specificity. Our results also indicate that adults who reported higher levels of maltreatment experiences exhibited lower levels of methylation at two CpG sites across SLC6A4 promoter region (out of 31). Our findings, however, contrast with the majority of previous studies, who rather reported higher levels of SLC6A4 methylation in blood samples of adults exposed to maltreatment experiences in childhood (Cecil, Zhang, and Nolte 2020; Parade et al. 2021)(Cecil, Zhang, and Nolte 2020; Parade et al. 2021). It is important to highlight that these studies mainly focused on experiences of sexual abuse in samples primarily composed of female participants. As women tend to report more experiences of sexual abuse than men (Finkelhor 1994), we pondered that these associations are likely to be sexually dimorphic. Interestingly, our results indicate that adults who reported higher levels of maltreatment experiences exhibited higher levels of methylation at two CpG sites and lower levels of methylation at two CpG sites, all four located within SLC6A3 promoter region (out of 27). To the best of our knowledge, no study has yet investigated the association between maltreatment experiences and SLC6A3 methylation levels in humans. Although some studies reported differential methylation levels of the FKBP5, IL6 and MAOA genes between adults with and without a history of child maltreatment (Cecil, Zhang, and Nolte 2020; Parade et al. 2021)(Cecil, Zhang, and Nolte 2020; Parade et al. 2021), we did not find evidence for associations between maltreatment experiences and methylation levels of any CpG sites within those genes. Our findings are thus in line with other studies that also reported no association between maltreatment experiences and the FKBP5 methylation levels (Bustamante et al. 2018; Farrell et al. 2018; Klinger-König et al. 2019; Yeo et al. 2017)(Bustamante et al. 2018; Farrell et al. 2018; Klinger-König et al. 2019; Yeo et al. 2017)(Bustamante et al. 2018; Farrell et al. 2018; Klinger-König et al. 2019; Yeo et al. 2017)(Bustamante et al. 2018; Farrell et al. 2018; Klinger-König et al. 2019; Yeo et al. 2017) or MAOA methylation levels (Peng et al. 2018). In addition to variation related to biological tissues used to measure DNAm, we speculated that the strategy to measure and operationalize child maltreatment (i.e., dichotomous variable or continuous variable) might further exacerbate these inconsistencies. As the majority of previous studies reported no overall association between maltreatment experiences and OXTR methylation levels (Cecil, Zhang, and Nolte 2020; Parade et al. 2021)(Cecil, Zhang, and Nolte 2020; Parade et al. 2021), we also found no association between maltreatment experiences and OXTR methylation levels at any of the CpG sites investigated within this gene. Nonetheless, additional studies are needed to further test the presence, strength and direction of the association between maltreatment experiences and DNAm levels.

Second, we found that current depressive symptoms were associated with DNAm levels of eight CpG sites (out of 191). Here again, the observed effect sizes were relatively small (B < 12%) and none of the CpG sites deemed nominally significant (p < 0.05) survived multiple testing correction. Specifically, adults who reported higher levels of depressive symptoms exhibited higher levels of methylation at two CpG sites across the NR3C1 promoter region (out of 34). Our findings are in line with some studies that also detected higher levels of NR3C1 methylation in blood samples of depressed adults in comparison to controls (Peng et al. 2018; Farrell et al. 2018; Roy, Shelton, and Dwivedi 2017)(Peng et al. 2018; Farrell et al. 2018; Roy, Shelton, and Dwivedi 2017)(Peng et al. 2018; Farrell et al. 2018; Roy, Shelton, and Dwivedi 2017). To the best of our knowledge, we are the first to investigate the association between depressive symptoms and NR3C1 methylation levels in saliva samples of adults. Thus, it is quite noteworthy that our findings are similar to those examining NR3C1 methylation in blood samples. Our results also indicate that adults who reported higher levels of depressive symptoms exhibited lower levels of methylation at three CpG sites across SLC6A4 promoter region (out of 31). Although the majority of studies found higher SLC6A4 methylation levels, some reported lower SLC6A4 methylation levels (Muzi Li et al. 2019). In addition to the absence of a “real” effect, inconsistent findings may be partly explained by the use of different biological tissues to extract DNA or the composition of the sample (population-based vs. clinically-based samples). To the best of our knowledge, even if dopamine plays a role in motivation, mood and cognition (Missale et al. 1998), no candidate gene study has yet investigated the association between depressive symptoms and SLC6A3 methylation levels. Interestingly, our results indicate that adults who reported higher levels of depressive symptoms exhibited lower levels of methylation at two CpG sites across the SLC6A3 promoter region (out of 27). Our results also indicate that adults who reported higher levels of depressive symptoms exhibited lower levels of methylation at one CpG site across IL6 promoter region (out of 10), which is consistent with the study of Ryan et al. (Ryan et al. 2017), who also reported lower levels of methylation at one CpG site across IL6 promoter region (out of 4) in saliva samples of depressed adults. Although some studies reported differential methylation levels CpG sites in the FKBP5, MAOA and OXTR genes between depressed and healthy participants (Muzi Li et al. 2019), we did not find evidence for associations between maltreatment experiences and methylation levels of any CpG sites within those genes. Similarly to the associations between maltreatment experiences and DNAm levels, additional studies with large prospective cohorts research design are needed to test these associations more robustly.

Third, we found that the methylation levels of two CpG sites, for which bivariate associations with maltreatment experiences and depressive symptoms were nominally significant (p < 0.05), did not independently explain (or mediate) the association between maltreatment experiences and depressive symptoms. To the best of our knowledge, only four studies have tested the putative mediating role of DNAm in the maltreatment-depression association. We were not able to replicate the findings reported for the NR3C1 and MAOA genes, for which DNAm levels were found to explain the maltreatment-depression association (Checknita et al. 2018; Peng et al. 2018)(Checknita et al. 2018; Peng et al. 2018). Nonetheless, our results somewhat echo with the other two studies that targeted other candidate genes, such as FKBP5 (Bustamante et al. 2018) and OXTR (Smearman et al. 2016) , for which DNAm levels did not explain the maltreatment-depression association. Interestingly, we found that a cumulative index of methylation, derived from the methylation levels of the two aforementioned CpG sites, explained 16% of the association between maltreatment experiences in childhood and depressive symptoms in adulthood. Our results somewhat echo with the study of Peng et al. (Peng et al. 2018), which highlighted the importance of testing the cumulative epigenetic effect of multiple CpG sites on complex phenotypes, which may help to unravel the molecular mechanisms through which early-life stress may become biologically embedded in stress-related neurobiological systems supporting mental health. Although additional studies with larger samples are required to replicate these preliminary findings, several alternative explanations deserve further consideration. First, DNAm may serve as a biological marker (i.e., biomarker) signalling exposure to child maltreatment and/or the presence of a depressive symptomatology, which could be of clinical utility, even without being directly involved in the causal pathways leading up to psychopathology. For instance, DNAm profiles have already been shown to be useful in the detection and prognosis of cancer as well as the prediction of response to treatment (Ladd-Acosta and Fallin 2016). Second, it is also possible that child maltreatment indeed influences DNAm patterns of stress-related genes in the days, weeks and years following these experiences, but that they represent only a small fraction of all the neurobiological changes leading to psychopathology. The multifactorial and dynamic nature of these pathways certainly complicates the detection of significant indirect effects.

Fourth, we found that the methylation levels of fourteen CpG sites (out of 191) independently modified (or moderated) the strength of the association between maltreatment experiences and depressive symptoms and this, in a nominally significant fashion (p < 0.05). On the one hand, our results indicated that child maltreatment was associated with higher risk of depressive symptoms among young male adults with moderate to high FKBP5 methylation levels at two CpG sites, but not for those with low FKBP5 methylation levels at these two CpG sites. A similar direction pattern was also observed for the methylation levels of one CpG site within the MAOA gene, one CpG site within the NR3C1 gene and three CpG sites within the SLC6A4 gene. On the other hand, our results indicate that child maltreatment was associated with higher risk of depressive symptoms among young male adults with low to moderate IL10 methylation levels at two CpG sites, but not for those with high IL10 methylation levels at these two CpG sites. A similar direction pattern was also observed for two CpG sites within the NR3C1 gene and three CpG sites within the SLC6A3 gene. Although we were able to replicate the findings reported by Radkte et al. (Radtke et al. 2015), for which NR3C1 methylation levels were found to interact with child maltreatment to predict psychopathology, we were not able to replicate the findings reported by Smearman et al. (Smearman et al. 2016), for which OXTR methylation levels were found to interact with physical abuse to predict depression and anxiety. Interestingly, we found that a cumulative index of methylation, derived from the methylation levels of the fourteen aforementioned CpG sites, significantly modulated the strength of the association between maltreatment experiences in childhood and depressive symptoms in adulthood, whereby young male adults who exhibited higher methylation risk scores reported higher levels of depressive symptoms following maltreatment experiences in childhood. Specifically, child maltreatment was associated with higher levels of depressive symptoms among young male adults with a moderate to high risk DNAm profile, but not for those with a low risk DNAm profile. Taken together, these independent and cumulative signals offer additional support to the moderating role of DNAm in the association between maltreatment experiences and depressive symptoms, although existing theoretical frameworks rather advance its mediating role.

