Epigenetic markers of disease risk and psychotherapy response in anxiety disorders – a longitudinal analysis of the DNA methylome

Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders ( N = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly ( p ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., GABBR2 , GABRD , GAST , IL12RB2 , LINC00293 , LOC101928626 , MFGE8 , NOTCH4 , PTPRN2 , RIMBP2 , SPTBN1 ) or in a recent cross-anxiety disorders EWAS ( TAOK1 ) after pre-processing and quality control ( N = 378 vs. N = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively ( p < 1E–5) associated with treatment response at POST ( ABCA7 , ADRA2C , LTBR , RPSAP52 , SH3RF3 , SLC47A2 , ZNF251 ) and FU ( ADGRD1 , PRSS58 , USP47 ). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU ( ADIPOR2 , EIF3B , OCA2 , TMCC1 ). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.