Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

Background

Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.

Aims

To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).

Method

Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.

Results

No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis.

Conclusions

This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.Anxiety disorders are the most common psychiatric disorders, with a lifetime prevalence of ~30%.1 They are a major cause of global disability, and impose considerable economic burdens on society.2,3 They commonly have their onset in childhood or adolescence and have been linked to the occurrence of later disorders, including depression and conduct disorder.1,4 Adults with anxiety disorders show rates of childhood anxiety diagnoses significantly above baseline.5 Given this potential gateway effect, and the distress caused by these disorders, there is a need to optimise and understand treatment effectiveness in childhood.Cognitive–behavioural therapy (CBT) is a first-line treatment for anxiety disorders in the UK, with 59% remission reported immediately post-treatment.6,7 Despite this high reported efficacy, variability exists in patient response that may be influenced in part by genetic variants. Multiple studies examining the genetics of differential response to psychological therapies (therapygenetics8) have been undertaken, and variants in seven genes (5HTT/SLC6A4, TPH2, MAOA, COMT, NGF, BDNF and GRIK4) have been implicated at least once in studies of CBT for anxiety disorders.9 However, findings have proven difficult to replicate,10 and the direction of effects found inconsistent. These problems may result from the low power of small cohort sizes, resulting in a high rate of false positives, and a narrow focus on a few genes that may have limited relevance to the phenotype.Genome-wide association studies (GWAS) provide a hypothesis-neutral alternative, agnostic to prior assumptions of relevance and with the potential to discover novel findings at a single variant level. By analysing thousands of variants across the genome, GWAS yield more information than the candidate gene approach, allowing for the acknowledgement and control of confounds such as ancestry and the quality of genotyping. Genome-wide information can also be used to investigate associations between phenotypic change and different levels of the genetic architecture, including the effect of all variants in a given gene, and the effect of all genotyped variants across the genome. However, the explicit requirement for multiple testing correction in GWAS imposes a need for large sample sizes.Although GWAS have not been used to study response to CBT, they have shown early promise in studying anxiety disorders. Genetic influences on the development of anxiety disorders may indicate processes underlying treatment response, and provide interesting genetic candidates.11 A detailed review of the genetics of anxiety disorders is available elsewhere.12 In brief, one variant, rs7309727 (TMEM132D), was associated with panic disorder in a cohort of European ancestry (P = 1.1 × 10−8, odds ratio (OR) = 1.45 (95% CI 1.20–1.72).13 A variant in the TMEM16B gene was reported at genome-wide significance in a Japanese cohort with panic disorder, but was not significant in replication analyses.14 Two GWAS of post-traumatic stress disorder (PTSD) have identified variants at genome-wide significance in the TLL1 gene (rs6812849, P = 3.13 × 10−9, OR not reported)15 and PRTFDC1 (rs6482463, P = 2.04 × 10−9, OR = 1.47 (95% CI 1.35–1.59)).16 However, these results require replication in larger studies; for example, variants in the RORA gene previously implicated in a GWAS of PTSD failed to attain significance in a larger replication effort.17 No significant findings from the anxiety literature to date had previously been considered in candidate gene studies.12To our knowledge, this is the first GWAS to examine response to psychological therapy in any disorder, and the first to examine treatment response of any kind in anxiety disorders. Participants were drawn from the Genes for Treatment (GxT) study, an international, multisite investigation of clinical, demographic and genetic predictors of response to CBT for anxiety in childhood and adolescence.10,18 Two analyses of association between single nucleotide polymorphisms (SNPs) and response to CBT were conducted, investigating change in symptom severity between baseline and immediately post-treatment (post-treatment), and between baseline and 6 months after treatment cessation (follow-up).