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Depression is associated with dietary factors and epigenetics. Serum cholesterol, which is prone to dietary influences, has been linked to symptoms of depression. This relationship may be (in part) due to altered epigenetic regulation of Methylenetetrahydrofolate Reductase (MTHFR). MTHFR codes for the MTHFRenzyme, which has diverse metabolic functions, and has recently been linked individually with diet, serum cholesterol levels and depressive symptoms. In 514 mother-child pairs, we examined prospective relationships between maternal (pregnancy) and child (7 years) serum cholesterol, MTHFRDNA methylation (DNAm; birth, 7 years), and development of depression symptoms from 8-15 years. After adjusting for potential confounding, we had three main findings. First, higher prenatal cholesterol associated (at a small effect size) with higher MTHFR DNAm at birth. Second, there was small effect size continuity for MTHFR DNAm between birth and age 7. Third, higher age 7 MTHFR DNAm associated with higher initial symptoms of depression symptoms at age 8, again at a small effect size. Overall, our findings provide preliminary evidence for a relationship between prenatal cholesterol, MTHFR DNAm, and symptoms of depression in children.

Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (P < 5e-05), with altered DNAm trajectories between ages 10–18 associated with severe adolescent victimization (∆Beta range = −5.5%−5.3%). Age-18 cross-sectional analyses revealed 72 blood (∆Beta range = −2.2%−3.4%) and 42 buccal (∆Beta range = −3.6%−4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) in LGR6 and ANK3 (Šidák P = 5e-09 and 4.07e-06), and one upstream of CCL27 (Šidák P = 2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization. [ABSTRACT FROM AUTHOR]

Importance: Urbanicity is a well-established risk factor for clinical (eg, schizophrenia) and subclinical (eg, hearing voices and paranoia) expressions of psychosis. To our knowledge, no studies have examined the association of air pollution with adolescent psychotic experiences, despite air pollution being a major environmental problem in cities.Objectives: To examine the association between exposure to air pollution and adolescent psychotic experiences and test whether exposure mediates the association between urban residency and adolescent psychotic experiences.Design, Setting, and Participants: The Environmental-Risk Longitudinal Twin Study is a population-based cohort study of 2232 children born during the period from January 1, 1994, through December 4, 1995, in England and Wales and followed up from birth through 18 years of age. The cohort represents the geographic and socioeconomic composition of UK households. Of the original cohort, 2066 (92.6%) participated in assessments at 18 years of age, of whom 2063 (99.9%) provided data on psychotic experiences. Generation of the pollution data was completed on October 4, 2017, and data were analyzed from May 4 to November 21, 2018.Exposures: High-resolution annualized estimates of exposure to 4 air pollutants-nitrogen dioxide (NO2), nitrogen oxides (NOx), and particulate matter with aerodynamic diameters of less than 2.5 (PM2.5) and less than 10 μm (PM10)-were modeled for 2012 and linked to the home addresses of the sample plus 2 commonly visited locations when the participants were 18 years old.Main Outcomes and Measures: At 18 years of age, participants were privately interviewed regarding adolescent psychotic experiences. Urbanicity was estimated using 2011 census data.Results: Among the 2063 participants who provided data on psychotic experiences, sex was evenly distributed (52.5% female). Six hundred twenty-three participants (30.2%) had at least 1 psychotic experience from 12 to 18 years of age. Psychotic experiences were significantly more common among adolescents with the highest (top quartile) level of annual exposure to NO2 (odds ratio [OR], 1.71; 95% CI, 1.28-2.28), NOx (OR, 1.72; 95% CI, 1.30-2.29), and PM2.5 (OR, 1.45; 95% CI, 1.11-1.90). Together NO2 and NOx statistically explained 60% of the association between urbanicity and adolescent psychotic experiences. No evidence of confounding by family socioeconomic status, family psychiatric history, maternal psychosis, childhood psychotic symptoms, adolescent smoking and substance dependence, or neighborhood socioeconomic status, crime, and social conditions occurred.Conclusions and Relevance: In this study, air pollution exposure-particularly NO2 and NOx-was associated with increased odds of adolescent psychotic experiences, which partly explained the association between urban residency and adolescent psychotic experiences. Biological (eg, neuroinflammation) and psychosocial (eg, stress) mechanisms are plausible. [ABSTRACT FROM AUTHOR]