Our findings should be considered in light of several limitations. First, we were unable to control for cell heterogeneity within our study. Since different types of cells show distinct patterns of methylation (Farré et al. 2015), it may have influenced DNAm profiles, which may have contributed to our reported null findings. Second, the sample size used in this study is small (N = 156), which may explain why we were not able to replicate some of the previous findings and that none of our results survived multiple testing correction. We thus recommend caution in interpreting these preliminary results, especially at the CpG level. Third, our sample only included young adult male participants. Therefore, our results may not apply to female participants or to younger or older populations, as DNAm varies in function of age and sex (Yousefi et al. 2015; Fraga et al. 2005)(Yousefi et al. 2015; Fraga et al. 2005). Fourth, our participants were recruited from the general population, so that only 4.5% of the sample reported severe levels of depressive symptoms. Therefore, our results may not apply to clinical populations. Moreover, only 35.9% of the sample reported at least one type of maltreatment experiences. The restricted variance in these key variables may have further undermined our statistical power to detect the expected associations. Fifth, we used a self-reported and retrospective questionnaire to assess child maltreatment, which may be subject to recall biases. However, previous studies reported that memories of maltreatment experiences in childhood and adolescence appear to be reliable in adulthood (Bifulco et al. 1997). Moreover, recall bias seems to explain less than 1% of the variance of child maltreatment scores (Fergusson, Horwood, and Boden 2011). Sixth, we cannot determine the temporal sequence of events since this study is cross-sectional. We also did not have the statistical power to investigate whether the association between maltreatment and DNAm varied according to individual characteristics (e.g., sex, genetic background) and/or maltreatment characteristics (e.g., onset, recency). For example, using a prospective design, Cicchetti et al. (Cicchetti et al. 2016) not only found genome-wide differences in DNAm levels between maltreated and non-maltreated children, but also significant interactions between maltreatment, its onset and sex on DNAm levels of specific genes (e.g., ALDH2). Seventh, the study relied on data analyzed in 2015 according to a candidate gene approach. As candidate gene and epigenome-wide studies share little to no overlap between target sequences (e.g., (Weder et al. 2014)), candidate gene studies remain relevant to examine the role of specific genes in the association between maltreatment experiences and depressive symptoms, as well as to inform future meta-analytic work targeting these genes.

Despite these limitations, our findings extend previous research that alluded to or directly tested the putative mediating or moderating roles of DNAm in the association between child maltreatment and depressive symptoms in emerging adulthood. Our study provides preliminary support for the cumulative effect of DNAm levels detected within several candidate genes on the emergence or aggravation of depressive symptoms following maltreatment experiences. The relative value of using methylation risk scores to examine the cumulative effect of DNAm levels of multiple CpG sites spanning multiple genes should be further investigated, as well as complemented by using other methylation risk scores, such as the EpiStress score (Provençal et al. 2019), the DunedinPACE (D. W. Belsky et al. 2022) and epigenetic clocks (Horvath 2013). Our findings are also consistent with the added value of using measures of maltreatment that span a wider range of severity and types of exposure [13]. Nevertheless, the putative effects of child maltreatment on DNAm should also be considered along other family risk factors (e.g., maternal and/or paternal psychopathology, alcohol and/or drug abuse), as preliminary evidence suggests that these additional stressful family experiences may have a cumulative effect on DNAm levels above and beyond child maltreatment (e.g., (Craig et al. 2021)). Moreover, the role of DNAm could be conditional on the allelic variations within the selected candidate genes (e.g., (Ramo-Fernández et al. 2019)). Finally, our study provides additional, albeit partial, support to the possibility that DNAm may further help to understand how or for whom child maltreatment may increase risk for depression later in life. Future studies would benefit from the collection of prospective measures of child maltreatment, DNAm levels and depressive symptoms, as well as the functional characterisation of DNAm findings, such as gene expression, to enhance understanding of the role of DNAm in the emergence or aggravation of depressive symptoms following maltreatment experiences.

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Supporting Information

S1 Table. Candidate genes.

Gene

Fragment

Coordinates

CpG Sites

COMT

1

chr22:19950027-19950348

16

2

chr22:19929067-19929331

37

FKBP5

1

chr6:35558387-35558567

5

IL6

1

chr7:22763499-22763846

11

2

chr7:22763911-22764031

4

IL10

1

chr1:206940522-206940.11

6

2

chr1:206840215-206939313

9

MAOA

1

chrX:43514936-43515089

8

2

chrX:43515295-43515647

27

3

chrX:43515676-43515991

6

NR3C1

1

chr5:142784279-142784593

15

2

chr5:142782988-142783500

84

3

chr5:142782766-142782551

26

OXTR

1

chr3:8809307-8809564

26

2

chr3:8810889-8810647

14

SLC6A3

1

chr5:104460585-1446430

16

2

chr5:1446393-1446001

45

SLC6A4

1

chr17:28563424-28563054

17

2

chr17:28563020-28562783

29

3

chr17:28562751-28562388

41

Note. Based on GRCh37/hg19 coordinates.

S2 Table. Associations between child maltreatment and DNA methylation.

CpG Name

Position

DNA Methylation

Unadjusted Models

Adjusted Models

 

 

