An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders.

Previous epigenome-wide association studies (EWAS) of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been inconsistent. This may be due to small sample sizes, and measurement and tissue differences. The current two EWA analyses of 473 World Trade Center responders are the largest to date for both PTSD and MDD. These analyses investigated DNA methylation patterns and biological pathways influenced by differentially methylated genes associated with each disorder. Methylation was profiled on blood samples using Illumina 450 K Beadchip. Two EWA analyses compared current versus never PTSD, and current versus never MDD, adjusting for cell types and demographic confounders. Pathway and gene set enrichment analyses were performed to understand the complex biological systems of PTSD and MDD. No significant epigenome-wide associations were found for PTSD or MDD at an FDR P<0.05. The majority of genes with differential methylation at a suggestive threshold did not overlap between the two disorders. Pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways, while only phosphatidylinositol signaling and cell cycle pathways emerged in MDD. The failure of the current EWA analyses to detect significant epigenome-wide associations is in contrast with disparate findings from previous, smaller EWA and candidate gene studies of PTSD and MDD. Enriched gene sets involved in several biological pathways, including stress response, inflammation and physical health, were identified in PTSD, supporting the view that multiple genes play a role in this complex disorder.

Aetiological influences on stability and change in emotional and behavioural problems across development: a systematic review.

Emotional and behavioural problems in childhood and adolescence can be chronic and are predictive of future psychiatric problems. Understanding what factors drive the development and maintenance of these problems is therefore crucial. Longitudinal behavioural genetic studies using twin, sibling or adoption data can be used to explore the developmental aetiology of stability and change in childhood and adolescent psychopathology. We present a systematic review of longitudinal, behavioural genetic analyses of emotional and behavioural problems between ages 0 to 18 years. We identified 58 studies, of which 19 examined emotional problems, 30 examined behavioural problems, and 9 examined both. In the majority of studies, stability in emotional and behavioural problems was primarily genetically influenced. Stable environmental factors were also widely found, although these typically played a smaller role. Both genetic and environmental factors were involved in change across development. We discuss the findings in the context of the wider developmental literature and make recommendations for future research.

A longitudinal twin and sibling study of the hopelessness theory of depression in adolescence and young adulthood.

BACKGROUND: Maladaptive cognitive biases such as negative attributional style and hopelessness have been implicated in the development and maintenance of depression. According to the hopelessness theory of depression, hopelessness mediates the association between attributional style and depression. The aetiological processes underpinning this influential theory remain unknown. The current study investigated genetic and environmental influences on hopelessness and its concurrent and longitudinal associations with attributional style and depression across adolescence and emerging adulthood. Furthermore, given high co-morbidity between depression and anxiety, the study investigated whether these maladaptive cognitions constitute transdiagnostic cognitive content common to both internalizing symptoms. METHOD: A total of 2619 twins/siblings reported attributional style (mean age 15 and 17 years), hopelessness (mean age 17 years), and depression and anxiety symptoms (mean age 17 and 20 years). RESULTS: Partial correlations revealed that attributional style and hopelessness were uniquely associated with depression but not anxiety symptoms. Hopelessness partially mediated the relationship between attributional style and depression. Hopelessness was moderately heritable (A = 0.37, 95% confidence interval 0.28-0.47), with remaining variance accounted for by non-shared environmental influences. Independent pathway models indicated that a set of common genetic influences largely accounted for the association between attributional style, hopelessness and depression symptoms, both concurrently and across development. CONCLUSIONS: The results provide novel evidence that associations between attributional style, hopelessness and depression symptoms are largely due to shared genetic liability, suggesting developmentally stable biological pathways underpinning the hopelessness theory of depression. Both attributional style and hopelessness constituted unique cognitive content in depression. The results inform molecular genetics research and cognitive treatment approaches.

The stability and change of etiological influences on depression, anxiety symptoms and their co-occurrence across adolescence and young adulthood.

BACKGROUND: Depression and anxiety persist within and across diagnostic boundaries. The manner in which common v. disorder-specific genetic and environmental influences operate across development to maintain internalizing disorders and their co-morbidity is unclear. This paper investigates the stability and change of etiological influences on depression, panic, generalized, separation and social anxiety symptoms, and their co-occurrence, across adolescence and young adulthood. METHOD: A total of 2619 twins/siblings prospectively reported symptoms of depression and anxiety at mean ages 15, 17 and 20 years. RESULTS: Each symptom scale showed a similar pattern of moderate continuity across development, largely underpinned by genetic stability. New genetic influences contributing to change in the developmental course of the symptoms emerged at each time point. All symptom scales correlated moderately with one another over time. Genetic influences, both stable and time-specific, overlapped considerably between the scales. Non-shared environmental influences were largely time- and symptom-specific, but some contributed moderately to the stability of depression and anxiety symptom scales. These stable, longitudinal environmental influences were highly correlated between the symptoms. CONCLUSIONS: The results highlight both stable and dynamic etiology of depression and anxiety symptom scales. They provide preliminary evidence that stable as well as newly emerging genes contribute to the co-morbidity between depression and anxiety across adolescence and young adulthood. Conversely, environmental influences are largely time-specific and contribute to change in symptoms over time. The results inform molecular genetics research and transdiagnostic treatment and prevention approaches.