Background: Several delivery formats of cognitive behaviour therapy (CBT) for child anxiety have been proposed, however, there is little consensus on the optimal delivery format. The primary goal of this study was to investigate the impact of the child's primary anxiety diagnosis on changes in clinical severity (of the primary problem) during individual CBT, group CBT and guided parent‐led CBT. The secondary goal was to investigate the impact of the child's primary anxiety diagnosis on rates of remission for the three treatment formats. Methods: A sample of 1,253 children (5–12 years; Mage = 9.3, SD = 1.7) was pooled from CBT trials carried out at 10 sites. Children had a primary diagnosis of generalised anxiety disorder (GAD), social anxiety disorder (SoAD), specific phobia (SP) or separation anxiety disorder (SAD). Children and parents completed a semistructured clinical interview to assess the presence and severity of DSM‐IV psychiatric disorders at preintervention, postintervention and follow‐up. Linear mixture modelling was used to evaluate the primary research question and logistic modelling was used to investigate the secondary research question. Results: In children with primary GAD, SAD or SoAD, there were no significant differences between delivery formats. However, children with primary SP showed significantly larger reductions in clinical severity following individual CBT compared to group CBT and guided parent‐led CBT. The results were mirrored in the analysis of remission responses with the exception that individual CBT was no longer superior to group CBT for children with a primary SP. The difference between individual and group was not significant when follow‐up data were examined separately. Conclusions: Data show there may be greater clinical benefit by allocating children with a primary SP to individual CBT, although future research on cost‐effectiveness is needed to determine whether the additional clinical benefits justify the additional resources required. [ABSTRACT FROM AUTHOR]

Objectives:Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences. We analysed the effect of gene expression and genetic markers separately and together on treatment response. Methods:Adult participants (n ≤ 181) diagnosed with panic disorder or a specific phobia underwent eCBT as part of standard care. Percentage decrease in the Clinical Global Impression severity rating was assessed across treatment, and between baseline and a 6-month follow-up. Associations with treatment response were assessed using expression data from 3,233 probes, and expression profiles clustered in a data- and literature-driven manner. A total of 3,343,497 genetic variants were used to predict treatment response alone and combined in polygenic risk scores. Genotype and expression data were combined in expression quantitative trait loci (eQTL) analyses. Results:Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified withq < 0.05, but interactions between genetic variants and treatment response did not affect expression levels significantly. Genetic variants did not significantly predict treatment response alone or in polygenic risk scores. Conclusions:We assessed gene expression alone and alongside genetic variants. No associations with treatment outcome were identified. Future studies require larger sample sizes to discover associations. [ABSTRACT FROM AUTHOR]

Background: Anxiety disorders are common, and cognitive-behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.Aims: To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).Method: Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.Results: No variants passed a genome-wide significance threshold (P = 5 × 10(-8)) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10(-6)) in association with response post-treatment, and three variants in the 6-month follow-up analysis.Conclusions: This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts. [ABSTRACT FROM AUTHOR]

Background: We previously reported an association between 5HTTLPR genotype and outcome following cognitive-behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome.Aims: To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).Method: Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.Results: There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes.Conclusions: The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples. [ABSTRACT FROM AUTHOR]

Background: Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).Methods: Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).Results: Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.Conclusions: Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner. [ABSTRACT FROM AUTHOR]

