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BackgroundAnxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction.MethodsIn total, 1937 twins aged 22–25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase.ResultsTwin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4–0.5).ConclusionsFear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Over the last 20 years, opportunities for young children to engage in self-directed free play with peers outdoors or during the school day has dramatically declined. Consequently, it is likely that play dates, defined as pre-arranged social contact at home, have become increasingly significant play environments for children. Preliminary research suggests that play dates are positively associated with young children’s social and emotional development, but that access can be strongly influenced by parental social networking priorities. However, little is currently known about the nature and frequency of play dates, the types of play children engage in, or the impact of parental management and supervision on children’s play in this context. Exploratory qualitative research is essential to understand the extent to which parental gatekeeping may limit opportunities for children and families perceived to have low social capital, and to begin to define the nature and content of young children’s play dates more broadly. Parents of children aged 5-6 years old took part in a semi-structured interview to describe common practices and attitudes (N = 11). Inductive thematic analysis indicated that play dates are complex play environments that parents associate with a range of social, emotional, and cognitive benefits for children. However, close parental monitoring and supervision may limit the extent to which play dates provide opportunities for self-directed free play. Findings also show that access to play dates is strongly influenced by parents’ motivations to enhance children’s social status which restricts access to some children. Implications for future research are discussed.

BACKGROUND Anxiety is the most common childhood mental health condition and is associated with impaired child outcomes, including increased risk of mental health difficulties in adulthood. Anxiety runs in families: when a parent has anxiety, their child has a 50 per cent higher chance of developing it themselves. Environmental factors are predominant in the intergenerational transmission of anxiety and, of these, parenting processes play a major role. Interventions that target parents to support them to limit the impact of any anxiogenic parenting behaviours are associated with reduced anxiety in their children. A brief UK-based group-based intervention delivered to parents within the UK National Health Service led to a 16 per cent reduction in children meeting criteria for an anxiety disorder. However, this intervention is not widely accessible. To widen access, a nine-module online version of this intervention has been developed. This course comprises psychoeducation and home practice delivered through text, video, animations, and practice tasks. OBJECTIVE To evaluate the feasibility of delivering a brief online intervention for parents and assess its effectiveness in reducing child anxiety symptoms. METHODS A randomised controlled trial (RCT) of a community sample of 1,754 parents with self-identified high levels of anxiety with a child aged 2-11. Parents in the intervention arm to receive access to the online course, which they undertake at a self-determined rate. The control arm receives no intervention. Follow-up data collection at 6 and 9-21 months. Intention to treat analysis will be conducted on outcomes including child anxiety, child mental health symptoms and wellbeing; parental anxiety, wellbeing; and parenting behaviours. RESULTS Funded in April 2020, recruitment started in February 2021 and projected to end October 2022. CONCLUSIONS The results of the RCT will provide evidence on the utility of an online course in preventing intergenerational transmission of anxiety and increase understanding of familial anxiety. CLINICALTRIAL Prospectively registered on ClinicalTrials.Gov NCT04755933 on Feb 16th 2021.

Objectives\ud We aimed to examine differences in fear conditioning between anxious and nonanxious participants in a single large sample.\ud \ud Materials and methods\ud We employed a remote fear conditioning task (FLARe) to collect data from participants from the Twins Early Development Study (n = 1,146; 41% anxious vs. 59% nonanxious). Differences between groups were estimated for their expectancy of an aversive outcome towards a reinforced conditional stimulus (CS+) and an unreinforced conditional stimulus (CS−) during acquisition and extinction phases.\ud \ud Results\ud During acquisition, the anxious group (vs. nonanxious group) showed greater expectancy towards the CS−. During extinction, the anxious group (vs. nonanxious group) showed greater expectancy to both CSs. These comparisons yielded effect size estimates (d = 0.26–0.34) similar to those identified in previous meta‐analyses.\ud \ud Conclusion\ud The current study demonstrates that remote fear conditioning can be used to detect differences between groups of anxious and nonanxious individuals, which appear to be consistent with previous meta‐analyses including in‐person studies.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy. Crown Copyright (C) 2021 Published by Elsevier B.V. All rights reserved.

