Meta-analysis of genome-wide association studies of anxiety disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

Predicting mental disorders from hypothalamic-pituitary-adrenal axis functioning: a 3-year follow-up in the TRAILS study.

BACKGROUND: Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. METHOD: Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). RESULTS: A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. CONCLUSIONS: Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable.

Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study.

Stress early in life is a known risk factor for the development of affective disorders later in life. Epigenetic mechanisms, such as DNA methylation, may have an important role in mediating that risk. Recent epigenetic research reported on the long-term relationship between traumatic stress in childhood and DNA methylation in adulthood. In this study, we examined the impact of various types of stress (perinatal stress, stressful life events (SLEs) and traumatic youth experiences) on methylation of the glucocorticoid receptor gene (NR3C1) in the blood of a population sample of 468 adolescents (50.4% female, mean age 16.1 years). Second, we determined whether stress at different ages was associated with higher NR3C1 methylation. NR3C1 methylation rates were higher after exposure to SLEs and after exposure to traumatic youth experiences. NR3C1 methylation in adolescence was not higher after exposure to perinatal stress. Experience of SLEs in adolescence was associated with a higher NR3C1 methylation, independently of childhood SLEs. We demonstrate that not only traumatic youth experiences but also (more common) SLEs are associated with higher NR3C1 methylation. In addition, our findings underline the relevance of adolescent stress for epigenetic changes in the NR3C1 gene.

[Symptoms of anxiety in adolescents. Findings from the TRAILS-study]. / Angstsymptomen bij adolescenten; bevindingen uit de TRAILS-studie.

BACKGROUND: The Dutch TRAILS-study focuses on development from early adolescence into adulthood. An important aspect of this development is the development of anxiety. Hitherto little has been known about typical development of symptoms of anxiety during adolescence. AIM: To describe both the normative development of anxiety during adolescence, and the risk indicators for high levels of anxiety in adolescents. METHOD: Studies were embedded in trails, a large cohort study that followed children from the age of 10 to adulthood. RESULTS: Our results showed that, on average, levels of anxiety decrease in early adolescence and subsequently increase in middle or late adolescence, depending on the subtype of anxiety involved. Child-, parent- and peer-factors at age 10-12 years were related to higher subsequent anxiety levels. Some factors, such as the style of upbringing, were related to higher anxiety levels solely in early adolescence, whereas other factors such as being bullied by peers were related to continuing higher anxiety levels throughout adolescence, irrespective of later victimisation. CONCLUSION: Our study should, we hope, lead to a better understanding of the normative development of anxiety in the general adolescent population.

Risk indicators of anxiety throughout adolescence: the TRAILS study.

BACKGROUND: The aim was to identify risk indicators from preadolescence (age period 10-12) that significantly predict unfavorable deviations from normal anxiety development throughout adolescence (age period 10-17 years). METHODS: Anxiety symptoms were assessed in a community sample of 2,220 boys and girls at three time-points across a 5-year interval. Risk indicators were measured at baseline and include indicators from the child, family, and peer domain. Associations with anxiety were measured with multilevel growth curve analyses. RESULTS: A stable difference in anxiety over adolescence was found between high and low levels of a range of child factors (frustration, effortful control), family factors (emotional warmth received from parents, lifetime parental internalizing problems), and peer factor (victims of bullying) (P <.001). In contrast, the difference in anxiety between high and low levels of factors, such as self-competence, unfavorable parenting styles, and bully victims, decreased over adolescence (P <.001). For other family factors, associations were weaker (.05

The developmental course of anxiety symptoms during adolescence: the TRAILS study.

BACKGROUND: Little is known about the development of anxiety symptoms from late childhood to late adolescence. The present study determined developmental trajectories of symptoms of separation anxiety disorder (SAD), social phobia (SoPh), generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD) in a large prospective community cohort. METHODS: Anxiety symptoms were assessed in a community sample of 2220 boys and girls at three time-points across a 5-year interval. The Revised Child Anxiety and Depression Scale (RCADS) was used to assess anxiety symptoms, and multilevel growth-curve analyses were performed. RESULTS: All subtypes of anxiety first showed a decrease in symptoms (beta for age ranged from -.05 to -.13, p < .0001), followed by a leveling off of the decrease, and a subsequent slight increase in symptoms (beta for age-squared ranged from .006 to .01, p < .0001) from middle adolescence (GAD, SoPh, SAD) or late adolescence (PD and OCD) onwards. This increase in anxiety symptoms could not be explained by a co-occurring increase in depression symptoms. Girls had more anxiety symptoms than boys, and this difference remained stable during adolescence (p < .0001). Gender differences were strongly attenuated by adjustment for symptoms of depression. CONCLUSIONS: The current study shows that, in the general population, anxiety symptoms first decrease during early adolescence, and subsequently increase from middle to late adolescence. These findings extend our knowledge on the developmental course of anxiety symptoms during adolescence. This is the first study to separate the development of anxiety symptoms from that of symptoms of depression.

Cooccurrence of lifestyle risk factors and the explanation of education inequalities in mortality: results from the GLOBE study.

BACKGROUND: To investigate whether the cooccurrence of two lifestyle risk factors (smoking, excessive alcohol consumption, physical inactivity in leisure time) has an additional contribution to the explanation of education inequalities in mortality, over and above the contribution of single risk factors. METHODS: Prospective cohort study, 1991-1998, in the South East of the Netherlands. Participants were 16,980 men and women aged 15-74 years at baseline. RESULTS: Education differences in the cooccurrence of risk factors were of a similar magnitude as education inequalities seen for single risk factors. A significant (P = 0.04) interaction effect on mortality was found between smoking and physical inactivity. Adjustment for both smoking and inactivity reduced the mortality hazard ratio of the lowest level of education by 30% (from 1.66 to 1.46). Further adjustment for the interaction between the two risk factors did not change the hazard ratio significantly. CONCLUSION: The cooccurrence of lifestyle risk factors did not provide any additional contribution to the explanation of education inequalities in mortality, over and above that of single risk factors. However, because risk factors tend to cooccur and have a higher prevalence among lower-educated people, it is still useful to focus interventions on more than one risk factor.