EPIGENOME-WIDE ASSOCIATION STUDIES IDENTIFY NOVEL EPIGENETIC SIGNATURES OF ANXIETY

Abstract

Anxiety disorders are a highly prevalent public health burden that significantly impair daily functioning and decrease quality of life. While they are moderately heritable, environmental factors also contribute and may interact with genetics to confer risk for anxiety disorders. A growing body of research suggests that DNA methylation may play a role as it is involved in critical adaptations to changing environments and thus may confer risk for anxiety disorders by invoking a maladaptive response to environmental triggers. A recent systematic review of epigenome-wide association studies of anxiety disorders found no overlapping DNA methylation sites across studies, which is likely due to small sample sizes in individual studies. Here, we aim to overcome this limitation by combining data from existing studies.

As the Psychiatric Genomics Consortium Anxiety Epigenetics Workgroup, we will conduct the largest cross-sectional meta-analysis of epigenome-wide association studies of anxiety disorders to date, involving over 18,434 participants (3,577 anxiety cases and 14,857 controls) from 12 cohorts. DNA methylation was assayed from blood using Illumina HumanMethylation 450 or MethylationEPIC (850K) Beadchips, or enrichment-based sequencing approaches. Within each cohort, DNA methylation will be regressed on anxiety case status, sex, age, estimated blood cell proportions, ancestry, smoking, and any cohort-specific comorbidities (e.g., depression). An inverse variance-weighted meta-analysis will be performed. Primary analyses will focus on current clinically assessed anxiety disorder diagnoses (i.e., cases had at least one current anxiety disorder diagnosis), while replication efforts will examine self-reported anxiety diagnoses. Secondary analyses will focus on identifying methylation sites specific to individual anxiety disorders as, for example, panic disorder may have different methylation signatures than fear-related disorders like specific phobias.

Preliminary results identified 28 sites significantly associated with anxiety case status (p < 9.0 × 10-08). The top finding was located in PFKP, a key regulator of glycolysis, which may impact anxiety by altering glucose metabolism in brain regions involved in emotion regulation. Characterization of top findings suggested potential dysregulation of cellular stress response systems as well as immune and inflammatory pathways. Replication efforts and disorder-specific analyses are ongoing. Although further work is needed, our preliminary results suggest DNA methylation as a promising approach to study biological mechanisms in anxiety research.