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Background: This study explored state-related tendencies in DNA methylation in people with anorexia nervosa., Methods: We measured genome-wide DNA methylation in 75 women with active anorexia nervosa (active), 31 women showing stable remission of anorexia nervosa (remitted) and 41 women with no eating disorder (NED). We also obtained post-intervention methylation data from 52 of the women from the active group., Results: Comparisons between members of the active and NED groups showed 58 differentially methylated sites (Q < 0.01) that corresponded to genes relevant to metabolic and nutritional status (lipid and glucose metabolism), psychiatric status (serotonin receptor activity) and immune function. Methylation levels in members of the remitted group differed from those in the active group on 265 probes that also involved sites associated with genes for serotonin and insulin activity, glucose metabolism and immunity. Intriguingly, the direction of methylation effects in remitted participants tended to be opposite to those seen in active participants. The chronicity of Illness correlated (usually inversely, at Q < 0.01) with methylation levels at 64 sites that mapped onto genes regulating glutamate and serotonin activity, insulin function and epigenetic age. In contrast, body mass index increases coincided (at Q < 0.05) with generally increased methylation-level changes at 73 probes associated with lipid and glucose metabolism, immune and inflammatory processes, and olfaction., Limitations: Sample sizes were modest for this type of inquiry, and findings may have been subject to uncontrolled effects of medication and substance use., Conclusion: Findings point to the possibility of reversible epigenetic alterations in anorexia nervosa, and suggest that an adequate pathophysiological model would likely need to include psychiatric, metabolic and immune components., Competing Interests: A. Labbe and R. Joober are members of the journal editorial board; they were not involved in the evaluation or acceptence of this manuscript for publication. R. Joober reports clinician-​scientist salary awards from Fonds de recherche du Quebec outside the scope of this work. He participates on the advisory boards and speakers bureaus of Pfizer, Janssen Ortho, Otsuka, Lundbeck, Purdue and Myelin and has received honoraria from those companies. He also reports honoraria from Shire and royalties from Henry Stewart Talks. No other authors have declared competing interests., (© 2019 Joule Inc. or its licensors)

Several studies have examined associations between peripheral DNA methylation patterns of the serotonin transporter gene (SLC6A4) promoter and symptoms of depression and anxiety. The SLC6A4 promoter methylation has also been associated with frontal-limbic brain responses to negative stimuli. However, it is unclear how much of this association is confounded by DNA sequence variations. We utilized a monozygotic-twin within-pair discordance design, to test whether DNA methylation at specific CpG sites in the SLC6A4 promoter of peripheral cells is associated with greater frontal-limbic brain responses to negative stimuli (sadness and fear), independently of DNA sequence effects. In total 48 pairs of healthy 15-year-old monozygotic twins from the Quebec Newborn Twin Study, followed regularly since birth, underwent functional magnetic resonance imaging while conducting an emotion-processing task. The SLC6A4 promoter methylation level was assessed in saliva samples using pyrosequencing. Relative to the co-twins with lower SLC6A4 promoter methylation levels, twins with higher peripheral SLC6A4 methylation levels showed greater orbitofrontal cortical (OFC) activity and left amygdala-anterior cingulate cortex (ACC) and left amygdala-right OFC connectivity in response to sadness as well as greater ACC-left amygdala and ACC-left insula connectivity in response to fearful stimuli. By utilising a monozygotic-twin design, we provided evidence that associations between peripheral SLC6A4 promoter methylation and frontal-limbic brain responses to negative stimuli are, in part, independent of DNA sequence variations. Although causality cannot be determined here, SLC6A4 promoter methylation may be one of the mechanisms underlying how environmental factors influence the serotonin system, potentially affecting emotional processing through frontal-limbic areas.

Background: Several studies have shown that the in utero environment, which can be indexed by birth weight (BW), is associated with cortical morphology in adolescence and adulthood. Work in monozygotic (MZ) twins suggests that this association is driven by non-shared environmental factors. This correlation could be the result of in utero impacts on DNA methylation. The aim of the present study with MZ twins is to replicate the association between discordance in BW and brain morphology and test whether discordance in DNA methylation mediates this relationship., Methods: One hundred and four adolescent MZ twins (52 pairs, of which 42% were male pairs) who have been followed regularly since birth underwent T1 weighted structural MRI, and epigenome-wide assessment of DNA methylation from saliva at age 15., Results: Co-twins had very similar measures of DNA methylation and cortical morphology. Higher BW members of a twin pair had increased total cortical surface area, and decreased cortical thickness compared to their lower BW sibling. BW Discordance was positively associated with both cortical surface area and cortical volume discordance. Genes involved in neurodevelopment were tentatively identified as mediators of both the BW - cortical volume, and BW- cortical surface area relationships., Conclusions: The association between BW and cortical morphology in adolescence appears to be attributable to in utero environmental effects, and DNA methylation may play a role in mediating this relationship. Hum Brain Mapp 38:2037-2050, 2017. © 2017 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: The aim of the present study was to investigate the association of fMRI blood oxygen-level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD)., Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing., Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation., Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn., Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.