In this conceptual article, we draw upon the literature regarding cognitive and behavioural factors that underpin childhood anxiety to outline how a range of these risk markers might be targeted through adventurous play. When children play in an adventurous way, climbing trees, riding their bikes fast downhill and jumping from rocks, they experience feelings of fear and excitement, thrill and adrenaline. We propose that the positive, thrilling and playful emotions associated with this type of child-led play facilitate exposure to fear-provoking situations and, in doing so, provide opportunities for children to learn about physiological arousal, uncertainty and coping. We hypothesise that these learning opportunities will, over time, reduce children’s risk for elevated anxiety by increasing children’s expectations and ability to cope with anxiety, decreasing intolerance of uncertainty and preventing catastrophic misinterpretations of physiological arousal. If our conceptual model is correct, then ensuring that children have the physical and psychological space required to play in an adventurous way may help to decrease their risk for elevated or clinical anxiety.

BackgroundAnxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction.Methods1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study (TEDS) took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app.In the fear acquisition phase participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase.ResultsTwin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15%, 30% and 15% respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations .4-.5).ConclusionsFear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

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).

In this conceptual article we draw upon the literature regarding cognitive and behavioural factors that underpin childhood anxiety to outline how a range of these risk markers might be targeted through adventurous play. When children play in an adventurous way, climbing trees, riding their bikes fast downhill, jumping from rocks, they experience feelings of fear and excitement, thrill and adrenaline. We propose that the positive, thrilling, playful emotions associated with this type of child-led play facilitates exposure to fear-provoking situations and, in doing so, provides opportunities for children to learn about physiological arousal, uncertainty and coping. We hypothesise that these learning opportunities will, over time, reduce children’s risk for elevated anxiety by increasing children’s expectations and ability to cope with anxiety, decreasing intolerance of uncertainty and preventing catastrophic misinterpretations of physiological arousal. If our conceptual model is correct then ensuring that children have the physical and psychological space required to play in an adventurous way may help to decrease their risk for elevated or clinical anxiety.

This study tested the theory that anxious fathers pose a quantitatively different environmental influence on childhood anxiety than anxious mothers. The analysed sample contained 502 linked adoption units from the Early Growth and Development Study (EGDS), a longitudinal multisite study that follows 561 adopted children (57.2% boys) and their adoptive and birth parents, who were recruited through US adoption agencies. A Bayesian latent growth model predicted child anxiety symptoms between 18 months and 4.5 years from inherited (birth parent anxiety) and rearing parent anxiety. This model revealed little evidence for a difference in the influence of maternal and paternal rearing parent anxiety on child anxiety symptoms. Contrary to theoretical predictions, anxiety in the rearing father is likely to have an equivalent influence to that of the mother on both child anxiety symptoms at 18 months old and their developmental trajectory over the preschool years.

We introduce the Parent Play Questionnaire (PPQ), a parent-report measure designed to assess frequency of parent-infant play, parents’ attitudes towards play with their infant, and infants’ use of digital media. We describe measure development and empirical data across three samples of parent-infant dyads (total N = 414, offspring aged 0.3 – 2.5 years). Three latent factors explain the PPQ, corresponding with theoretically defined subscales. Summary scores showed good internal consistency and normally distributed results. Weak to moderate correlations were found between the frequency and attitude play scales, and with standardised measures of family social and emotional characteristics. Overall, frequency of digital media use was not correlated with play or broader family variables. Results suggest that the PPQ will be a useful tool for researchers interested in assessing parent-child play during early childhood.

