Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. OBJECTIVE: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. METHODS: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. RESULTS: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. CONCLUSIONS: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.

The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF). The aim of our two-center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two-center study, 62 adult patients with MDD and 71 healthy matched controls underwent high-resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress-gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met-allele of the BDNF polymorphism.

Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression.

Early emotional stress is associated with a life-long burden of risk for later depression and stressful life events contribute to the development of depressive episodes. In this study we investigated whether childhood stress is associated with structural brain alterations in patients with major depression (MD). Forty-three patients with MD and 44 age as well as gender matched healthy control subjects were investigated using high-resolution magnetic resonance imaging (MRI). Region of interest analysis of the hippocampus, whole brain voxel-based morphometry (VBM) and assessment of childhood stress was carried out. Significantly smaller hippocampal white matter and prefrontal gray matter volume was observed in patients with MD compared to healthy controls. In particular left hippocampal white matter was smaller in patients, who had emotional childhood neglect, compared to those without neglect. For male patients this effect was seen in the left and right hippocampus. Moreover, physical neglect during childhood affected prefrontal gray matter volume in healthy subjects. Both emotional neglect and brain structural abnormalities predicted cumulative illness duration and there was a significant interaction between emotional neglect and prefrontal volumes as well as hippocampal white matter on the illness course. Childhood neglect resulted in hippocampal white matter changes in patients with major depression, pronounced at the left side and in males. Most interestingly, childhood stress and brain structure volumes independently predicted cumulative illness course. Subjects with both, structural brain changes and childhood emotional neglect seem to be at a very high risk to develop a more severe illness course.

Childhood stress, serotonin transporter gene and brain structures in major depression.

The underlying neurobiology of major depression (MD) is likely to represent an interaction between genetic susceptibility and environmental factors such as stress. We investigated, in a multimodal high-resolution magnetic resonance imaging (MRI) genetic study, whether reduced hippocampal volumes and other brain alterations are associated with the tri-allelic polymorphism of the serotonin transporter and childhood stress in patients with MD and healthy subjects. Patients with MD and healthy participants were investigated using high-resolution MRI and genotyping for serotonin transporter polymorphism in the promoter region of the serotonin transporter gene (SLC6A4, 5-HTTLPR). Region of interest analysis of the hippocampus, whole-brain voxel-based morphometry (VBM), and assessment of childhood stress were carried out. Patients carrying the risk S-allele developed smaller hippocampal volumes when they had a history of emotional neglect compared with patients who only had one risk factor (environmental or genetic). In patients, childhood stress also predicted further hippocampal white matter alterations independently from the genotype. Moreover, the left prefrontal cortex was smaller in patients, whereby childhood stress resulted in larger prefrontal volumes in those subjects carrying the non-risk L-allele, suggesting preventive effects. The findings indicate that subjects with both environmental and genetic risk factors are susceptible to stress-related hippocampal changes. Structural brain changes due to stress represent part of the mechanism by which the illness risk and outcome might be genetically mediated.