B

SE

p

R2

FDR

B

SE

p

R2

FDR

COMT

COMT_1_CpG_3

chr22:19950055

-0.042

0.063

0.501

0.003

0.912

-0.056

0.062

0.374

0.042

0.878

COMT_1_CpG_4

chr22:19950064

0.018

0.075

0.816

0.000

0.982

-0.003

0.073

0.967

0.076

0.994

COMT_1_CpG_5

chr22:19950158

-0.031

0.079

0.691

0.001

0.982

-0.051

0.077

0.509

0.075

0.893

COMT_1_CpG_7

chr22:19950222

-0.096

0.123

0.433

0.004

0.909

-0.124

0.122

0.311

0.043

0.878

COMT_1_CpG_8

chr22:19950236

0.064

0.148

0.665

0.001

0.982

0.073

0.149

0.625

0.009

0.959

COMT_1_CpG_9

chr22:19950250

-0.080

0.082

0.330

0.006

0.909

-0.099

0.080

0.219

0.075

0.852

COMT_1_CpG_10

chr22:19950257

-0.038

0.091

0.678

0.001

0.982

-0.063

0.088

0.477

0.073

0.878

COMT_1_CpG_12

chr22:19950272

-0.031

0.082

0.702

0.001

0.982

-0.053

0.079

0.510

0.076

0.893

COMT_1_CpG_13

chr22:19950299

-0.030

0.081

0.711

0.001

0.982

-0.048

0.078

0.542

0.081

0.917

COMT_1_CpG_14and15

chr22:19950323

-0.043

0.081

0.593

0.002

0.982

-0.063

0.079

0.428

0.069

0.878

chr22:19950329

COMT_1_CpG_16

chr22:19950348

-0.021

0.079

0.787

0.000

0.982

-0.042

0.077

0.583

0.081

0.946

COMT_2_CpG_3and4

chr22:19929115

0.040

0.038

0.288

0.007

0.909

0.039

0.038

0.308

0.017

0.878

chr22:19929117

COMT_2_CpG_5

chr22:19929131

0.016

0.013

0.214

0.010

0.909

0.015

0.013

0.248

0.015

0.852

COMT_2_CpG_6to9

chr22:19929149

-0.007

0.005

0.147

0.014

0.909

-0.007

0.005

0.132

0.017

0.852

chr22:19929152

chr22:19929154

chr22:19929156

COMT_2_CpG_11to14

chr22:19929179

0.000

0.013

0.992

0.000

0.995

0.000

0.013

0.982

0.001

0.994

chr22:19929183

chr22:19929185

chr22:19929187

COMT_2_CpG_15and16

chr22:19929198

-0.005

0.011

0.663

0.001

0.982

-0.004

0.011

0.721

0.046

0.966

chr22:19929200

COMT_2_CpG_17and18

chr22:19929206

-0.010

0.007

0.187

0.011

0.909

-0.011

0.008

0.152

0.021

0.852

chr22:19929211

COMT_2_CpG_25and26

chr22:19929255

-0.018

0.013

0.158

0.013

0.909

-0.019

0.013

0.135

0.029

0.852

chr22:19929259

COMT_2_CpG_27to29

chr22:19929264

0.002

0.014

0.880

0.000

0.982

0.003

0.014

0.822

0.012

0.966

chr22:19929271

chr22:19929275

COMT_2_CpG_31

chr22:19929287

0.006

0.007

0.422

0.004

0.909

0.005

0.007

0.454

0.006

0.878

COMT_2_CpG_32

chr22:19929302

0.005

0.006

0.460

0.004

0.909

0.005

0.006

0.466

0.006

0.878

COMT_2_CpG_33

chr22:19929307

-0.084

0.044

0.061

0.023

0.909

-0.077

0.044

0.087

0.045

0.852

COMT_2_CpG_34

chr22:19929313

0.010

0.055

0.855

0.000

0.982

0.011

0.055

0.844

0.004

0.966

COMT_2_CpG_35

chr22:19929322

0.012

0.015

0.439

0.004

0.909

0.012

0.016

0.428

0.005

0.878

COMT_2_CpG_36and37

chr22:19929328

-0.006

0.008

0.435

0.004

0.909

-0.007

0.008

0.337

0.037

0.878

chr22:19929331

FKBP5

FKBP5_1_CpG_1

chr6:35558387

-0.021

0.046

0.657

0.001

0.982

-0.020

0.046

0.673

0.019

0.966

FKBP5_1_CpG_2

chr6:35558439

-0.091

0.058

0.120

0.016

0.909

-0.082

0.058

0.158

0.058

0.852

FKBP5_1_CpG_3

chr6:35558489

-0.062

0.038

0.109

0.017

0.909

-0.066

0.039

0.092

0.025

0.852

FKBP5_1_CpG_4

chr6:35558514

-0.016

0.037

0.674

0.001

0.982

-0.023

0.037

0.542

0.039

0.917

FKBP5_1_CpG_5

chr6:35558567

0.151

0.100

0.135

0.016

0.909

0.138

0.101

0.177

0.025

0.852

IL6

IL6_1_CpG_1

chr7:22763499

0.066

0.057

0.247

0.009

0.909

0.078

0.056

0.165

0.054

0.852

IL6_1_CpG_3

chr7:22763600

0.036

0.049

0.462

0.004

0.909

0.048

0.049

0.331

0.037

0.878

IL6_1_CpG_4

chr7:22763717

-0.059

0.045

0.191

0.011

0.909

-0.061

0.046

0.181

0.013

0.852

IL6_1_CpG_5

chr7:22763745

-0.074

0.062

0.233

0.009

0.909

-0.071

0.063

0.261

0.013

0.874

IL6_1_CpG_6and7

chr7:22763750

-0.013

0.015

0.387

0.005

0.909

-0.013

0.015

0.377

0.008

0.878

chr7:22763752

IL6_1_CpG_8

chr7:22763784

-0.005

0.020

0.798

0.000

0.982

-0.002

0.020

0.912

0.015

0.993

IL6_1_CpG_9

chr7:22763808

-0.009

0.036

0.805

0.000

0.982

-0.018

0.035

0.612

0.043

0.955

IL6_1_CpG_10and11

chr7:22763840

-0.079

0.235

0.736

0.001

0.982

-0.083

0.237

0.728

0.006

0.966

chr7:22763846

IL6_2_CpG_1and2

chr7:22763911

-0.004

0.005

0.482

0.003

0.909

-0.004

0.005

0.434

0.026

0.878

chr7:22763914

IL6_2_CpG_3and4

chr7:22764029

-0.027

0.029

0.341

0.006

0.909

-0.029

0.029

0.326

0.012

0.878

chr7:22764031

IL10

IL10_1_CpG_1

chr1:206940522

0.021

0.013

0.113

0.016

0.909

0.022

0.013

0.104

0.018

0.852

IL10_1_CpG_2and3

chr1:206940451

-0.013

0.021

0.527

0.003

0.941

-0.011

0.021

0.591

0.008

0.949

chr1:206940447

IL10_1_CpG_4

chr1:206940364

-0.021

0.017

0.223

0.010

0.909

-0.020

0.017

0.245

0.014

0.852

IL10_1_CpG_5

chr1:206940327

-0.068

0.043

0.113

0.016

0.909

-0.066

0.043

0.126

0.018

0.852

IL10_1_CpG_6

chr1:206940311

0.195

0.117

0.098

0.018

0.909

0.204

0.118

0.086

0.027

0.852

IL10_2_CpG_1

chr1:206940215

-0.014

0.016

0.375

0.005

0.909

-0.017

0.016

0.267

0.035

0.878

IL10_2_CpG_2

chr1:206940208

-0.007

0.032

0.837

0.000

0.982

-0.007

0.032

0.835

0.000

0.966

IL10_2_CpG_3

chr1:206940167

-0.020

0.015

0.189

0.011

0.909

-0.019

0.015

0.199

0.014

0.852

IL10_2_CpG_4

chr1:206940003

0.021

0.042

0.611

0.002

0.982

0.033

0.041

0.426

0.071

0.878

IL10_2_CpG_5

chr1:206939984

0.026

0.021

0.224

0.010

0.909

0.031

0.021

0.135

0.066

0.852

IL10_2_CpG_6

chr1:206939954

0.029

0.028

0.302

0.007

0.909

0.036

0.028

0.191

0.069

0.852

IL10_2_CpG_7

chr1:206939896

0.031

0.041

0.448

0.004

0.909

0.041

0.040

0.302

0.074

0.878

IL10_2_CpG_9

chr1:206939813

0.026

0.037

0.478

0.003

0.909

0.036

0.036

0.320

0.063

0.878

MAOA

MAOA_1_CpG_1

chrX:43514917

-0.008

0.020

0.672

0.001

0.982

-0.005

0.020

0.801

0.021

0.966

chrX:43514948

-0.020

0.019

0.283

0.008

0.909

-0.016

0.019

0.394

0.039

0.878

MAOA_1_CpG_4

chrX:43514973

-0.011

0.021

0.591

0.002

0.982

-0.007

0.021

0.745

0.030

0.966

MAOA_1_CpG_5

chrX:43514995

-0.010

0.023

0.678

0.001

0.982

-0.006

0.023

0.790

0.014

0.966

MAOA_1_CpG_6

chrX:43515023

-0.007

0.025

0.769

0.001

0.982

-0.001

0.024

0.983

0.046

0.994

MAOA_1_CpG_7

chrX:43515066

-0.017

0.025

0.492

0.003

0.909

-0.011

0.025

0.645

0.036

0.963

MAOA_1_CpG_8

chrX:43515089

-0.030

0.028

0.288

0.007

0.909

-0.024

0.028

0.384

0.030

0.878

MAOA_2_CpG_2and3

chrX:43515327

-0.011

0.015

0.480

0.003

0.909

-0.009

0.015

0.566

0.022

0.932

chrX:43515330

MAOA_2_CpG_4and5

chrX:43515350

-0.012

0.010

0.237

0.009

0.909

-0.009

0.010

0.352

0.054

0.878

chrX:43515355

MAOA_2_CpG_6

chrX:43515378

-0.004

0.016

0.823

0.000

0.982

-0.002

0.017

0.901

0.007

0.993

MAOA_2_CpG_7to9

chrX:43515403

-0.004

0.013

0.730

0.001

0.982

-0.002

0.013

0.856

0.017

0.966

chrX:43515413

chrX:43515419

MAOA_2_CpG_10and11

chrX:43515440

0.004

0.009

0.678

0.001

0.982

0.005

0.009

0.566

0.022

0.932

chrX:43515445

MAOA_2_CpG_12and13

chrX:43515458

-0.029

0.015

0.048

0.025

0.909

-0.026

0.015

0.074

0.052

0.852

chrX:43515468

MAOA_2_CpG_18

chrX:43515545

-0.002

0.014

0.889

0.000

0.982