Differential DNA methylation of the hypothalamic-pituitary-adrenal 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 cognitive behavioural therapy (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 = 3.90 × 10-4 ), 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 = .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 large number of studies document that children differ in the degree they are shaped by their developmental context with some being more sensitive to environmental influences than others. Multiple theories suggest that Environmental Sensitivity is a common trait predicting the response to negative as well as positive exposures. However, most research to date has relied on more or less proximal markers of Environmental Sensitivity. In this paper we introduce a new questionnaire-the Highly Sensitive Child (HSC) scale-as a promising self-report measure of Environmental Sensitivity. After describing the development of the short 12-item HSC scale for children and adolescents, we report on the psychometric properties of the scale, including confirmatory factor analysis and test-retest reliability. After considering bivariate and multivariate associations with well-established temperament and personality traits, we apply Latent Class Analysis to test for the existence of hypothesized sensitivity groups. Analyses are conducted across 5 studies featuring 4 different U.K.-based samples ranging in age from 8-19 years and with a total sample size of N = 3,581. Results suggest the 12-item HSC scale is a psychometrically robust measure that performs well in both children and adolescents. Besides being relatively independent from other common traits, the Latent Class Analysis suggests that there are 3 distinct groups with different levels of Environmental Sensitivity-low (approx. 25-35%), medium (approx. 41-47%), and high (20-35%). Finally, we provide exploratory cut-off scores for the categorization of children into these different groups which may be useful for both researchers and practitioners. (PsycINFO Database Record

A substantial proportion of adults with eating disorders are parents. Studies suggest these parents may experience a range of parenting challenges, and their children may be at an increased risk for the development of eating disorders themselves. With parenting practices being one potential environmental mechanism for the intergenerational transmission of eating disorders, we systematically searched Scopus, Web of Science, PubMed, MEDLINE, PsychINFO, and PsychArticles for controlled studies in which parenting attitudes, behaviours, and parent-child interactions were examined for parents with and without probable eating disorders. 26,512 abstracts were screened, and 167 full-text manuscripts were retrieved, with 33 studies meeting the review inclusion criteria. Studies suggest that parents with eating disorders experience higher levels of parenting stress than control parents, and may on average be more intrusive, less sensitive, and provide less structuring/facilitation in non-feeding interactions with their children. These parents also appear, on average, to experience increased concern about their children's weight, and parent-child mealtime interactions may be problematic and characterised by high levels of conflict. Suggestions for future research are made with a view to enhancing understandings of the intergenerational transmission of eating disorders, which may lead to the identification of intervention targets for parents with eating disorders and their children.

Background and objectives Fear conditioning paradigms use various measures to assess learned fear, including autonomic arousal responses like skin conductance, and self-reports of both associative (US-expectancies) and evaluative (affective ratings) learning. The present study uses a dimensional approach to examine associations among fear indices directly. Methods Seventy-three participants completed a differential fear conditioning experiment, during which a neutral stimulus (CS+) was paired with an electric shock (US), while another stimulus (CS-) was never paired with the shock (partially instructed fear acquisition). Ten minutes later, both stimuli were presented without any shocks (fear extinction). Skin conductance responses and US-expectancy ratings were recorded during each phase, while self-reported negative affect was assessed for each CS at the end of extinction. Results Results showed a positive association among US-expectancy ratings and skin conductance responses during acquisition and early extinction. US-expectancy ratings during overall extinction were positively associated with post-extinction negative affect. Limitations The lack of affective ratings post-acquisition may have obscured associations between associative and evaluative learning indices. Conclusions Results provide evidence for the expected correspondence among different indices of associative fear learning. Findings emphasize the need for incorporating both associative and evaluative learning measures in fear conditioning paradigms., Highlights • Fear conditioning studies use physiological and self-report measures to assess fear. • We examined the association among these indices using a dimensional approach. • Autonomic arousal was associated with US-expectancy ratings. • US-expectancy ratings during extinction predicted post-extinction negative affect. • Results support the need for both associative and evaluative indices of learned fear.

