Methylome-wide association studies of physical injury stratified by depression status assesses exposure by diagnosis effects in oxytocin-signaling and synaptic plasticity.

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. We performed phenotypic, methylome-wide (MWAS) and methylome by diagnosis interaction (MWEIS) studies of traumatic injury in individuals with recurrent major depression (rMDD), single/recurrent MDD (MDD) and controls (n = 4,308). We investigated the effect genetic and epigenetic variation in the biological pathways with evidence of DNA methylation x traumatic injury interactions on the risk of trauma exposure, PTSD and MDD in an independent sample (n = 2,759) using gene set enrichment, methylation and polygenic-risk scores, and SNP heritability analyses. Nominally significant MWEIS for traumatic injury in controls versus rMDD were associated with CpG sites at the first exon, 3’ UTR 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 found pathways associated with rMDD and PTSD including axon development and neuron projection organisation for both methylation-risk scores and SNP heritability, and polygenic-risk scores weighted by trauma phenotypes. 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.