0.001

0.014

0.938

0.029

0.994

MAOA_2_CpG_22and23

chrX:43515617

0.001

0.016

0.959

0.000

0.982

0.002

0.017

0.915

0.003

0.993

chrX:43515619

MAOA_2_CpG_24

chrX:43515632

-0.047

0.062

0.448

0.004

0.909

-0.037

0.062

0.549

0.053

0.921

MAOA_2_CpG_26

chrX:43515641

0.001

0.015

0.936

0.000

0.982

0.003

0.015

0.843

0.010

0.966

MAOA_2_CpG_27

chrX:43515647

-0.049

0.052

0.348

0.006

0.909

-0.046

0.053

0.386

0.010

0.878

MAOA_3_CpG_1

chrX:43515676

-0.036

0.041

0.382

0.005

0.909

-0.030

0.041

0.462

0.014

0.878

MAOA_3_CpG_2

chrX:43515681

0.003

0.018

0.850

0.000

0.982

0.004

0.019

0.824

0.001

0.966

MAOA_3_CpG_3

chrX:43515763

-0.030

0.159

0.848

0.000

0.982

-0.041

0.160

0.796

0.007

0.966

MAOA_3_CpG_4

chrX:43515802

0.041

0.039

0.302

0.007

0.909

0.042

0.039

0.289

0.024

0.878

MAOA_3_CpG_5

chrX:43515937

0.004

0.067

0.951

0.000

0.982

-0.013

0.065

0.846

0.072

0.966

MAOA_3_CpG_6

chrX:43515991

-0.013

0.058

0.822

0.000

0.982

-0.027

0.057

0.629

0.056

0.959

NR3C1

NR3C1_1_CpG_3

chr5:142784324

0.004

0.009

0.607

0.002

0.982

0.004

0.009

0.615

0.002

0.955

NR3C1_1_CpG_4

chr5:142784343

-0.001

0.010

0.961

0.000

0.982

0.000

0.010

0.981

0.026

0.994

NR3C1_1_CpG_5

chr5:142784370

-0.001

0.008

0.914

0.000

0.982

0.000

0.008

0.994

0.011

0.994

NR3C1_1_CpG_6and7

chr5:142784381

-0.007

0.009

0.415

0.004

0.909

-0.007

0.009

0.429

0.007

0.878

chr5:142784383

NR3C1_1_CpG_8

chr5:142784395

-0.005

0.010

0.592

0.002

0.982

-0.007

0.010

0.498

0.017

0.893

NR3C1_1_CpG_9

chr5:142784413

0.030

0.013

0.021

0.034

0.807

0.029

0.013

0.022

0.065

0.705

NR3C1_1_CpG_10

chr5:142784436

0.001

0.006

0.848

0.000

0.982

0.000

0.006

0.963

0.015

0.994

NR3C1_1_CpG_11

chr5:142784446

0.005

0.005

0.280

0.008

0.909

0.005

0.005

0.302

0.009

0.878

NR3C1_1_CpG_12

chr5:142784463

0.029

0.038

0.445

0.004

0.909

0.027

0.038

0.478

0.006

0.878

NR3C1_1_CpG_13

chr5:142784523

-0.020

0.013

0.115

0.016

0.909

-0.022

0.013

0.086

0.031

0.852

NR3C1_1_CpG_14and15

chr5:142784586

-0.001

0.009

0.873

0.000

0.982

-0.002

0.009

0.859

0.015

0.966

chr5:142784593

NR3C1_2_CpG_19and20

chr5:142783096

-0.001

0.008

0.901

0.000

0.982

-0.001

0.008

0.879

0.018

0.982

chr5:142783102

NR3C1_2_CpG_22

chr5:142783113

-0.001

0.007

0.860

0.000

0.982

-0.002

0.007

0.810

0.019

0.966

NR3C1_2_CpG_23and24

chr5:142783121

-0.002

0.009

0.803

0.000

0.982

-0.003

0.009

0.739

0.005

0.966

chr5:142783129

NR3C1_2_CpG_27to29

chr5:142783162

-0.002

0.012

0.837

0.000

0.982

0.000

0.012

0.979

0.020

0.994

chr5:142783165

chr5:142783168

NR3C1_2_CpG_32and33

chr5:142783190

0.010

0.147

0.946

0.000

0.982

0.026

0.147

0.859

0.029

0.966

chr5:142783192

NR3C1_2_CpG_34and35

chr5:142783205

-0.015

0.008

0.075

0.020

0.909

-0.015

0.008

0.066

0.024

0.852

chr5:142783214

NR3C1_2_CpG_37

chr5:142783222

0.026

0.022

0.243

0.009

0.909

0.027

0.022

0.233

0.015

0.852

NR3C1_2_CpG_43to45

chr5:142783257

0.009

0.010

0.340

0.006

0.909

0.007

0.010

0.436

0.053

0.878

chr5:142783260

chr5:142783262

NR3C1_2_CpG_46

chr5:142783272

0.022

0.029

0.441

0.004

0.909

0.022

0.029

0.444

0.016

0.878

NR3C1_2_CpG_47and48

chr5:142783280

-0.009

0.009

0.326

0.006

0.909

-0.009

0.009

0.329

0.021

0.878

chr5:142783282

NR3C1_2_CpG_49to52

chr5:142783299

0.041

0.015

0.006

0.048

0.807

0.040

0.015

0.008

0.052

0.603

chr5:142783303

chr5:142783310

chr5:142783314

NR3C1_2_CpG_53to58

chr5:142783322

0.014

0.016

0.398

0.005

0.909

0.014

0.017

0.412

0.008

0.878

chr5:142783324

chr5:142783326

chr5:142783329

chr5:142783333

chr5:142783335

NR3C1_2_CpG_60

chr5:142783361

-0.005

0.005

0.349

0.006

0.909

-0.004

0.005

0.361

0.008

0.878

NR3C1_2_CpG_61to63

chr5:142783380

0.057

0.031

0.066

0.022

0.909

0.055

0.031

0.078

0.024

0.852

chr5:142783384

chr5:142783386

NR3C1_2_CpG_64to68

chr5:142783401

0.001

0.018

0.961

0.000

0.982

-0.001

0.018

0.961

0.006

0.994

chr5:142783408

chr5:142783410

chr5:142783412

chr5:142783419

NR3C1_2_CpG_69and70

chr5:142783427

-0.001

0.008

0.948

0.000

0.982

-0.001

0.008

0.911

0.028

0.993

chr5:142783433

NR3C1_2_CpG_71and72

chr5:142783436

-0.004

0.009

0.682

0.001

0.982

-0.003

0.009

0.736

0.012

0.966

chr5:142783439

NR3C1_3_CpG_8

chr5:142782723

-0.006

0.004

0.158

0.013

0.909

-0.006

0.004

0.125

0.030

0.852

NR3C1_3_CpG_10to13

chr5:142782703

-0.013

0.010

0.203

0.010

0.909

-0.012

0.011

0.244

0.016

0.852

chr5:142782696

chr5:142782693

chr5:142782691

NR3C1_3_CpG_14

chr5:142782664

0.006

0.005

0.232

0.009

0.909

0.006

0.005

0.236

0.018

0.852

NR3C1_3_CpG_15and16

chr5:142782633

-0.001

0.005

0.822

0.000

0.982

-0.001

0.005

0.859

0.005

0.966

chr5:142782629

NR3C1_3_CpG_17

chr5:142782626

0.005

0.008

0.527

0.003

0.941

0.006

0.008

0.462

0.016

0.878

NR3C1_3_CpG_19to21

chr5:142782609

-0.006

0.007

0.398

0.005

0.909

-0.006

0.007

0.434

0.011

0.878

chr5:142782607

chr5:142782605

OXTR

OXTR_1_CpG_1

chr3:8809307

-0.024

0.027

0.375

0.005

0.909

-0.025

0.027

0.363

0.036

0.878

OXTR_1_CpG_3and4

chr3:8809325

-0.032

0.025

0.194

0.011

0.909

-0.033

0.024

0.181

0.043

0.852

chr3:8809328

OXTR_1_CpG_5and6

chr3:8809340

-0.009

0.025

0.704

0.001

0.982

-0.012

0.024

0.632

0.052

0.959

chr3:8809342

OXTR_1_CpG_7to9

chr3:8809365

-0.007

0.024

0.775

0.001

0.982

-0.007

0.024

0.766

0.029

0.966

chr3:8809368

chr3:8809370

OXTR_1_CpG_11and12

chr3:8809395

-0.023

0.022

0.304

0.007

0.909

-0.023

0.022

0.302

0.052

0.878

chr3:8809400

OXTR_1_CpG_13to17

chr3:8809414

-0.004

0.022

0.841

0.000

0.982

-0.007

0.022

0.743

0.052

0.966

chr3:8809418

chr3:8809423

chr3:8809426

chr3:8809429

OXTR_1_CpG_20

chr3:8809443

-0.016

0.015

0.288

0.007

0.909

-0.016

0.015

0.273

0.050

0.878

OXTR_1_CpG_21

chr3:8809465

-0.036

0.026

0.170

0.012

0.909

-0.037

0.026

0.167

0.036

0.852

OXTR_1_CpG_23

chr3:8809537

-0.018

0.016

0.247

0.009

0.909

-0.019

0.015

0.225

0.072

0.852

OXTR_1_CpG_24and25

chr3:8809550

-0.002

0.009

0.853

0.000

0.982

-0.003

0.009

0.722

0.026

0.966

chr3:8809556

OXTR_2_CpG_1

chr3:8810889

-0.062

0.036

0.085

0.020

0.909

-0.062

0.090

0.021

0.852

OXTR_2_CpG_2

chr3:8810874

-0.014

0.021

0.490

0.003

0.909

-0.017

0.021

0.415

0.014

0.878

OXTR_2_CpG_3

chr3:8810862

-0.028

0.020

0.172

0.012

0.909

-0.029

0.020

0.152

0.017

0.852

OXTR_2_CpG_4

chr3:8810855

-0.007

0.037

0.848

0.000

0.982

-0.017

0.037

0.654

0.046

0.966

OXTR_2_CpG_5

chr3:8810832

0.016

0.035

0.641

0.001

0.982

0.012

0.035

0.726

0.016

0.966

OXTR_2_CpG_6and7

chr3:8810807

0.043

0.037

0.247

0.009

0.909

0.043

0.037

0.250

0.012

0.852

chr3:8810797

OXTR_2_CpG_8

chr3:8810774

-0.038

0.052

0.457

0.004

0.909

-0.038

0.052

0.466

0.004

0.878

OXTR_2_CpG_9

chr3:8810733

0.053

0.069

0.447

0.004

0.909

0.051

0.070

0.469

0.005

0.878

OXTR_2_CpG_10

chr3:8810708

-0.008

0.020

0.685

0.001

0.982

-0.006

0.020

0.749

0.039

0.966

OXTR_2_CpG_11

