Background Cognitive biases have long been hypothesized to influence the development and maintenance of symptoms of internalizing problems. Anxiety sensitivity represents one such bias and refers to sensitivity to the physical and emotional symptoms of anxiety and the belief that these are harmful. Twin studies indicate a role for both environmental and genetic influences on anxiety sensitivity. However, little work has been done specifying environments or genes involved in this phenotype. In light of this, we looked at the association between stressful life events, the serotonin transporter gene polymorphism (5HTTLPR), and anxiety sensitivity in a longitudinal sample of adolescents. Methods Stressful life events and anxiety sensitivity were measured in over 1,500 individuals at three time points (mean ages 15, 17, and 20 years). 5HTTLPR was genotyped in 1,109 participants. Results There was consistent evidence for an association between stressful life events and both anxiety sensitivity and change in anxiety sensitivity over time. Although the effect of independent stressful life events was relatively short lived, dependent stressful life events were associated with anxiety sensitivity over time. There was no evidence for a main effect of 5HTTLPR on anxiety sensitivity. 5HTTLPR genotype did not moderate the effect of stressful life events on anxiety sensitivity. Conclusions The current study extends previous work by showing that stressful life events, independent of the individual, explained change in cognitions associated with anxiety and depression. This effect does not, however, appear to be moderated by genotype.
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. Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.
Although genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. This study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. PRS-MDD was significant correlated with total number of SLEs (β = 0.13, 95 % CI:0.04–0.22, p = 0.003) and dependent SLEs (β = 0.09, 95 % CI:0.02–0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (β = 0.11, 95 % CI:0.02–0.20, p = 0.015) and dependent SLEs (β = 0.08, 95 % CI:0.01–0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: β = 0.19, 95 % CI:0.04–0.35, p = 0.015; PRS-BD: β = 0.16, 95 % CI:0.01–0.32, p = 0.042) and dependent SLEs (PRS-MDD: β = 0.14, 95 % CI:0.03–0.26, p = 0.015; PRS-BD: β = 0.12, 95 % CI:0.004–0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. Use of a larger sample size would be beneficial. The relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.
Introduction Cognitive–behavioural therapy for insomnia (CBT-I) leads to insomnia symptom improvements in a substantial proportion of patients. However, not everyone responds well to this treatment, and it is unclear what determines individual differences in response. The broader aim of this work is to examine to what extent response to CBT-I is due to genetic and environmental factors. The purpose of this pilot study is to examine feasibility of a design to test hypotheses focusing on an unselected sample, that is, without selection on insomnia complaints, in order to plan a larger behavioural genetics study where most participants will likely not have an insomnia disorder. Methods and analysis A two parallel-group randomised controlled trial is being conducted across three London universities. Female students (minimum age 18 years) enrolled on a psychology programme at one of the three sites were invited to participate. The target number of participants to be recruited is 240. Following baseline assessments, participants were randomly allocated to either the treatment group, where they received weekly sessions of digital CBT-I for 6 weeks, or the control group, where they completed an online puzzle each week for 6 weeks. Follow-up assessments have taken place mid-intervention (3 weeks) and end of intervention (6 weeks). A 6-month follow-up assessment will also occur. Primary outcomes will be assessed using descriptive statistics and effect size estimates for intervention effects. Secondary outcomes will be analysed using multivariate generalised estimating equation models. Ethics and dissemination The study received ethical approval from the Research Ethics and Integrity subcommittee, Goldsmiths, University of London (application reference: EA 1305). DNA sample collection for the BioResource received ethical approval from the NRES Committee South Central—Oxford (reference number: 15/SC/0388). The results of this work shall be published in peer-reviewed journals. Trial registration number NCT03062891 ; Results.
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.To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.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.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.
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.
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