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Differential DNA methylation in peripheral tissues has been associated with Borderline Personality Disorder (BPD). Alterations have been found in several genes, among them the Catechol-O-methyltransferase (COMT) gene. COMT is a known neuropsychiatric candidate gene, which contains a genotype variant (Val108/158Met) that affects protein function and has been found associated with several psychiatric disorders. In addition, this variant also affects COMT DNA methylation. However, in previous epigenetic studies, the DNA methylation results have not always been controlled for genotype, even though overrepresentation of the Met allele has been frequently reported in cohorts of BPD patients. Therefore, in the present study, we investigated whether alteration of COMT DNA methylation in BPD patients is indeed associated with mental health status or merely influenced by a differential distribution of the COMT genotype between BPD patients and healthy control individuals. We found significant group differences, as well as a strong effect of genotype on COMT DNA methylation. While the direction of effect was different compared to a previous study, our study supports the finding of altered COMT DNA methylation in patients with BPD and reinforces the need to include genotype information in future DNA methylation studies of COMT.

Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information.

Background Alcohol Dependence (AD) is a severe disorder that has long-lasting detrimental consequences, resulting in considerable health, economic and societal burden. According to the World Health Organization, alcohol related diseases account for approximately 3.3 million deaths per year (WHO, 2014). The pathogenesis of AD is complex, as the disease arises from the interaction of genetic as well as environmental factors. One of the most compelling candidate mechanisms for the mediation of such gene x environment effects is epigenetic regulation, among which DNA methylation is the most frequently studied mechanism. In fact, several recent studies have shown an association of alcohol dependence with DNA methylation (DNAm), suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. Methods In the present study, we assessed genome-wide DNAm profiles of purified CD3+ T-cells of a well-characterized cohort of long-term chronic AD patients participating in a clinical 3-week alcohol treatment program, along with the profiles of healthy controls closely matched for sex, age, ethnicity and smoking behaviour. 42,43 Furthermore, by comparing the patients before and after 3 weeks of participating in a clinical alcohol treatment program, we sought to identify differentially methylated sites that may play a potential role in alcohol withdrawal and early recovery. In order to test whether our findings were robust, we validated four of our top-ranked hits by pyrosequencing, replicated the top-ranking hits in an independent second cohort of AD patients and matched controls and additionally confirmed the top-ranking hits in whole blood DNA of our cohort samples. Results We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNAm was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNAm of HECW2 and SRPK3 in whole blood. Discussion The reduction in mean global DNAm observed in AD patients and our finding that DNAm in patients reverts back to levels comparable to those in controls after alcohol treatment are supported by previous studies. However, the top hits of differentially methylated sites derived from T-cells did not overlap with previously reported associations of AD with DNAm.This can at least in part be explained by the use of heterogeneous biological material (i.e. whole blood, PBMCs), differences in the cohorts used or in the strategies applied to match patients and controls as well as by varying methodologies for DNAm measurement, with reduced or discordant coverage of CpG sites in previous studies. Still, our top-ranking hits in HECW2 and SRPK3 might contribute to reveal mechanisms that may play a role in AD. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising blood-based candidates to follow up in future studies.

Background Coping with the complexity of our daily life requires cognitive flexibility and control over emotions and behavior. Deficits in cognitive control are often involved in the psychopathology of psychiatric diseases, e.g. Major Depressive Disorder (MDD), a severe mental illness characterized by increased receptiveness for negative stimuli and unbalanced emotion processing. On a neural basis, MDD as well as deficient cognitive control are associated with hypoactivity of the Dorsolateral Prefrontal Cortex (dlPFC). Transcranial Direct Current Stimulation (tDCS) is a well-established brain stimulation technique inducing targeted modulation of cortical activity. It is discussed as promising approach to support conventional psychiatric therapies but so far little is known about the underlying molecular mechanisms. Epigenetic changes might be a potential mechanism how tDCS effects manifest as long-lasting cognitive improvements and amelioration of psychiatric symptoms. In two previous stimulation genetics studies, we demonstrated an influence of the COMT genotype, which renders this gene an interesting candidate for a stimulation epigenetics study. Methods For the present study, healthy male participants performed a potentially frustrating and challenging task, a 2-back version of the Paced Auditory Serial Addition Task (PASAT), once under sham stimulation and once under anodal tDCS over the left dlPFC. Participants’ affective states were assessed several times throughout the experiment. To investigate epigenetic effects of the stimulation protocol, one blood sample was collected before the PASAT and five blood samples were collected after task completion. DNA methylation status of the COMT gene promoter region was assessed by pyrosequencing. Results Our results provide further evidence that anodal tDCS applied to the left dlPFC improves task performance. In addition, tDCS seems to prevent task-induced decline in positive affect, whereas task-related negative affect was suppressed. Furthermore, our data suggest a dynamic increase in DNA methylation of the COMT gene promoter region in response to the task. Depending on the type of stimulation (anodal or sham) participants received during their first session, they showed different methylation levels in their second session. Discussion Together, our data extend previous findings showing improved cognitive performance under anodal stimulation, which correlates with enhanced control over emotions. In response to stimulation, we observed increased positive affect and reduced negative affect, which supports the idea of tDCS as a potential treatment approach for MDD targeting the negativity bias. In addition, we observed dynamic methylation changes in the COMT gene promoter region in response to a challenging cognitive task, which might be differentially modulated by tDCS. COMT is an enzyme involved in the degradation of dopamine and dopamine levels are critical in executive functioning. Therefore, the observed changes in COMT promoter methylation might indicate an adaptive process to the task and they might indicate an underlying mechanism to induce long-lasting tDCS effects.