Methylome-wide association study in blood suggests cell type-specific relationships between DNA methylation and lifetime anxiety

Anxiety disorders are prevalent and can greatly impact well-being. The biological mechanisms behind anxiety are not fully understood, but growing evidence suggests a role for DNA methylation. Here, we conduct a large-scale methylome-wide association study of lifetime anxiety in 14,443 participants (1817 cases and 12,626 controls) in whole blood, and, through epigenomic deconvolution, 12 different blood cell types. We detect four CpG associations at methylome-wide significance in whole blood, and a range between 15 and 124 associations among the cell types. Top cell type-specific findings include genes potentially involved in stress response such as FAM171A2 and VIPAS39 and genes that have been previously linked to anxiety, such as NCOR1. Whole blood and all cell type-specific findings significantly overlap with findings from two previous methylome-wide association studies of lifetime anxiety and an anxiety GWAS, suggesting results are robust. Pathway analyses broadly implicate anxiety-related impacts on cellular stress response. Analyses of five epigenetic clocks suggest DNA methylation-based phenotypic aging and pace of aging may be accelerated in anxiety. Our results support a cell type-specific relationship between DNA methylation and anxiety and highlight the utility of including cell type-specific analyses in whole blood studies of DNA methylation.