A multi-site study of the genetics of child anxiety and predictors of treatment response

Background: Anxiety is a common and debilitating problem for our youth, shows continuity into adulthood and is associated with wide-ranging difficulties. Those individuals who first experience an anxiety disorder during their childhood show the poorest long-term outcomes. For example, such children are much more likely than other children to be absent for significant portions of their schooling missing out on the opportunity for both social and academic development. Whilst it is clear that both genetic and environmental influences are important in the development of anxiety, we know relatively little about the specific factors and mechanisms involved. More is known about the genetics of depression, which has been shown to be genetically similar to anxiety, thus providing several useful starting points for genetic studies of anxiety. Finally, whilst child anxiety is most commonly treated using a ?talking treatment? called cognitive-behaviour therapy (CBT), around two-fifths of patients do not improve. Younger girls seem more likely to respond well, whereas those with worse symptoms or whose parents also have difficulties with anxiety and/or depression respond less well. These two factors suggest that these children may have a heavier genetic loading for anxiety, implying a possible genetic influence on treatment response. Research Plan: Genes for which there is theoretical and experimental evidence for involvement in anxiety or depression will be considered in this study. For example, genes involved in the serotonin system, the target of common anti-depressants such as Prozac, have been shown to play a role in the development and pharmacological treatment of depression, and in several anxiety-related characteristics such as extreme shyness in children. We will consider the role of these and other selected genes in the development and treatment of child anxiety. DNA (genetic material) collected from a sample of 2500 children with clinical anxiety, most of whom are being treated with CBT will be used to examine two core questions. First, are there specific genes associated with childhood anxiety disorders? Second, can we predict treatment outcome from factors such as age, sex, severity of anxiety, parental mental health and specific genes? Identifying genes relevant to the development of anxiety disorders could enable targeted prevention work, whilst knowledge of genes relevant to treatment response could allow for individualised treatment programmes.

Background. Anxiety disorders are highly debilitating illnesses. They affect 5-10% of children at any time and show considerable continuity into adulthood. They are influenced by genetic and environmental factors, but the specific genes involved remain largely unknown. The most common treatment is cognitive-behaviour therapy (CBT), which leads to an improvement in around 60% of cases, thus 40% remain anxious. Younger girls tend to do well following CBT, whereas adolescents and males respond less well. Furthermore, those with more severe symptoms and a history of parental anxiety/depression, also respond poorly indicating that treatment response may be partially under genetic influence.

Objectives. The two key goals are: first, to identify associations between specific candidate genes and childhood anxiety disorder; second, to consider predictors of treatment response including age, sex, symptom severity, parental psychopathology and specific genetic markers.

Design. We will collect DNA from around 2500 children with clinically diagnosed anxiety, the majority of whom are undergoing cognitive-behaviour therapy. Controls consist of 4,000 children from a longitudinal study based at the SGDP Centre. DNA will be extracted from cheek swab samples, and selected markers will be genotyped.

Methodology. Anxiety will be assessed before and after treatment and at the 6-month follow-up. Assessment will be made dichotomously (i.e. diagnosis), and by use of questionnaire scales with both the child and parent as reporter. Furthermore, clinicians will complete a standardised improvement scale following treatment.

Analyses. Associations between genetic markers and anxiety will be considered first for all anxiety disorders as a single group, and then for each anxiety disorder sub-type individually. Comorbidity with depression and other covariates (e.g. sex) will also be considered. Associations will also be tested with respect to variation in symptom levels (i.e. is there a dose-response for the association such that two copies of a risk allele lead to even higher levels of anxiety). Associations with treatment response will be considered in terms of (a) presence/absence of disorder, (b) change in symptom level and (c) clinical rating of improvement. Again, important covariates such as age, sex, symptoms severity, and parental mental health will also be considered.

Scientific and medical opportunities. This programme of research provides the opportunity to collect a unique dataset that will have implications for understanding both the development and treatment of child anxiety. The possibility of predicting treatment outcomes and thus tailoring treatments for children with anxiety disorders is highly valuable in both financial and human cost terms.