chr3:8810699

0.006

0.017

0.740

0.001

0.982

0.004

0.017

0.793

0.043

0.966

OXTR_2_CpG_12and13

chr3:8810681

-0.003

0.028

0.928

0.000

0.982

-0.006

0.029

0.834

0.009

0.966

chr3:8810679

OXTR_2_CpG_14

chr3:8810647

0.000

0.021

0.983

0.000

0.995

-0.001

0.021

0.949

0.001

0.994

SLC6A3

SLC6A3_1_CpG_1and2

chr5:1446585

0.007

0.025

0.777

0.001

0.982

0.006

0.026

0.822

0.003

0.966

chr5:1446583

SLC6A3_1_CpG_3

chr5:1446545

-0.014

0.024

0.549

0.002

0.961

-0.016

0.024

0.518

0.004

0.899

SLC6A3_1_CpG_4

chr5:1446537

0.079

0.031

0.012

0.040

0.807

0.080

0.032

0.012

0.041

0.603

SLC6A3_1_CpG_5

chr5:1446517

0.009

0.022

0.674

0.001

0.982

0.008

0.022

0.726

0.007

0.966

SLC6A3_1_CpG_7

chr5:1446498

-0.017

0.013

0.169

0.012

0.909

-0.019

0.013

0.124

0.030

0.852

SLC6A3_1_CpG_8to11

chr5:1446488

-0.022

0.010

0.031

0.030

0.909

-0.024

0.010

0.016

0.068

0.603

chr5:1446485

chr5:1446478

chr5:1446474

SLC6A3_1_CpG_12

chr5:1446462

0.016

0.022

0.476

0.003

0.909

0.011

0.022

0.611

0.035

0.955

SLC6A3_1_CpG_14and15

chr5:1446445

0.009

0.026

0.722

0.001

0.982

0.008

0.027

0.750

0.006

0.966

chr5:1446443

SLC6A3_1_CpG_16

chr5:1446430

-0.050

0.021

0.018

0.036

0.807

-0.053

0.021

0.015

0.043

0.603

SLC6A3_2_CpG_2to4

chr5:1446371

0.026

0.011

0.019

0.035

0.807

0.027

0.011

0.016

0.043

0.603

chr5:1446369

chr5:1446367

SLC6A3_2_CpG_5and6

chr5:1446348

0.003

0.014

0.818

0.000

0.982

0.003

0.014

0.820

0.011

0.966

chr5:1446344

SLC6A3_2_CpG_11

chr5:1446287

0.006

0.061

0.926

0.982

0.014

0.061

0.819

0.013

0.966

SLC6A3_2_CpG_12and13

chr5:1446268

0.000

0.017

0.995

0.000

0.995

0.002

0.017

0.889

0.016

0.987

chr5:1446263

SLC6A3_2_CpG_14

chr5:1446243

-0.037

0.033

0.275

0.008

0.909

-0.039

0.034

0.244

0.019

0.852

SLC6A3_2_CpG_16to18

chr5:1446232

-0.008

0.013

0.546

0.002

0.961

-0.009

0.013

0.506

0.006

0.893

chr5:1446223

chr5:1446217

SLC6A3_2_CpG_21

chr5:1446188

-0.003

0.021

0.900

0.000

0.982

-0.009

0.021

0.680

0.056

0.966

SLC6A3_2_CpG_22to24

chr5:1446165

0.004

0.006

0.573

0.002

0.982

0.003

0.006

0.638

0.008

0.960

chr5:1446161

chr5:1446156

SLC6A3_2_CpG_25and26

chr5:1446150

0.005

0.010

0.650

0.001

0.982

0.004

0.010

0.696

0.966

chr5:1446148

SLC6A3_2_CpG_28to30

chr5:1446121

0.006

0.011

0.630

0.002

0.982

0.004

0.012

0.718

0.019

0.966

chr5:1446119

chr5:1446113

SLC6A3_2_CpG_32and33

chr5:1446102

-0.005

0.013

0.705

0.001

0.982

-0.004

0.013

0.782

0.018

0.966

chr5:1446099

SLC6A3_2_CpG_34

chr5:1446092

0.019

0.014

0.155

0.013

0.909

0.021

0.014

0.122

0.034

0.852

SLC6A3_2_CpG_35to37

chr5:1446079

-0.001

0.010

0.885

0.000

0.982

-0.002

0.010

0.857

0.015

0.966

chr5:1446076

chr5:1446068

SLC6A3_2_CpG_39

chr5:1446050

0.019

0.014

0.166

0.012

0.909

0.018

0.014

0.192

0.016

0.852

SLC6A3_2_CpG_40and41

chr5:1446043

-0.015

0.016

0.328

0.006

0.909

-0.019

0.016

0.227

0.046

0.852

chr5:1446040

SLC6A3_2_CpG_42

chr5:1446026

-0.007

0.009

0.399

0.005

0.909

-0.008

0.009

0.383

0.014

0.878

SLC6A3_2_CpG_43and44

chr5:1446012

0.010

0.012

0.391

0.005

0.909

0.009

0.012

0.438

0.008

0.878

chr5:1446010

SLC6A3_2_CpG_45

chr5:1446001

-0.006

0.015

0.674

0.001

0.982

-0.007

0.015

0.614

0.006

0.955

SLC6A4

SLC6A4_1_CpG_1

chr17:28563424

-0.060

0.046

0.194

0.011

0.909

-0.060

0.046

0.193

0.016

0.852

SLC6A4_1_CpG_4

chr17:28563253

0.002

0.009

0.795

0.000

0.982

0.002

0.009

0.833

0.003

0.966

SLC6A4_1_CpG_7

chr17:28563185

0.000

0.012

0.988

0.000

0.995

0.000

0.012

0.976

0.014

0.994

SLC6A4_1_CpG_9

chr17:28563159

-0.012

0.012

0.346

0.006

0.909

-0.011

0.013

0.388

0.009

0.878

SLC6A4_1_CpG_17

chr17:28563054

-0.011

0.011

0.327

0.006

0.909

-0.013

0.011

0.233

0.051

0.852

SLC6A4_2_CpG_13and14

chr17:28562914

0.001

0.007

0.916

0.000

0.982

0.000

0.007

0.990

0.005

0.994

chr17:28562909

SLC6A4_2_CpG_15to17

chr17:28562904

-0.005

0.006

0.483

0.003

0.909

-0.006

0.006

0.391

0.020

0.878

chr17:28562902

chr17:28562888

SLC6A4_2_CpG_18

chr17:28562884

0.016

0.017

0.337

0.006

0.909

0.014

0.017

0.412

0.016

0.878

SLC6A4_2_CpG_19

chr17:28562869

0.001

0.005

0.899

0.000

0.982

0.000

0.005

0.944

0.009

0.994

SLC6A4_2_CpG_20and21

chr17:28562863

-0.005

0.004

0.247

0.009

0.909

-0.004

0.004

0.296

0.015

0.878

chr17:28562861

SLC6A4_2_CpG_22to25

chr17:28562855

-0.009

0.007

0.196

0.011

0.909

-0.010

0.007

0.190

0.032

0.852

chr17:28562853

chr17:28562849

chr17:28562847

SLC6A4_2_CpG_26

chr17:28562826

0.000

0.005

0.940

0.000

0.982

-0.001

0.005

0.827

0.078

0.966

SLC6A4_2_CpG_28and29

chr17:28562786

-0.010

0.005

0.034

0.029

0.909

-0.010

0.005

0.038

0.066

0.852

chr17:28562783

SLC6A4_3_CpG_1and2

chr17:28562751

-0.013

0.008

0.126

0.015

0.909

-0.013

0.008

0.110

0.020

0.852

chr17:28562749

SLC6A4_3_CpG_3to8

chr17:28562737

0.029

0.025

0.260

0.008

0.909

0.026

0.025

0.304

0.024

0.878

chr17:28562733

chr17:28562731

chr17:28562728

chr17:28562725

chr17:28562717

SLC6A4_3_CpG_9to12

chr17:28562706

-0.013

0.014

0.369

0.005

0.909

-0.017

0.014

0.216

0.088

0.852

chr17:28562703

chr17:28562700

chr17:28562691

SLC6A4_3_CpG_13and14

chr17:28562685

0.003

0.011

0.782

0.001

0.982

0.000

0.010

0.977

0.102

0.994

chr17:28562683

SLC6A4_3_CpG_15

chr17:28562672

-0.004

0.012

0.755

0.001

0.982

-0.008

0.011

0.485

0.138

0.883

SLC6A4_3_CpG_16

chr17:28562659

-0.005

0.004

0.267

0.008

0.909

-0.005

0.004

0.218

0.029

0.852

SLC6A4_3_CpG_22

chr17:28562596

-0.033

0.023

0.151

0.013

0.909

-0.035

0.023

0.125

0.022

0.852

SLC6A4_3_CpG_23and24

chr17:28562572

0.001

0.014

0.952

0.000

0.982

0.003

0.014

0.853

0.010

0.966

chr17:28562567

SLC6A4_3_CpG_27and28

chr17:28562536

-0.002

0.016

0.909

0.000

0.982

-0.009

0.015

0.538

0.156

0.917

chr17:28562529

SLC6A4_3_CpG_29

chr17:28562521

-0.004

0.050

0.940

0.000

0.982

-0.009

0.051

0.855

0.012

0.966

SLC6A4_3_CpG_30

chr17:28562507

-0.042

0.050

0.407

0.004

0.909

-0.048

0.051

0.346

0.016

0.878

SLC6A4_3_CpG_31to33

chr17:28562499

-0.018

0.014

0.200

0.011

0.909

-0.020

0.014

0.138

0.052

0.852

chr17:28562492

chr17:28562489

SLC6A4_3_CpG_34

chr17:28562474

0.012

0.018

0.495

0.003

0.909

0.010

0.018

0.585

0.025

0.946

SLC6A4_3_CpG_35

chr17:28562465

-0.043

0.038

0.264

0.008

0.909

-0.045

0.039

0.247

0.011

0.852

SLC6A4_3_CpG_36

-0.029

0.015

0.046

0.026

0.909

-0.032

0.015

0.027

0.060

0.724

SLC6A4_3_CpG_38

chr17:28562412

-0.022

0.013

0.098

0.018

0.909

-0.024

0.013

0.070

0.041

0.852

SLC6A4_3_CpG_39

chr17:28562401

0.006

0.025

0.798

0.000

0.982

0.002

0.025

0.941

0.021

0.994

SLC6A4_3_CpG_40and41

chr17:28562392

-0.042

0.028

0.137

0.014

0.909

-0.048

0.028

0.080

0.056

0.852

chr17:28562388

 

 

 

 

 

 

 

 

 

 

Note. Based on GRCh37/hg19 coordinates.

S3 Table. Associations between depressive symptoms and DNA methylation.

CpG Name

Position

DNA Methylation

Unadjusted Models

Adjusted Models

 

 