We introduce the Parent Play Questionnaire (PPQ), a parent-report measure designed to assess frequency of parent–infant play, parents’ attitudes towards play with their infant, and infants’ use of digital media. We describe measure development and empirical data across three samples of parent–infant dyads (total N = 414, offspring a ged 0.3–2.5 years). Three latent factors explain the PPQ, corresponding with theoretically defined subscales. Summary scores showed good internal consistency and normally distributed results. Weak to moderate correlations were found between the frequency and attitude play scales, and with standardized measures of family social and emotional characteristics. Overall, frequency of digital media use was not correlated with play or broader family variables. Results suggest that the PPQ will be a useful tool for researchers interested in assessing parent–child play during early childhood.

The transition from primary to secondary school is often associated with a period of heightened anxiety and worry. For most children, any feelings of anxiety subside relatively quickly but for a small minority, emotional difficulties can continue into the first year of secondary school and beyond. This study recruited 109 children and measured their anxiety symptoms and school concerns toward the end of primary school and again at the end of their first term of secondary school. We investigated for the first time whether pre-transition measures of attentional and interpretation bias, and the magnitude of change in attentional bias toward and away from threat stimuli were associated with pre- and post-transition measures of anxiety and school concerns, and the change in these measures over time. Over 50% of the current sample exceeded clinical levels of anxiety at pre-transition. However, anxiety symptoms and school concerns had significantly reduced by post-transition. Higher levels of pre-transition anxiety or school concerns, and a greater magnitude of change in attentional bias towards threat stimuli predicted a larger reduction in anxiety symptoms and school concerns across the transition period. A greater interpretation bias toward threat was associated with higher pre-transition anxiety symptoms and school concerns but not post-transition scores, or the change in these scores. While many children experience heightened anxiety prior to school transition, this appears to be largely temporary and self-resolves. Nonetheless, the current findings highlight the importance of monitoring children’s anxiety and concerns, and related cognitive processes during this important transition period. Electronic supplementary material The online version of this article (10.1007/s10802-019-00528-3) contains supplementary material, which is available to authorized users.

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samplesnecessary for the analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely using a loud human scream as an aversive stimulus. Three groups of participants (total n = 152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases during which online US-expectancy ratings were collected during every trial with evaluative ratings of negative affect at three time points. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature., Highlights • A smartphone app reliably delivers a differential fear conditioning paradigm using an aversive human scream. • Within-person associations of fear conditioning between laboratory and app delivery do not differ from those across time. • App-based administration is able to detect individual differences in anxiety related processes. • Fear conditioning data can be collected with minimal financial and time cost.

The Children of the Twins Early Development Study (CoTEDS) is a new prospective children-of-twins study in the UK, designed to investigate intergenerational associations across child developmental stages. CoTEDS will enable research on genetic and environmental factors that underpin parent–child associations, with a focus on mental health and cognitive-related traits. Through CoTEDS, we will have a new lens to examine the roles that parents play in influencing child development, as well as the genetic and environmental factors that shape parenting behavior and experiences. Recruitment is ongoing from the sample of approximately 20,000 contactable adult twins who have been enrolled in the Twins Early Development Study (TEDS) since infancy. TEDS twins are invited to register all offspring to CoTEDS at birth, with 554 children registered as of May 2019. By recruiting the second generation of TEDS participants, CoTEDS will include information on adult twins and their offspring from infancy. Parent questionnaire-based data collection is now underway for 1- and 2-year-old CoTEDS infants, with further waves of data collection planned. Current data collection includes the following primary constructs: child mental health, temperament, language and cognitive development; parent mental health and social relationships; parenting behaviors and feelings; and other socioecological factors. Measurement tools have been selected with reference to existing genetically informative cohort studies to ensure overlap in phenotypes measured at corresponding stages of development. This built-in study overlap is intended to enable replication and triangulation of future analyses across samples and research designs. Here, we summarize study protocols and measurement procedures and describe future plans.

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.

