Methylome-Wide Association Studies of Physical Injury Stratified by Depression Status Assesses Exposure by Diagnosis Effects in Oxytocin Signaling and Synaptic Plasticity.

BACKGROUND

Physical injury is associated with psychological trauma and is a risk factor for major depressive disorder (MDD). DNA methylation has been suggested as a key mediator of psychopathology following trauma.

METHODS

We performed phenotypic, methylome-wide association (MWASs) and methylome-wide environment interaction (MWEISs) studies of traumatic injury in individuals with recurrent major depression (rMDD), individuals with single/recurrent MDD (MDD), and control participants (n = 4308). We investigated the effect of genetic and epigenetic variation in the biological pathways with evidence of DNA methylation × traumatic injury interactions on the risk of trauma exposure, posttraumatic stress disorder (PTSD), and MDD in an independent sample (n = 2759) using gene set enrichment, methylation, and polygenic risk scores, as well as single nucleotide polymorphism (SNP) heritability analyses.

RESULTS

Nominally significant MWEIS association for traumatic injury in control participants versus participants with rMDD was associated with CpG sites at the first exon, 3' untranslated region, and exon boundaries and in the oxytocin-signaling pathway. Differential DNA methylation in rMDD was associated with gene expression in the limbic lobes and supraoptic nuclei brain regions. Downstream analyses identified pathways associated with rMDD and PTSD including axon development and neuron projection organization for both methylation risk scores and SNP heritability and polygenic risk scores weighted by trauma phenotypes.

CONCLUSIONS

Our results suggest that oxytocin and synaptic plasticity-related pathways show differing patterns of DNA methylation associated with traumatic injury dependent on diagnosis, highlighting their involvement in psychopathology after traumatic injury, potentially explaining the heterogeneity seen in response to oxytocin treatment for stress-related disorders. Further studies using longitudinal samples will be required to confirm this.