B

SE

p

R2

FDR

B

SE

p

R2

FDR

COMT

COMT_1_CpG_3

chr22:19950055

-0.086

0.080

0.284

0.007

0.759

-0.057

0.082

0.485

0.040

0.759

COMT_1_CpG_4

chr22:19950064

-0.116

0.096

0.232

0.009

0.750

-0.059

0.096

0.540

0.079

0.750

COMT_1_CpG_5

chr22:19950158

-0.168

0.100

0.095

0.018

0.680

-0.108

0.100

0.282

0.079

0.680

COMT_1_CpG_7

chr22:19950222

-0.224

0.156

0.154

0.013

0.688

-0.190

0.159

0.235

0.046

0.688

COMT_1_CpG_8

chr22:19950236

0.059

0.190

0.755

0.001

0.864

0.098

0.196

0.616

0.009

0.864

COMT_1_CpG_9

chr22:19950250

-0.141

0.105

0.179

0.012

0.698

-0.078

0.105

0.461

0.070

0.698

COMT_1_CpG_10

chr22:19950257

-0.125

0.116

0.284

0.007

0.759

-0.062

0.116

0.592

0.072

0.759

COMT_1_CpG_12

chr22:19950272

-0.156

0.104

0.136

0.014

0.688

-0.094

0.104

0.368

0.079

0.688

COMT_1_CpG_13

chr22:19950299

-0.142

0.103

0.171

0.012

0.695

-0.070

0.103

0.497

0.081

0.695

COMT_1_CpG_14and15

chr22:19950323

-0.152

0.103

0.143

0.014

0.688

-0.093

0.103

0.369

0.071

0.688

chr22:19950329

COMT_1_CpG_16

chr22:19950348

-0.147

0.101

0.146

0.014

0.688

-0.084

0.101

0.403

0.083

0.688

COMT_2_CpG_3and4

chr22:19929115

-0.027

0.049

0.581

0.002

0.864

-0.013

0.050

0.791

0.011

0.864

chr22:19929117

COMT_2_CpG_5

chr22:19929131

0.004

0.017

0.830

0.000

0.916

0.002

0.017

0.889

0.007

0.916

COMT_2_CpG_6to9

chr22:19929149

-0.002

0.006

0.720

0.001

0.864

-0.002

0.006

0.737

0.003

0.864

chr22:19929152

chr22:19929154

chr22:19929156

COMT_2_CpG_11to14

chr22:19929179

-0.005

0.016

0.743

0.001

0.864

-0.006

0.017

0.733

0.002

0.864

chr22:19929183

chr22:19929185

chr22:19929187

COMT_2_CpG_15and16

chr22:19929198

-0.004

0.014

0.752

0.001

0.864

-0.014

0.014

0.333

0.051

0.864

chr22:19929200

COMT_2_CpG_17and18

chr22:19929206

-0.006

0.010

0.567

0.002

0.864

-0.006

0.010

0.578

0.009

0.864

chr22:19929211

COMT_2_CpG_25and26

chr22:19929255

-0.016

0.017

0.345

0.006

0.822

-0.021

0.017

0.214

0.024

0.822

chr22:19929259

COMT_2_CpG_27to29

chr22:19929264

0.022

0.018

0.217

0.010

0.750

0.018

0.018

0.331

0.018

0.750

chr22:19929271

chr22:19929275

COMT_2_CpG_31

chr22:19929287

0.008

0.009

0.399

0.005

0.864

0.008

0.009

0.372

0.007

0.864

COMT_2_CpG_32

chr22:19929302

-0.005

0.008

0.566

0.002

0.864

-0.004

0.008

0.655

0.004

0.864

COMT_2_CpG_33

chr22:19929307

-0.024

0.058

0.677

0.001

0.864

-0.045

0.059

0.450

0.030

0.864

COMT_2_CpG_34

chr22:19929313

0.024

0.070

0.731

0.001

0.864

0.013

0.073

0.861

0.004

0.864

COMT_2_CpG_35

chr22:19929322

-0.003

0.020

0.896

0.000

0.935

-0.004

0.020

0.857

0.001

0.935

COMT_2_CpG_36and37

chr22:19929328

0.004

0.010

0.681

0.001

0.864

0.002

0.010

0.873

0.031

0.864

chr22:19929331

FKBP5

FKBP5_1_CpG_1

chr6:35558387

0.037

0.060

0.536

0.002

0.864

0.015

0.061

0.806

0.018

0.864

FKBP5_1_CpG_2

chr6:35558439

-0.020

0.075

0.791

0.000

0.889

-0.064

0.076

0.400

0.049

0.889

FKBP5_1_CpG_3

chr6:35558489

-0.044

0.050

0.374

0.005

0.840

-0.036

0.051

0.482

0.010

0.840

FKBP5_1_CpG_4

chr6:35558514

-0.039

0.048

0.414

0.004

0.864

-0.019

0.048

0.700

0.037

0.864

FKBP5_1_CpG_5

chr6:35558567

0.249

0.128

0.054

0.026

0.602

0.237

0.132

0.075

0.035

0.602

IL6

IL6_1_CpG_1

chr7:22763499

0.102

0.073

0.162

0.013

0.688

0.072

0.074

0.330

0.047

0.688

IL6_1_CpG_3

chr7:22763600

0.068

0.063

0.286

0.007

0.759

0.055

0.064

0.395

0.036

0.759

IL6_1_CpG_4

chr7:22763717

0.018

0.058

0.753

0.001

0.864

0.018

0.060

0.768

0.001

0.864

IL6_1_CpG_5

chr7:22763745

-0.057

0.080

0.475

0.003

0.864

-0.055

0.083

0.510

0.007

0.864

IL6_1_CpG_6and7

chr7:22763750

-0.009

0.019

0.653

0.001

0.864

-0.006

0.020

0.766

0.004

0.864

chr7:22763752

IL6_1_CpG_8

chr7:22763784

0.003

0.026

0.905

0.000

0.940

-0.002

0.027

0.929

0.015

0.940

IL6_1_CpG_9

chr7:22763808

0.024

0.046

0.603

0.002

0.864

0.040

0.046

0.386

0.046

0.864

IL6_1_CpG_10and11

chr7:22763840

-0.229

0.301

0.448

0.004

0.864

-0.300

0.311

0.336

0.011

0.864

chr7:22763846

IL6_2_CpG_1and2

chr7:22763911

0.007

0.007

0.330

0.006

0.822

0.004

0.007

0.526

0.025

0.822

chr7:22763914

IL6_2_CpG_3and4

chr7:22764029

-0.082

0.037

0.028

0.033

0.597

-0.093

0.038

0.015

0.046

0.597

chr7:22764031

IL10

IL10_1_CpG_1

chr1:206940522

0.019

0.017

0.269

0.008

0.759

0.019

0.018

0.272

0.009

0.759

IL10_1_CpG_2and3

chr1:206940451

-0.032

0.027

0.237

0.009

0.753

-0.036

0.028

0.198

0.017

0.753

chr1:206940447

IL10_1_CpG_4

chr1:206940364

-0.004

0.022

0.847

0.000

0.918

-0.002

0.022

0.946

0.005

0.918

IL10_1_CpG_5

chr1:206940327

-0.045

0.055

0.414

0.004

0.864

-0.044

0.057

0.446

0.007

0.864

IL10_1_CpG_6

chr1:206940311

0.211

0.151

0.163

0.013

0.688

0.185

0.156

0.237

0.017

0.688

IL10_2_CpG_1

chr1:206940215

-0.030

0.020

0.137

0.014

0.688

-0.028

0.021

0.173

0.039

0.688

IL10_2_CpG_2

chr1:206940208

-0.026

0.041

0.530

0.003

0.864

-0.027

0.042

0.528

0.003

0.864

IL10_2_CpG_3

chr1:206940167

0.011

0.019

0.574

0.002

0.864

0.008

0.020

0.680

0.004

0.864

IL10_2_CpG_4

chr1:206940003

0.110

0.053

0.040

0.027

0.597

0.084

0.054

0.119

0.082

0.597

IL10_2_CpG_5

chr1:206939984

0.033

0.027

0.227

0.009

0.750

0.021

0.027

0.444

0.055

0.750

IL10_2_CpG_6

chr1:206939954

0.068

0.036

0.060

0.023

0.636

0.051

0.036

0.160

0.070

0.636

IL10_2_CpG_7

chr1:206939896

0.085

0.052

0.103

0.017

0.680

0.056

0.052

0.289

0.075

0.680

IL10_2_CpG_9

chr1:206939813

0.072

0.047

0.126

0.015

0.688

0.052

0.047

0.269

0.065

0.688

MAOA

MAOA_1_CpG_1

chrX:43514917

-0.003

0.026

0.910

0.000

0.940

-0.008

0.026

0.750

0.021

0.940

MAOA_1_CpG_3

chrX:43514948

-0.014

0.024

0.573

0.002

0.864

-0.018

0.025

0.464

0.038

0.864

MAOA_1_CpG_4

chrX:43514973

-0.014

0.027

0.619

0.002

0.864

-0.015

0.028

0.596

0.031

0.864

MAOA_1_CpG_5

chrX:43514995

-0.005

0.030

0.881

0.000

0.929

-0.006

0.031

0.858

0.014

0.929

MAOA_1_CpG_6

chrX:43515023

-0.006

0.032

0.856

0.000

0.918

-0.011

0.033

0.731

0.047

0.918

MAOA_1_CpG_7

chrX:43515066

0.003

0.032

0.918

0.000

0.943

-0.002

0.033

0.955

0.034

0.943

MAOA_1_CpG_8

chrX:43515089

-0.022

0.036

0.540

0.002

0.864

-0.025

0.037

0.502

0.028

0.864

MAOA_2_CpG_2and3

chrX:43515327

-0.017

0.019

0.386

0.005

0.848

-0.024

0.020

0.224

0.029

0.848

chrX:43515330

MAOA_2_CpG_4and5

chrX:43515350

0.012

0.013

0.346

0.006

0.822

0.009

0.013

0.472

0.052

0.822

chrX:43515355

MAOA_2_CpG_6

chrX:43515378

-0.010

0.021

0.642

0.001

0.864

-0.014

0.022

0.536

0.010

0.864

MAOA_2_CpG_7to9

chrX:43515403

-0.015

0.016

0.364

0.005

0.840

-0.018

0.017

0.296

0.024

0.840

chrX:43515413

chrX:43515419

MAOA_2_CpG_10and11

chrX:43515440

-0.004

0.012

0.759

0.001

0.864

-0.002

0.012

0.869

0.020

chrX:43515445

MAOA_2_CpG_12and13

chrX:43515458

-0.013

0.019

0.492

0.003

0.864

-0.020

0.019

0.315

0.038

0.864

chrX:43515468

MAOA_2_CpG_18

chrX:43515545

-0.006

0.018

0.760

0.001

0.864

-0.007

0.018

0.717

0.030

0.864

MAOA_2_CpG_22and23

chrX:43515617

-0.025

0.021

0.231

0.009

0.750

-0.025

0.022

0.254

0.012

0.750

chrX:43515619

MAOA_2_CpG_24

chrX:43515632

-0.012

