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

Abstract

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.

Fig. 1

Manhattan plot of genetic associations with cognitive–behavioural therapy response baseline to post-treatment. X-axis shows the top million most associated single nucleotide polymorphisms, arranged by position on the chromosome. Lines show conventional thresholds for genome-wide significance (P = 5 × 10⁻⁸) and suggestive significance (P = 5 × 10⁻⁶).

Fig. 2

Quantile–quantile plot of P-values (pruned for linkage disequilibrium) from genetic associations with cognitive–behavioural therapy response post-treatment. X-axis shows spread of P-values expected under the null chi-squared distribution. Y-axis shows observed data. Grey region shows rough 95% confidence intervals around each point on the line x = y. Lambda median is a measure of inflation of the observed distribution of associations compared with expected null distribution. Lambda ⩽1 implies no inflation.

Fig. 3

Manhattan plot of genetic associations with cognitive–behavioural therapy response baseline to 6 months after treatment.

Fig. 4

Quantile–quantile plot of P-values from genetic associations with cognitive–behavioural therapy response baseline to 6-month follow-up, including lambda median.