A systematic review of methylome-wide associations with anxiety disorders

Anxiety disorders (ANX) are a prevalent public health burden that significantly impair daily functioning and decrease quality of life. A growing body of research suggests that DNA methylation (DNAm), an epigenetic modification that can impact gene expression, may be altered in ANX. The current review used a systematic approach to identify and synthesize the literature regarding methylome-wide association studies (MWASs) of ANX 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 ANX-associated DNAm in blood. In total, 2,023 DNAm sites corresponding to 985 genes were significantly associated with ANX. No DNAm sites significantly replicated across studies and four nominally replicated. This is likely a result of a lack of replication attempts, small sample sizes, and differences in data analysis choices. Findings suggest that ANX-associated DNAm 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 ANX-related alterations to DNAm in whole blood and multiple blood cell-types. Future MWASs of ANX could benefit from larger sample sizes, a standardized analytic pipeline, longitudinal study designs, and the examination of DNAm in additional cell-types and tissues.