0.081

0.883

0.000

0.929

-0.063

0.082

0.441

0.055

0.929

MAOA_2_CpG_26

chrX:43515641

0.010

0.020

0.618

0.002

0.864

0.011

0.020

0.572

0.012

0.864

MAOA_2_CpG_27

chrX:43515647

-0.110

0.068

0.107

0.018

0.680

-0.108

0.070

0.128

0.022

0.680

MAOA_3_CpG_1

chrX:43515676

0.099

0.053

0.065

0.024

0.649

0.102

0.055

0.063

0.035

0.649

MAOA_3_CpG_2

chrX:43515681

0.005

0.024

0.848

0.000

0.918

0.005

0.024

0.843

0.001

0.918

MAOA_3_CpG_3

chrX:43515763

-0.104

0.202

0.607

0.002

0.864

-0.077

0.210

0.715

0.007

0.864

MAOA_3_CpG_4

chrX:43515802

0.003

0.051

0.949

0.000

0.969

0.022

0.052

0.670

0.018

0.969

MAOA_3_CpG_5

chrX:43515937

-0.104

0.086

0.228

0.009

0.750

-0.052

0.086

0.544

0.074

0.750

MAOA_3_CpG_6

chrX:43515991

-0.071

0.074

0.340

0.006

0.822

-0.036

0.074

0.627

0.056

0.822

NR3C1

NR3C1_1_CpG_3

chr5:142784324

-0.008

0.011

0.486

0.003

0.864

-0.008

0.011

0.485

0.003

0.864

NR3C1_1_CpG_4

chr5:142784343

0.026

0.013

0.051

0.025

0.602

0.021

0.013

0.123

0.041

0.602

NR3C1_1_CpG_5

chr5:142784370

0.004

0.010

0.689

0.001

0.864

0.006

0.011

0.572

0.013

0.864

NR3C1_1_CpG_6and7

chr5:142784381

0.001

0.011

0.956

0.000

0.971

0.002

0.011

0.860

0.003

0.971

chr5:142784383

NR3C1_1_CpG_8

chr5:142784395

-0.007

0.013

0.585

0.002

0.864

-0.008

0.013

0.519

0.017

0.864

NR3C1_1_CpG_9

chr5:142784413

-0.006

0.017

0.706

0.001

0.864

0.002

0.017

0.884

0.033

0.864

NR3C1_1_CpG_10

chr5:142784436

0.000

0.008

0.980

0.000

0.988

-0.001

0.008

0.923

0.016

0.988

NR3C1_1_CpG_11

chr5:142784446

0.003

0.636

0.001

0.864

0.003

0.007

0.648

0.003

0.864

NR3C1_1_CpG_12

chr5:142784463

-0.022

0.048

0.657

0.001

0.864

-0.017

0.050

0.727

0.003

0.864

NR3C1_1_CpG_13

chr5:142784523

-0.024

0.017

0.142

0.014

0.688

-0.027

0.017

0.120

0.027

0.688

NR3C1_1_CpG_14and15

chr5:142784586

-0.020

0.011

0.084

0.019

0.680

-0.016

0.012

0.158

0.028

0.680

chr5:142784593

NR3C1_2_CpG_19and20

chr5:142783096

-0.012

0.011

0.258

0.008

0.759

-0.009

0.011

0.440

0.022

0.759

chr5:142783102

NR3C1_2_CpG_22

chr5:142783113

0.003

0.009

0.741

0.001

0.864

0.000

0.010

0.999

0.019

0.864

NR3C1_2_CpG_23and24

chr5:142783121

-0.006

0.012

0.608

0.002

0.864

-0.006

0.012

0.646

0.006

0.864

chr5:142783129

NR3C1_2_CpG_27to29

chr5:142783162

-0.004

0.015

0.783

0.000

0.885

-0.005

0.015

0.755

0.021

0.885

chr5:142783165

chr5:142783168

NR3C1_2_CpG_32and33

chr5:142783190

-0.028

0.194

0.885

0.000

0.929

-0.094

0.195

0.632

0.031

0.929

chr5:142783192

NR3C1_2_CpG_34and35

chr5:142783205

-0.008

0.011

0.481

0.003

0.864

-0.008

0.011

0.498

0.005

0.864

chr5:142783214

NR3C1_2_CpG_37

chr5:142783222

-0.001

0.029

0.983

0.000

0.988

-0.007

0.029

0.803

0.006

0.988

NR3C1_2_CpG_43to45

chr5:142783257

0.012

0.012

0.348

0.006

0.822

0.019

0.012

0.119

0.065

0.822

chr5:142783260

chr5:142783262

NR3C1_2_CpG_46

chr5:142783272

-0.020

0.037

0.579

0.002

0.864

-0.034

0.038

0.374

0.018

0.864

NR3C1_2_CpG_47and48

chr5:142783280

0.009

0.011

0.421

0.004

0.864

0.005

0.012

0.639

0.016

0.864

chr5:142783282

NR3C1_2_CpG_49to52

chr5:142783299

0.043

0.019

0.027

0.031

0.597

0.048

0.020

0.016

0.044

0.597

chr5:142783303

chr5:142783310

chr5:142783314

NR3C1_2_CpG_53to58

chr5:142783322

0.000

0.021

0.993

0.000

0.993

0.004

0.022

0.852

0.004

0.993

chr5:142783324

chr5:142783326

chr5:142783329

chr5:142783333

chr5:142783335

NR3C1_2_CpG_60

chr5:142783361

-0.009

0.006

0.130

0.015

0.688

-0.009

0.006

0.157

0.016

0.688

NR3C1_2_CpG_61to63

chr5:142783380

0.099

0.039

0.013

0.039

0.597

0.107

0.041

0.009

0.048

0.597

chr5:142783384

chr5:142783386

NR3C1_2_CpG_64to68

chr5:142783401

0.009

0.023

0.683

0.001

0.864

0.010

0.024

0.659

0.007

0.864

chr5:142783408

chr5:142783410

chr5:142783412

chr5:142783419

NR3C1_2_CpG_69and70

chr5:142783427

0.004

0.011

0.711

0.001

0.864

-0.001

0.011

0.943

0.028

0.864

chr5:142783433

NR3C1_2_CpG_71and72

chr5:142783436

-0.011

0.011

0.316

0.007

0.806

-0.015

0.012

0.184

0.023

0.806

chr5:142783439

NR3C1_3_CpG_8

chr5:142782723

0.002

0.005

0.640

0.001

0.864

0.002

0.005

0.766

0.015

0.864

NR3C1_3_CpG_10to13

chr5:142782703

-0.005

0.013

0.733

0.001

0.864

-0.006

0.014

0.664

0.009

0.864

chr5:142782696

chr5:142782693

chr5:142782691

NR3C1_3_CpG_14

chr5:142782664

-0.010

0.006

0.102

0.017

0.680

-0.009

0.006

0.164

0.022

0.680

NR3C1_3_CpG_15and16

chr5:142782633

-0.005

0.007

0.435

0.004

0.864

-0.004

0.007

0.513

0.008

0.864

chr5:142782629

NR3C1_3_CpG_17

chr5:142782626

0.005

0.010

0.663

0.001

0.864

0.002

0.011

0.861

0.012

0.864

NR3C1_3_CpG_19to21

chr5:142782609

-0.008

0.010

0.420

0.004

0.864

-0.010

0.010

0.291

0.015

0.864

chr5:142782607

chr5:142782605

OXTR

OXTR_1_CpG_1

chr3:8809307

-0.041

0.035

0.246

0.009

0.759

-0.024

0.036

0.493

0.034

0.759

OXTR_1_CpG_3and4

chr3:8809325

-0.036

0.032

0.262

0.008

0.759

-0.020

0.032

0.526

0.034

0.759

chr3:8809328

OXTR_1_CpG_5and6

chr3:8809340

-0.044

0.031

0.164

0.013

0.688

-0.025

0.032

0.433

0.054

0.688

chr3:8809342

OXTR_1_CpG_7to9

chr3:8809365

-0.030

0.031

0.337

0.006

0.822

-0.016

0.032

0.616

0.030

0.822

chr3:8809368

chr3:8809370

OXTR_1_CpG_11and12

chr3:8809395

-0.026

0.029

0.366

0.005

0.840

-0.009

0.029

0.744

0.046

0.840

chr3:8809400

OXTR_1_CpG_13to17

chr3:8809414

-0.011

0.028

0.689

0.001

0.864

0.007

0.029

0.807

0.052

0.864

chr3:8809418

chr3:8809423

chr3:8809426

chr3:8809429

OXTR_1_CpG_20

chr3:8809443

-0.019

0.019

0.310

0.007

0.800

-0.009

0.019

0.653

0.044

0.800

OXTR_1_CpG_21

chr3:8809465

-0.011

0.034

0.743

0.001

0.864

0.004

0.035

0.918

0.024

0.864

OXTR_1_CpG_23

chr3:8809537

-0.014

0.020

0.499

0.003

0.864

0.001

0.020

0.968

0.063

0.864

OXTR_1_CpG_24and25

chr3:8809550

-0.005

0.011

0.683

0.001

0.864

-0.001

0.011

0.931

0.025

0.864

chr3:8809556

OXTR_2_CpG_1

chr3:8810889

-0.066

0.047

0.158

0.014

0.688

-0.074

0.048

0.125

0.018

0.688

OXTR_2_CpG_2

chr3:8810874

-0.037

0.027

0.166

0.012

0.688

-0.035

0.027

0.203

0.021

0.688

OXTR_2_CpG_3

chr3:8810862

-0.046

0.026

0.075

0.020

0.680

-0.050

0.027

0.063

0.026

0.680

OXTR_2_CpG_4

chr3:8810855

0.069

0.048

0.147

0.014

0.688

0.072

0.048

0.135

0.059

0.688

OXTR_2_CpG_5

chr3:8810832

0.015

0.045

0.731

0.001

0.864

0.030

0.046

0.516

0.018

0.864

OXTR_2_CpG_6and7

chr3:8810807

0.054

0.047

0.257

0.008

0.759

0.066

0.049

0.179

0.016

0.759

chr3:8810797

OXTR_2_CpG_8

chr3:8810774

0.026

0.066

0.701

0.001

0.864

0.029

0.069

0.674

0.001

0.864

OXTR_2_CpG_9

chr3:8810733

0.049

0.088

0.577

0.002

0.864

0.050

0.091

0.582

0.003

0.864

OXTR_2_CpG_10

chr3:8810708

-0.034

0.025

0.178

0.012

0.698

-0.024

0.026

0.364

0.044

0.698

OXTR_2_CpG_11

chr3:8810699

-0.046

0.021

0.032

0.029

0.597

-0.035

0.022

0.107

0.058

0.597

OXTR_2_CpG_12and13

chr3:8810681

-0.059

0.036

0.102

0.017

0.680

-0.059

0.037

0.118

0.025

0.680

chr3:8810679

OXTR_2_CpG_14

chr3:8810647

-0.035

0.027

0.192

0.011

0.718

-0.035

0.027

0.205

0.012

0.718

SLC6A3

SLC6A3_1_CpG_1and2

chr5:1446585

-0.039

0.032

0.229

0.009

0.750

-0.039