Genetic and environmental influences on obsessive-compulsive behaviour across development: a longitudinal twin study.

BACKGROUND: Little is known about the factors influencing the stability of obsessive-compulsive behaviour (OCB) from childhood to adolescence. The current study aimed to investigate: (1) the stability of paediatric OCB over a 12-year period; (2) the extent to which genetic and environmental factors influence stability; and (3) the extent to which these influences are stable or dynamic across development. METHOD: The sample included 14 743 twins from a population-based study. Parental ratings of severity of OCB were collected at ages 4, 7, 9 and 16 years. RESULTS: OCB was found to be moderately stable over time. The genetic influence on OCB at each age was moderate, with significant effects also of non-shared environment. Genetic factors exerted a substantial influence on OCB persistence, explaining 59-80% of the stability over time. The results indicated genetic continuity, whereby genetic influences at each age continue to affect the expression of OCB at subsequent ages. However, we also found evidence for genetic attenuation in that genetic influences at one age decline in their influence over time, and genetic innovation whereby new genes 'come on line' at each age. Non-shared environment influenced stability of OCB to a lesser extent and effects were largely unique to each age and displayed negligible influences on OCB at later time points. CONCLUSIONS: OCB appears to be moderately stable across development, and stability is largely driven by genetic factors. However, the genetic effects are not entirely constant, but rather the genetic influence on OCB appears to be a developmentally dynamic process.

Cognitive content specificity in anxiety and depressive disorder symptoms: a twin study of cross-sectional associations with anxiety sensitivity dimensions across development.

BACKGROUND: The classification of anxiety and depressive disorders has long been debated and has important clinical implications. The present study combined a genetically sensitive design and multiple time points to investigate cognitive content specificity in anxiety and depressive disorder symptoms across anxiety sensitivity dimensions, a cognitive distortion implicated in both disorders. METHOD: Phenotypic and genetic correlations between anxiety sensitivity dimensions, anxiety and depressive disorder symptoms were examined at five waves of data collection within childhood, adolescence and early adulthood in two representative twin studies (n pairs = 300 and 1372). RESULTS: The physical concerns dimension of anxiety sensitivity (fear of bodily symptoms) was significantly associated with anxiety but not depression at all waves. Genetic influences on physical concerns overlapped substantially more with anxiety than depression. Conversely, mental concerns (worry regarding cognitive control) were phenotypically more strongly associated with depression than anxiety. Social concerns (fear of publicly observable symptoms of anxiety) were associated with both anxiety and depression in adolescence. Genetic influences on mental and social concerns were shared to a similar extent with both anxiety and depression. CONCLUSIONS: Phenotypic patterns of cognitive specificity and broader genetic associations between anxiety sensitivity dimensions, anxiety and depressive disorder symptoms were similar at all waves. Both disorder-specific and shared cognitive concerns were identified, suggesting it is appropriate to classify anxiety and depression as distinct but related disorders and confirming the clinical perspective that cognitive therapy is most likely to benefit by targeting cognitive concerns relating specifically to the individual's presenting symptoms across development.

Genetic and environmental influences on relationship between anxiety sensitivity and anxiety subscales in children.

Anxiety sensitivity, a belief that symptoms of anxiety are harmful, has been proposed to influence development of panic disorder. Recent research suggests it may be a vulnerability factor for many anxiety subtypes. Moderate genetic influences have been implicated for both anxiety sensitivity and anxiety, however, little is known about the aetiology of the relationship between these traits in children. Self-reports of anxiety sensitivity and anxiety symptoms were collected from approximately 300 twin pairs at two time points. Partial correlations indicated that anxiety sensitivity at age 8 was broadly associated with most anxiety subtypes at age 10 (r=0.11-0.17, p<0.05). The associations were largely unidirectional, underpinned by stable genetic influences. Non-shared environment had unique influences on variables. Phenotypic results showed that anxiety sensitivity is a broad predictor of anxiety symptoms in childhood. Genetic results suggest that childhood is a developmental period characterised by genetic stability and time-specific environmental influences on anxiety-related traits.