Therapygenetics refers to the prediction of psychological therapy outcomes from genetic markers. The rationale for this research derives from the gene–environment interaction literature, which has shown that individual differences in susceptibility to the environment are at least partly due to genetic variation for a wide range of phenotypes. While initially framed within the context of the diathesis-stress model, this idea has since been developed in a number of ways. Most notably, some genetic markers that place an individual at risk of a poor outcome following a stressful event may reflect environmental susceptibility markers, and thus may also enhance the likelihood of an individual benefiting from a positive environment, including psychological intervention. This chapter reviews the current evidence from candidate gene and genome-wide association studies that genetic factors can explain individual differences in response to psychological therapy. As this is a field in its infancy, future directions and opportunities are outlined. Following an initial discussion on the need to move toward a “therapygenomics” approach utilizing genome-wide methodologies, the importance of identifying mechanisms underlying associations between genes and psychological therapy outcomes is outlined. Finally, the possible future clinical implications of therapygenetics work, both scientific and ethical, are considered.

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samples, necessary for analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely. Three groups of participants (total n=152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery, and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature.

BackgroundWe 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.AimsTo replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).MethodLogistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.ResultsThere 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.ConclusionsThe 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.

This paper explores whether the increased vulnerability\ud of children of anxious parents to develop anxiety disorders may be partially explained by these children having increased cognitive biases towards threat compared with children of non-anxious parents. Parents completed questionnaires about their child’s anxiety symptoms. Children aged 5–9 (n = 85) participated in two cognitive bias tasks: 1) an emotion recognition task, and 2) an ambiguous situations questionnaire. For the emotion recognition task, there were no significant differences between at-risk children and children of non-anxious parents in their cognitive bias scores for reaction times or for accuracy in identifying angry or happy facial expressions. In addition, there were no significant differences between at-risk children and children of non-anxious parents in the number of threat interpretations made for the ambiguous situations questionnaire. It is possible that these cognitive biases only become present subsequent to the development of an anxiety disorder, or only in older at-risk children.

International audience; BackgroundIn order to retrieve episodic past events, the missing information needs to be reconstructed using information stored in semantic memory. Failures in these reconstructive processes are expressed as false memories. KIBRA single nucleotide polymorphism (rs17070145) has been linked to episodic memory performance as well as an increased risk of Alzheimer’s disease and post-traumatic stress disorder (PTSD).MethodsHere, the role of KIBRA rs17070145 polymorphism (male and female CC vs. CT/TT carriers) in reconstructive episodic memory in the Deese-Roediger-McDermott (DRM) paradigm was investigated in N = 219 healthy individuals.ResultsFemale participants outperformed males in the free recall condition. Furthermore, a trend towards a gender x genotype interaction was found for false recognition rates. Female CT/TT carriers exhibited a lower proportion of false recognition rates for associated critical lures as compared to male CT/TT. Additionally, an association between KIBRA rs17070145 genotype, familiarity and recollection based recognition performance was found. In trials with correct recognition of listed items CT/TT carriers showed more “remember”, but fewer “know” responses as compared to CC carriers.Discussion and conclusionOur findings suggest that the T-allele of KIBRA rs17070145 supports recollection based episodic memory retrieval and contributes to memory accuracy in a gender dependent manner. Findings are discussed in the context of the specific contribution of KIBRA related SNPs to reconstructive episodic memory and its implications for cognitive and emotional symptoms in dementia and PTSD.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.

Contains fulltext : 187781.pdf (Publisher’s version ) (Closed access) Dopamine D2 receptors (DRD2) have been strongly implicated in reward processing of natural stimuli and drugs. Using the approach-avoidance task (AAT), we recently demonstrated that smokers show an increased approach-bias toward smoking-related cues but not toward naturally rewarding stimuli. Here, we examined the contribution of the DRD2 Taq1B polymorphism to smokers' and non-smokers' responsivity toward smoking versus naturally rewarding stimuli in the AAT. Smokers carrying the minor B1 allele of the DRD2 Taq1B polymorphism showed reduced approach behavior for food-related pictures compared to non-smokers with the same allele. In the group of smokers, a higher approach-bias toward smoking-related compared to food-related pictures was found in carriers of the B1 allele. This pattern was not evident in smokers homozygous for the B2 allele. In addition, smokers with the B1 allele reported fewer attempts to quit smoking relative to smokers homozygous for the B2 allele. This is the first study demonstrating that behavioral shifts in response to smoking relative to natural rewards in smokers are mediated by the DRD2 Taq1B polymorphism. Our results indicate a reduced natural-reward brain reactivity in smokers with a genetically determined decrease in dopaminergic activity (i.e., reduction of DRD2 availability). It remains to be determined whether this pattern might be related to a different outcome after psychological cessation interventions, i.e., AAT modification paradigms, in smokers. 8 p.