DNA methylation patterns are characterized by highly conserved developmental programs, but allow for divergent gene expression resulting from stochastic epigenetic drift or divergent environments. Genome-wide methylation studies in monozygotic (MZ) twins are providing insight into the extent of epigenetic variation that occurs, irrespective of genotype. However, little is known about the variability of DNA methylation patterns in adolescence, a period involving significant and rapid physical, emotional, social, and neurodevelopmental change. Here, we assessed genome-wide DNA methylation using the 450 K Illumina BeadChip in a sample of 37 MZ twin pairs followed longitudinally since birth to investigate: 1) the extent of variation in DNA methylation in identical genetic backgrounds in adolescence and; 2) whether these variations are randomly distributed or enriched in particular functional pathways. We also assessed stability of DNA methylation over 3-6 months to distinguish stable trait-like and variable state-like genes. A pathway analysis found high within-pair variability in genes associated with development, cellular mechanisms, tissue and cell morphology, and various disorders. Test-retest analyses performed in a sub-sample of 8 twin pairs demonstrated enrichment in gene pathways involved in organismal development, cellular growth and proliferation, cell signaling, and particular disorders. The variability found in functional gene pathways may plausibly underlie phenotypic differences in this adolescent MZ twin sample. Furthermore, we assessed stability of methylation over 3-6 months and found that some genes were stable while others were unstable, suggesting that the methylome remains dynamic in adolescence and that dynamic sites tend to be organized in certain gene pathways.

The functioning of the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic (5-HT) system are known to be intertwined with mood. Alterations in these systems are often associated with depression. However, neither are sufficient to cause depression in and of themselves. It is now becoming increasingly clear that the environment plays a crucial role, particularly, the perinatal environment. In this review, we posit that early environmental stress triggers a series of epigenetic mechanisms that adapt the genome and programme the HPA axis and 5-HT system for survival in a harsh environment. We focus on DNA methylation as it is the most stable epigenetic mark. Given that DNA methylation patterns are in large part set within the perinatal period, long-term gene expression programming by DNA methylation is especially vulnerable to environmental insults during this period. We discuss specific examples of genes in the 5-HT system (serotonin transporter) and HPA axis (glucocorticoid receptor and arginine vasopressin enhancer) whose DNA methylation state is associated with early life experience and may potentially lead to depression vulnerability. We conclude with a discussion on the relevance of studying epigenetic mechanisms in peripheral tissue as a proxy for those occurring in the human brain and suggest avenues for future research.

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

Genetic and early environmental factors are interwoven in the etiology of Borderline Personality Disorder (BPD). Epigenetic mechanisms offer the molecular machinery to adapt to environmental conditions. There are gaps in the knowledge about how epigenetic mechanisms are involved in the effects of early affective environment, development of BPD, and psychotherapy response. We reviewed the available evidence of the effects of psychotherapy on changes in DNA methylation and conducted a pilot study in a sample of 11 female adolescents diagnosed with BPD, exploring for changes in peripheral DNA methylation of FKBP5 gene, which encodes for a stress response protein, in relation to psychotherapy, on symptomatology and underlying psychological processes. For this purpose, measures of early trauma, borderline and depressive symptoms, psychotherapy outcome, mentalization, and emotional regulation were studied. A reduction in the average FKBP5 methylation levels was observed over time. Additionally, the decrease in FKBP5 methylation observed occurred only in those individuals who had early trauma and responded to psychotherapy. The results suggest an effect of psychotherapy on epigenetic mechanisms associated with the stress response. The finding that epigenetic changes were only observed in patients with early trauma suggests a specific molecular mechanism of recovery. The results should be taken with caution given the small sample size. Also, further research is needed to adjust for confounding factors and include endocrinological markers and therapeutic process variables. [ABSTRACT FROM AUTHOR]

Longitudinal epidemiological studies with birth cohorts have shown that physical aggression in humans does not appear suddenly in adolescence as commonly thought. In fact, physically aggressive behaviour is observed as early as 12 months after birth, its frequency peaks around 2 - 4 years of age and decreases in frequency until early adulthood. However, a minority of children (3-7%) maintain a high frequency of physical aggression from childhood to adolescence and develop serious social adjustment problems during adulthood. Genetic factors and early social experiences, as well as their interaction, have been shown to play an important role in the development of chronic aggressive behaviour. However, the biological mechanisms underlying these associations are just beginning to be uncovered. Recent evidence suggests that epigenetic mechanisms are responsive to adverse environments and could be involved in the development of chronic aggression. Using both gene candidate and genomic approaches, recent studies have identified epigenetic marks, such as DNA methylation alterations in genes involved in the stress response and the serotonin and immune systems to be partly responsible for the long-lasting effects of early adversity. Further longitudinal studies with biological, environmental and behavioural assessments from birth onwards are needed to elucidate the sequence of events that leads to these long-lasting epigenetic marks associated with early adversity and aggression. [ABSTRACT FROM AUTHOR]

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms are believed to link environmental exposures to alterations in gene expression, and in so doing, to provide a physical substrate for the activation of hereditary potentials by life experiences. In keeping with this idea, accumulating data suggest that epigenetic processes are implicated in eating-disorder (ED) etiology. This paper reviews literature on putative links between epigenetic factors and EDs, and examines ways in which epigenetic programming of gene expression could account for gene-environment interactions acting in the EDs. The paper also presents evidence suggesting that epigenetic processes link malnutrition and life stresses (gestational, perinatal, childhood, and adult) to risk of ED development. Drawing from empirical evidence and clinical experience, we propose that an epigenetically informed understanding of ED etiology can benefit patients, caregivers, and clinicians alike, in the sense that the perspective can reduce judgmental or blameful attitudes on the part of clinicians and caregivers, and increase self-acceptance and optimism about recovery on the part of those affected. [ABSTRACT FROM AUTHOR]