A systematic review of methylome-wide associations with anxiety disorders.

Anxiety disorders are a prevalent public health burden that significantly impair daily functioning and decrease quality of life. A growing body of research suggests DNA methylation (DNAm), an epigenetic modification that can impact gene expression, may be altered in anxiety disorders. The current review used a systematic approach to identify and synthesize the literature regarding epigenome-wide association studies (EWASs) of anxiety disorders in humans. We screened 804 articles returned by a search in PubMed in May 2025 and identified 12 studies for inclusion. All included studies examined DNAm in blood. In total, 2023 DNAm sites corresponding to 985 genes were significantly associated with anxiety disorders. Three DNAm sites significantly replicated across studies and four nominally replicated, meeting methylome-wide significance in one study and nominal significance (p < 0.05) in at least one other. This low replicability is likely a result of phenotypic heterogeneity, small sample sizes, the use of different multiple testing correction methods, and inconsistent adjustment for relevant comorbidities. Findings suggest DNAm associated with anxiety disorders may promote dysregulation of immune and inflammatory processes, some possibly sex-dependent. Collectively, the findings from studies included in this review provide preliminary evidence of DNAm alterations related to anxiety in whole blood and multiple blood cell-types. Future EWASs of anxiety disorders could benefit from using more ethnically diverse participants and longitudinal study designs.