BACKGROUND\ud \ud Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored.\ud \ud METHODS\ud \ud Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. There were 18 pairs of MZ twins identified in which one member scored consistently higher (group mean within the clinically significant range) on self-rated depression than the other. We assessed genome-wide patterns of DNA methylation in twin buccal cell DNA using the Infinium HumanMethylation450 BeadChip from Illumina. Quality control and data preprocessing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. The top differentially methylated DMP was successfully validated by bisulfite-pyrosequencing, and identified DMPs were tested in postmortem brain samples obtained from patients with major depressive disorder (n = 14) and matched control subjects (n = 15).\ud \ud RESULTS\ud \ud Two reproducible depression-associated DMPs were identified, including the top-ranked DMP that was located within STK32C, which encodes a serine/threonine kinase, of unknown function.\ud \ud CONCLUSIONS\ud \ud Our data indicate that DNA methylation differences are apparent in MZ twins discordant for adolescent depression and that some of the disease-associated variation observed in buccal cell DNA is mirrored in adult brain tissue obtained from individuals with clinical depression.

One theory suggests that anxious fathers may pose a greater environmental influence on childhood anxiety than anxious mothers. This study uses the Early Growth and Development Study (EGDS) to test rearing parent anxiety influences from mothers and fathers on child anxiety symptoms between 18 months and 4.5, while considering inherited influences. The EGDS is a longitudinal, multisite study of adopted children recruited through US adoption agencies, and their adoptive and birth parents. Bayesian latent growth models of the trajectory of child anxiety symptoms over 3 years predicted from inherited (birth parent anxiety) and adoptive parent anxiety influences were compared for maternal and paternal measures. Parameter estimates and their HPD intervals provided evidence that the slope for anxiety symptoms between 18 and 54 months is trivially affected by both rearing parent anxiety and inherited influences from both mothers and fathers. Similarly, rearing parental anxiety and inherited influence from both mothers and fathers had only a very small effect on the intercept for growth (anxiety symptoms at 18 months old). The evidence for differences between mothers and fathers for any of these parameters was, at best, weak. Contrary to theoretical predictions, anxiety in the rearing father is unlikely to have a more important role in fostering child anxiety symptoms than that in the rearing mother.

Sleep and circadian rhythms are intrinsically linked, with several sleep traits, including sleep timing and duration, influenced by both sleep homeostasis and the circadian phase. Genetic variation in several circadian genes has been associated with diurnal preference (preference in timing of sleep), although there has been limited research on whether they are associated with other sleep measurements. We investigated whether these genetic variations were associated with diurnal preference (Morningness-Eveningness Questionnaire) and various sleep measures, including: the global Pittsburgh Sleep Quality index score; sleep duration; and sleep latency and sleep quality. We genotyped 10 polymorphisms in genes with circadian expression in participants from the G1219 sample (n = 966), a British longitudinal population sample of young adults. We conducted linear regressions using dominant, additive and recessive models of inheritance to test for associations between these polymorphisms and the sleep measures. We found a significant association between diurnal preference and a polymorphism in period homologue 3 (PER3) (P < 0.005, recessive model) and a novel nominally significant association between diurnal preference and a polymorphism in aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) (P < 0.05, additive model). We found that a polymorphism in guanine nucleotide binding protein beta 3 (GNβ3) was associated significantly with global sleep quality (P < 0.005, recessive model), and that a rare polymorphism in period homologue 2 (PER2) was associated significantly with both sleep duration and quality (P < 0.0005, recessive model). These findings suggest that genes with circadian expression may play a role in regulating both the circadian clock and sleep homeostasis, and highlight the importance of further studies aimed at dissecting the specific roles that circadian genes play in these two interrelated but unique behaviours. © 2014 The Authors.

Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with numerous psychiatric disorders, most notably symptoms of depression. Twin studies have suggested that genetic influences partially underlie the variation seen for numerous sleep-related traits across individuals. Recently, two Genome-Wide Association Studies (GWAS) conducted for sleep traits have revealed new candidate genes for sleep-related measures. We attempted to replicate the two most significant associations from these two studies, CACNA1C (a l-type calcium channel) with sleep latency and quality and ABCC9 (an ATP-sensitive potassium channel) with sleep duration, using the G1219 British population sample. We genotyped single-nucleotide polymorphisms (SNPs) for each of the two different sleep GWAS loci. Linear regression analyses were conducted to assess main effects of these SNPs on their corresponding sleep measures, as well as for depressive symptoms. We successfully replicated an association of a genetic variant in the CACNA1C gene (rs16929277) with sleep quality using an additive model of inheritance. A significant association of the ABCC9 gene (rs11046209) with sleep duration was seen only in a recessive models based upon a rare homozygous genotype (n = 2). There was also a significant association between a different ABCC9 gene variant (rs11046205) and depressive symptoms. These findings add further support for the involvement of calcium channels in the mechanisms regulating sleep function and suggest a possible role of the ABCC9 gene in depression.

Attentional biases are most often framed in a threat relevance framework. Alternatively, it could be that not only threat-related stimuli draw attention but also that preferential attention is drawn to all stimuli that have relevance for an individual. We investigated this stimulus relevance theory in primary school-age children by means of a visual search task. As predicted, children displayed attentional biases toward evolutionary and modern threat-related stimuli, such as spiders and guns, but also toward other relevant, positive stimuli (i.e., cakes, gifts, and happy faces). These results suggest that attentional biases are not specific to threat, but seem to apply to all relevant stimuli, both positive and negative in valence, providing first evidence for the stimulus relevance theory of preferential attention in children.

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.\ud \ud 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.\ud \ud Results: Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified with q

Cognitive bias modification (CBM) procedures follow from the view that interpretive biases play an important role in the development and maintenance of anxiety. As such, understanding the link between interpretive biases and anxiety in youth at risk for anxiety (e.g., behaviorally inhibited children) could elucidate the mechanisms involved in the development of pediatric anxiety. However, to date, the majority of CBM-I work only studies adult populations. The present article presents the results of a CBM study examining effects of positive interpretive bias modification on mood, stress vulnerability, and threat-related attention bias in a group of behaviorally inhibited children (n = 45). Despite successful modification of interpretive bias in the at-risk youth, minimal effects on stress vulnerability or threat-related attention bias were found. The current findings highlight the need for continued research on cognitive biases in anxiety.

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.

Background: Childhood anxiety and depression frequently co-occur. Exploring specificity in cognitive processes for anxiety and depression in childhood can provide insight into cognitive vulnerabilities contributing to the development of anxiety and depressive disorders and inform targeted psychological interventions. Anxiety sensitivity and rumination are robust cognitive vulnerabilities for anxiety and depression, respectively. However, despite conceptual similarities, they are rarely considered together within a single study. Aims: The current study explored specific and shared associations between anxiety sensitivity subscales and rumination and anxiety and depressive symptoms in unselected children. Method: Multiple regression analyses explored to what extent specific self-reported anxiety sensitivity subscales (physical, social and mental concerns) and rumination predicted anxiety and depressive symptoms in 147 unselected children, aged 7–11 years. Results: Physical and social concern subscales of anxiety sensitivity were specifically associated with anxiety, whilst rumination was specifically associated with depressive symptoms. The mental concerns subscale of anxiety sensitivity was independently associated with both anxiety and depressive symptoms. These associations were only partially mediated by rumination. Conclusions: Anxiety and depression in young people are characterized by specific and shared cognitions. Evidence for shared and specific associations between the cognitive vulnerabilities of anxiety sensitivity and rumination, and anxiety and depression highlight the utility of transdiagnostic research and confirm that cognitive therapies may benefit from targeting cognitive concerns relating specifically to the patient's presenting symptoms.

