ABSTRACT: BACKGROUND:Currently the leading cause of global disability, clinical depression is a heterogeneous condition characterised by low mood, anhedonia and cognitive impairments. Its growing incidence among young people, often co-occurring with self-harm, is of particular concern. We recently reported very high rates of depression among first year university students in Northern Ireland, with over 25% meeting the clinical criteria, based on DSM IV. However, the causes of depression in such groups remain unclear, and diagnosis is hampered by a lack of biological markers. The aim of this exploratory study was to examine DNA methylation patterns in saliva samples from individuals with a history of depression and matched healthy controls. RESULTS:From our student subjects who showed evidence of a total lifetime major depressive event (MDE, n = 186) we identified a small but distinct subgroup (n = 30) with higher risk scores on the basis of co-occurrence of self-harm and attempted suicide. Factors conferring elevated risk included being female or non-heterosexual, and intrinsic factors such as emotional suppression and impulsiveness. Saliva samples were collected and a closely matched set of high-risk cases (n = 16) and healthy controls (n = 16) similar in age, gender and smoking status were compared. These showed substantial differences in DNA methylation marks across the genome, specifically in the late cornified envelope (LCE) gene cluster. Gene ontology analysis showed highly significant enrichment for immune response, and in particular genes associated with the inflammatory skin condition psoriasis, which we confirmed using a second bioinformatics approach. We then verified methylation gains at the LCE gene cluster at the epidermal differentiation complex and at MIR4520A/B in our cases in the laboratory, using pyrosequencing. Additionally, we found loss of methylation at the PSORSC13 locus on chromosome 6 by array and pyrosequencing, validating recent findings in brain tissue from people who had died by suicide. Finally, we could show that similar changes in immune gene methylation preceded the onset of depression in an independent cohort of adolescent females. CONCLUSIONS:Our data suggests an immune component to the aetiology of depression in at least a small subgroup of cases, consistent with the accumulating evidence supporting a relationship between inflammation and depression. Additionally, DNA methylation changes at key loci, detected in saliva, may represent a valuable tool for identifying at-risk subjects.