Psychotic Symptoms (PS) are often distressing and can be predictive of schizophrenia, other psychiatric disorders and suicide attempts in adulthood, particularly if they persist during adolescence. Previous research in diagnosis-discordant monozygotic twin-pairs and patient-control samples has demonstrated that changes in epigenetic processes could be potential biomarkers of the emergence and persistence of PS. Investigation in large, pre-clinical population-based samples is urgently required. The aim of this study is to explore the association between DNA methylation and the emergence, persistence, and remission of PS in childhood and adolescence. DNA methylation data (Illumina 450k) were obtained from the ARIES subsample of the ALSPAC birth cohort at birth, age 7, and age 15/17 (N=901). PS were assessed in private interviews with the participants at ages 12 and 18. EWAS were conducted to determine the association between DNA methylation at each time-point and reports of PS at ages 12 and 18, controlling for pregnancy and birth-related covariates and cell-type composition. Gene Ontology (GO) term enrichment analyses of the top probes were performed to identify important pathways. The top probes from each EWAS were used to investigate the role of DNA methylation in the persistence and remission of PS by comparing individuals with no history of PS, those whose symptoms persisted, and those whose symptoms remitted. Multilevel models were then constructed to test the association between the longitudinal methylomic trajectory of the top CpG sites and the trajectory of psychotic symptoms. Results from a replication of the top findings in an independent cohort will also be presented. A number of probes were differentially methylated (p<5×10-5) at each time-point between those who experienced PS at age 12 and age 18, although these were not significant after applying stringent correction for multiple testing (p<1.3×10-7). The top ranked GO terms from enrichment analyses at each time-point included those related to neuronal development, immune processes, and the Wnt signalling pathway. Investigation of the top probes revealed differences in DNA methylation profiles between PS trajectories in adolescence, in both a time-point specific manner and longitudinally across development. At many of these probes, individuals whose symptoms remitted between 12 and 18 showed DNA methylation profiles more similar to those with no history of PS, and those whose symptoms persisted showed the largest difference in DNA methylation. Findings from this large, population-based study suggest that epigenetic processes at multiple stages of development may be associated with the emergence, remission, and persistence of PS in late childhood and adolescence. Research uncovering biomarkers associated with pre-clinical PS is important as it has the potential to facilitate early identification of individuals at increased risk and target preventive interventions. [ABSTRACT FROM AUTHOR]

Questionnaire measures offer a time and cost-effective alternative to full diagnostic assessments for identifying and differentiating between potential anxiety disorders and are commonly used in clinical practice. Little is known, however, about the capacity of questionnaire measures to detect specific anxiety disorders in clinically anxious preadolescent children. This study aimed to establish the ability of the Spence Children's Anxiety Scale (SCAS) subscales to identify children with specific anxiety disorders in a large clinic-referred sample (N = 1,438) of children aged 7 to 12 years. We examined the capacity of the Separation Anxiety, Social Phobia, Generalized Anxiety, and Physical Injury Fears (phobias) subscales to discriminate between children with and without the target disorder. We also identified optimal cutoff scores on subscales for accurate identification of children with the corresponding disorder, and examined the contribution of child, mother, and father reports. The Separation Anxiety subscale was able to accurately identify children with separation anxiety disorder, and this was replicated across all 3 reporters. Mother- and father-reported Social Phobia subscales also accurately identified children with social anxiety disorder, although child report was only able to accurately detect social anxiety disorder in girls. Using 2 or more reporters improved the sensitivity of the Separation Anxiety and Social Phobia subscales but reduced specificity. The Generalized Anxiety and Physical Injury Fears subscales failed to accurately identify children with the corresponding disorders. These findings have implications for the potential use of mother-, father-, and child-report SCAS subscales to detect specific disorders in preadolescent children in clinical settings. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

Highlights from the article: Sa65dna methylome marks of exposure to psychosocial stress during adolescence: analysis of a novel longitudinal mz discordant twin study B Background: b Prolonged activation of the stress response system during key developmental periods such as early childhood development and puberty are strongly linked with a range of stress-related diseases and cognitive impairments that persist well into adulthood. B Discussion: b The current longitudinal epigenome-wide study of MZ twins discordant for psychosocial stress exposure during adolescence represents a novel approach in elucidating how stress gets under the skin to leave lasting biological imprints.