BACKGROUND Twin studies in children reveal that familial aggregation of anxiety disorders is due to both genetic and environmental factors. Cognitive biases for threat information are considered a robust characteristic of childhood anxiety. However, little is known regarding the underlying aetiology of such biases and their role in anxiety disorders. METHOD A face version of the dot-probe task measuring attentional biases for negative (anger, fear, sad, disgust) and positive (happy) facial expressions was completed by 600, 8-year-old twins; the largest study of its kind. Twin correlations for attentional bias scores were compared to estimate genetic and environmental effects. Parent-report diagnostic interviews identified children with an anxiety disorder. Indices of inferred genetic and familial risk for anxiety disorders were created for each child. Data were analysed using a series of logistic regressions. RESULTS Anxious children showed greater attentional avoidance of negative faces than nonanxious children; t (548) = 2.55, p < .05. Attentional avoidance was not under genetic or shared environmental influence. Risk for anxiety disorders was predicted by familial factors. Both attentional avoidance and inferred familial risk were significant but independent predictors of anxiety disorders (ORs = .65 and 3.64, respectively). CONCLUSIONS Anxiety-related attentional biases and familial risk play important but independent roles in childhood anxiety disorders. If replicated, these findings indicate that links between genetic risk and anxiety disorders lie outside the domain of attentional processes.

Cognitive biases are known to play an important role in anxiety. In this study we investigate whether maternal anxiety is associated with biases in interpretation, attention, and catastrophic processing about self-referent stimuli that may signal potential threat in the mother's own environment. We also investigate whether maternal anxiety is associated with biases about stimuli that their own child may encounter or to child-related stimuli more broadly. Three hundred mothers with a child aged 6 to 10 years participated. All participants completed a trait anxiety measure and an ambiguous sentences task to assess interpretation bias for self- and child-referent situations. A subset of the sample completed a catastrophizing interview about a self- (n = 194) or child-referent (n = 99) worry topic and an attentional dot-probe task (n = 99) with general threat and child threat stimuli. Maternal anxiety was not significantly associated with an attentional bias for general or child threat stimuli but was significantly associated with a bias for threat interpretations of both self and child-referent situations. Higher maternal anxiety was also significantly associated with generating more catastrophic outcomes to both a self-referent and child-referent hypothetical worry situation. We consider whether maternal cognitive biases, which extend to influence how mothers process potential threats in their child's world, may be an important mechanism through which intergenerational transmission of anxiety could occur.

Diurnal preference is an individual's preference for daily activities and sleep timing and is strongly correlated with the underlying circadian clock and the sleep-wake cycle validating its use as an indirect circadian measure in humans. Recent research has implicated DNA methylation as a mechanism involved in the regulation of the circadian clock system in humans and other mammals. In order to evaluate the extent of epigenetic differences associated with diurnal preference, we examined genome-wide patterns of DNA methylation in DNA from monozygotic (MZ) twin-pairs discordant for diurnal preference. MZ twins were selected from a longitudinal twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. Fifteen pairs of MZ twins were identified in which one member scored considerably higher on the Horne–Ostberg Morningness–Eveningness Questionnaire (MEQ) than the other. Genome-wide DNA methylation patterns were assessed in twins’ buccal cell DNA using the Illumina Infinium HumanMethylation450 BeadChips. Quality control and data pre-processing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. Our data indicate that DNA methylation differences are detectable in MZ twins discordant for diurnal preference. Moreover, downstream gene ontology (GO) enrichment analysis on the top-ranked diurnal preference associated DMPs revealed significant enrichment of pathways that have been previously associated with circadian rhythm regulation, including cell adhesion processes and calcium ion binding.

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.