0.034

0.248

0.011

0.750

chr5:1446583

SLC6A3_1_CpG_3

chr5:1446545

0.060

0.031

0.051

0.024

0.602

0.063

0.032

0.046

0.027

0.602

SLC6A3_1_CpG_4

chr5:1446537

-0.015

0.041

0.713

0.001

0.864

-0.012

0.042

0.773

0.001

0.864

SLC6A3_1_CpG_5

chr5:1446517

-0.018

0.028

0.535

0.003

0.864

-0.013

0.029

0.650

0.007

0.864

SLC6A3_1_CpG_7

chr5:1446498

-0.033

0.016

0.041

0.027

0.597

-0.035

0.016

0.033

0.044

0.597

SLC6A3_1_CpG_8to11

chr5:1446488

-0.009

0.013

0.501

0.003

0.864

-0.010

0.013

0.464

0.035

0.864

chr5:1446485

chr5:1446478

chr5:1446474

SLC6A3_1_CpG_12

chr5:1446462

-0.061

0.029

0.035

0.028

0.597

-0.054

0.029

0.064

0.055

0.597

SLC6A3_1_CpG_14and15

chr5:1446445

-0.013

0.034

0.713

0.001

0.864

-0.020

0.035

0.576

0.008

0.864

chr5:1446443

SLC6A3_1_CpG_16

chr5:1446430

-0.065

0.027

0.018

0.036

0.597

-0.064

0.028

0.023

0.038

0.597

SLC6A3_2_CpG_2to4

chr5:1446371

0.006

0.015

0.681

0.001

0.864

0.008

0.015

0.580

0.008

0.864

chr5:1446367

SLC6A3_2_CpG_5and6

chr5:1446348

-0.026

0.018

0.137

0.014

0.688

-0.022

0.018

0.219

0.020

0.688

chr5:1446344

SLC6A3_2_CpG_11

chr5:1446287

0.128

0.077

0.099

0.018

0.680

0.123

0.080

0.125

0.027

0.680

SLC6A3_2_CpG_12and13

chr5:1446268

0.007

0.022

0.759

0.001

0.864

0.001

0.022

0.956

0.015

0.864

chr5:1446263

SLC6A3_2_CpG_14

chr5:1446243

-0.027

0.042

0.524

0.003

0.864

-0.038

0.044

0.380

0.015

0.864

SLC6A3_2_CpG_16to18

chr5:1446232

-0.011

0.017

0.511

0.003

0.864

-0.010

0.017

0.577

0.005

0.864

chr5:1446223

chr5:1446217

SLC6A3_2_CpG_21

chr5:1446188

0.007

0.027

0.810

0.000

0.899

0.018

0.027

0.512

0.058

0.899

SLC6A3_2_CpG_22to24

chr5:1446165

-0.004

0.008

0.598

0.002

0.864

-0.003

0.008

0.682

0.008

0.864

chr5:1446161

chr5:1446156

SLC6A3_2_CpG_25and26

chr5:1446150

0.007

0.013

0.576

0.002

0.864

0.013

0.013

0.353

0.021

0.864

chr5:1446148

SLC6A3_2_CpG_28to30

chr5:1446121

-0.003

0.015

0.865

0.000

0.923

0.002

0.015

0.882

0.018

0.923

chr5:1446119

chr5:1446113

SLC6A3_2_CpG_32and33

chr5:1446102

0.018

0.016

0.264

0.008

0.759

0.024

0.017

0.157

0.031

0.759

chr5:1446099

SLC6A3_2_CpG_34

chr5:1446092

0.022

0.018

0.213

0.010

0.750

0.028

0.018

0.126

0.033

0.750

SLC6A3_2_CpG_35to37

chr5:1446079

-0.007

0.013

0.569

0.002

0.864

-0.003

0.013

0.824

0.015

0.864

chr5:1446076

chr5:1446068

SLC6A3_2_CpG_39

chr5:1446050

0.025

0.018

0.151

0.013

0.688

0.029

0.018

0.117

0.021

0.688

SLC6A3_2_CpG_40and41

chr5:1446043

-0.023

0.020

0.262

0.008

0.759

-0.016

0.020

0.440

0.040

0.759

chr5:1446040

SLC6A3_2_CpG_42

chr5:1446026

-0.018

0.011

0.104

0.017

0.680

-0.016

0.011

0.168

0.022

0.680

SLC6A3_2_CpG_43and44

chr5:1446012

0.004

0.015

0.800

0.000

0.893

0.005

0.016

0.773

0.005

0.893

chr5:1446010

SLC6A3_2_CpG_45

chr5:1446001

0.033

0.019

0.074

0.021

0.680

0.037

0.019

0.055

0.028

0.680

SLC6A4

SLC6A4_1_CpG_1

chr17:28563424

0.021

0.059

0.720

0.001

0.864

0.010

0.061

0.875

0.005

0.864

SLC6A4_1_CpG_4

chr17:28563253

-0.012

0.011

0.276

0.008

0.759

-0.012

0.012

0.322

0.009

0.759

SLC6A4_1_CpG_7

chr17:28563185

0.006

0.016

0.703

0.001

0.864

0.012

0.016

0.478

0.017

0.864

SLC6A4_1_CpG_9

chr17:28563159

-0.012

0.016

0.454

0.004

0.864

-0.013

0.016

0.414

0.008

0.864

SLC6A4_1_CpG_17

chr17:28563054

-0.007

0.014

0.614

0.002

0.864

-0.013

0.014

0.355

0.047

0.864

SLC6A4_2_CpG_13and14

chr17:28562914

-0.005

0.009

0.545

0.002

0.864

-0.006

0.009

0.531

0.008

0.864

chr17:28562909

SLC6A4_2_CpG_15to17

chr17:28562904

-0.005

0.008

0.508

0.003

0.864

-0.004

0.008

0.617

0.017

0.864

chr17:28562902

chr17:28562888

SLC6A4_2_CpG_18

chr17:28562884

-0.012

0.022

0.573

0.002

0.864

-0.012

0.022

0.594

0.014

0.864

SLC6A4_2_CpG_19

chr17:28562869

0.007

0.007

0.304

0.007

0.795

0.006

0.007

0.407

0.013

0.795

SLC6A4_2_CpG_20and21

chr17:28562863

0.003

0.005

0.512

0.003

0.864

0.004

0.005

0.498

0.011

0.864

chr17:28562861

SLC6A4_2_CpG_22to25

chr17:28562855

-0.007

0.009

0.452

0.004

0.864

-0.003

0.010

0.726

0.022

0.864

chr17:28562853

chr17:28562849

chr17:28562847

SLC6A4_2_CpG_26

chr17:28562826

-0.014

0.006

0.033

0.029

0.597

-0.009

0.006

0.154

0.090

0.597

SLC6A4_2_CpG_28and29

chr17:28562786

-0.013

0.006

0.024

0.033

0.597

-0.011

0.006

0.069

0.060

0.597

chr17:28562783

SLC6A4_3_CpG_1and2

chr17:28562751

-0.021

0.010

0.048

0.025

0.602

-0.022

0.011

0.039

0.031

0.602

chr17:28562749

SLC6A4_3_CpG_3to8

chr17:28562737

-0.006

0.033

0.852

0.000

0.918

-0.016

0.034

0.629

0.019

0.918

chr17:28562733

chr17:28562731

chr17:28562728

chr17:28562725

chr17:28562717

SLC6A4_3_CpG_9to12

chr17:28562706

-0.050

0.018

0.005

0.050

0.597

-0.042

0.018

0.020

0.111

0.597

chr17:28562703

chr17:28562700

chr17:28562691

SLC6A4_3_CpG_13and14

chr17:28562685

-0.005

0.014

0.689

0.001

0.864

0.005

0.013

0.726

0.103

0.864

chr17:28562683

SLC6A4_3_CpG_15

chr17:28562672

-0.019

0.015

0.214

0.010

0.750

-0.006

0.015

0.685

0.136

0.750

SLC6A4_3_CpG_16

chr17:28562659

-0.003

0.005

0.531

0.003

0.864

-0.002

0.006

0.778

0.020

0.864

SLC6A4_3_CpG_22

chr17:28562596

-0.066

0.029

0.022

0.034

0.597

-0.065

0.030

0.030

0.038

0.597

SLC6A4_3_CpG_23and24

chr17:28562572

0.004

0.018

0.836

0.000

0.918

0.005

0.019

0.810

0.010

0.918

chr17:28562567

SLC6A4_3_CpG_27and28

chr17:28562536

-0.035

0.020

0.083

0.020

0.680

-0.023

0.019

0.230

0.162

0.680

chr17:28562529

SLC6A4_3_CpG_29

chr17:28562521

-0.070

0.064

0.278

0.008

0.759

-0.057

0.067

0.396

0.017

0.759

SLC6A4_3_CpG_30

chr17:28562507

-0.058

0.065

0.373

0.005

0.840

-0.069

0.066

0.302

0.018

0.840

SLC6A4_3_CpG_31to33

chr17:28562499

-0.041

0.018

0.021

0.034

0.597

-0.034

0.018

0.058

0.061

0.597

chr17:28562492

chr17:28562489

SLC6A4_3_CpG_34

chr17:28562474

0.012

0.023

0.607

0.002

0.864

0.022

0.024

0.366

0.029

0.864

SLC6A4_3_CpG_35

chr17:28562465

-0.038

0.050

0.442

0.004

0.864

-0.036

0.051

0.487

0.005

0.864

SLC6A4_3_CpG_36

chr17:28562435

-0.025

0.019

0.190

0.011

0.718

-0.020

0.019

0.304

0.036

0.718

SLC6A4_3_CpG_38

chr17:28562412

-0.015

0.017

0.379

0.005

0.842

-0.010

0.017

0.561

0.022

0.842

SLC6A4_3_CpG_39

chr17:28562401

0.023

0.032

0.477

0.003

0.864

0.026

0.033

0.436

0.025

0.864

SLC6A4_3_CpG_40and41

chr17:28562392

-0.014

0.036

0.705

0.001

0.864

-0.003

0.037

0.927

0.037

0.864

chr17:28562388

Note. Based on GRCh37/hg19 coordinates.

 

 

 

 

 

 

 

 

 

 

S1 Figure. Moderation analyses.

(A) Adjusted model for FKBP5_1_CpG_3. (B) Adjusted model for FKBP5_1_CpG_4. (C) Adjusted model for IL10_2_CpG_5. (D) Adjusted model for IL10_2_CpG_6. (E) Adjusted model for MAOA_3_CpG_1. (F) Adjusted model for NR3C1_1_CpG_5.

S2 Figure.

Moderation analyses. (G) Adjusted model for NR3C1_2_CpG_60. (H) Adjusted model for NR3C1_3_CpG_8. (I) Adjusted model for SLC6A3_1_CpG_7. (J) Adjusted model for SLC6A3_2_CpG_28to30. (K) Adjusted model for SLC6A3_2_CpG_35to37. (L) Adjusted model for SLC6A4_3_CpG_13and14.

S3 Figure.

Moderation analyses. (M) Adjusted model for SLC6A4_3_CpG_23and24. (N) Adjusted model for SLC6A4_3_CpG_36

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