HPA axis related genes and response to psychological therapies: genetics and epigenetics

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

DNA methylation of FKBP5 and response to exposure-based psychological therapy

Differential DNA methylation of the HPA-axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences, and may play a role in how well people respond to psychological treatments. Participants (n=111) received exposure-based CBT for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (β=-4.26, p=3.90x10-4), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p=0.045), but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure-based CBT. In addition, there was suggestive evidence that allele-specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences

A genome-wide test of the differential susceptibility hypothesis reveals a genetic predictor of differential response to psychological treatments for child anxiety Disorders

Background: The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in children with anxiety disorders. Methods: We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of environmental sensitivity based on the whole-genome findings and tested the score as a moderator of parenting on emotional problems in 1,406 children and response to individual, group and brief parent-led CBT in 973 children with anxiety disorders. Results: The polygenic score significantly moderated the effects of parenting on emotional problems and the effects of treatment. Individuals with a high score responded significantly better to individual CBT than group CBT or brief parent-led CBT (remission rates: 70.9, 55.5 and 41.6%, respectively). Conclusions: Pending successful replication, our results should be considered exploratory. Nevertheless, if replicated, they suggest that individuals with the greatest environmental sensitivity may be more likely to develop emotional problems in adverse environments but also benefit more from the most intensive types of treatment

Genetic variation in the endocannabinoid system and response to cognitive behavioural therapy for child anxiety disorders

Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders

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 with q < 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

Multipurpose acoustic networks in the integrated arctic ocean observing system

The dramatic reduction of sea ice in the Arctic Ocean will increase human activities in the coming years. This activity will be driven by increased demand for energy and the marine resources of an Arctic Ocean accessible to ships. Oil and gas exploration, fisheries, mineral extraction, marine transportation, research and development, tourism, and search and rescue will increase the pressure on the vulnerable Arctic environment. Technologies that allow synoptic in situ observations year-round are needed to monitor and forecast changes in the Arctic atmosphere-ice-ocean system at daily, seasonal, annual, and decadal scales. These data can inform and enable both sustainable development and enforcement of international Arctic agreements and treaties, while protecting this critical environment. In this paper, we discuss multipurpose acoustic networks, including subsea cable components, in the Arctic. These networks provide communication, power, underwater and under-ice navigation, passive monitoring of ambient sound (ice, seismic, biologic, and anthropogenic), and acoustic remote sensing (tomography and thermometry), supporting and complementing data collection from platforms, moorings, and vehicles. We support the development and implementation of regional to basin-wide acoustic networks as an integral component of a multidisciplinary in situ Arctic Ocean observatory

The utility of the SCAS-C/P to detect specific anxiety disorders among clinically anxious children

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

The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study

Genetic architecture of Environmental Sensitivity reflects multiple heritable components: a twin study with adolescents

Humans differ substantially in how strongly they respond to similar experiences. Theory suggests that such individual differences in susceptibility to environmental influences have a genetic basis. The present study investigated the genetic architecture of Environmental Sensitivity (ES) by estimating its heritability, exploring the presence of multiple heritable components and its genetic overlap with common personality traits. ES was measured with the Highly Sensitive Child (HSC) questionnaire and heritability estimates were obtained using classic twin design methodology in a sample of 2868 adolescent twins. Results indicate that the heritability of sensitivity was 0.47, and that the genetic influences underlying sensitivity to negative experiences are relatively distinct from sensitivity to more positive aspects of the environment, supporting a multi-dimensional genetic model of ES. The correlation between sensitivity, neuroticism and extraversion was largely explained by shared genetic influences, with differences between these traits mainly attributed to unique environmental influences operating on each trait

Clinical predictors of response to cognitive-behavioral therapy in pediatric anxiety disorders: the genes for treatment (GxT) study.

OBJECTIVE The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child's gender, type of anxiety disorder, initial severity and comorbidity, and parents' psychopathology would significantly predict outcome. METHOD A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. RESULTS Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. CONCLUSION SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes