C. Ziegler

MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy.

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.

Attachment style and oxytocin receptor gene variation interact in influencing social anxiety

Abstract Objectives: Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene–environment (G × E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands. Methods: Participants (N = 388; 219 females, 169 males; age 24.7 ± 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype. Results: A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes. Conclusions: The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene–environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder.

Influence of 5-HTT variation, childhood trauma and self-efficacy on anxiety traits: a gene-environment-coping interaction study

Environmental vulnerability factors such as adverse childhood experiences in interaction with genetic risk variants, e.g., the serotonin transporter gene linked polymorphic region (5-HTTLPR), are assumed to play a role in the development of anxiety and affective disorders. However, positive influences such as general self-efficacy (GSE) may exert a compensatory effect on genetic disposition, environmental adversity, and anxiety traits. We, thus, assessed childhood trauma (Childhood Trauma Questionnaire, CTQ) and GSE in 678 adults genotyped for 5-HTTLPR/rs25531 and their interaction on agoraphobic cognitions (Agoraphobic Cognitions Questionnaire, ACQ), social anxiety (Liebowitz Social Anxiety Scale, LSAS), and trait anxiety (State-Trait Anxiety Inventory, STAI-T). The relationship between anxiety traits and childhood trauma was moderated by self-efficacy in 5-HTTLPR/rs25531 LALA genotype carriers: LALA probands maltreated as children showed high anxiety scores when self-efficacy was low, but low anxiety scores in the presence of high self-efficacy despite childhood maltreatment. Our results extend previous findings regarding anxiety-related traits showing an interactive relationship between 5-HTT genotype and adverse childhood experiences by suggesting coping-related measures to function as an additional dimension buffering the effects of a gene-environment risk constellation. Given that anxiety disorders manifest already early in childhood, this insight could contribute to the improvement of psychotherapeutic interventions by including measures strengthening self-efficacy and inform early targeted preventive interventions in at-risk populations, particularly within the crucial time window of childhood and adolescence.

Epigenetic signature of MAOA and MAOB genes in mental disorders

Epigenetic processes such as DNA methylation are considered key mechanisms at the crossroads between genetics and environment in the etiology of mental disorders. The monoamine oxidases A and B (MAOA/MAOB) are prime candidates for the investigation into the role of DNA methylation in mental disorders, given their pivotal role in the metabolism of monoamines and as pharmacological targets of potent antidepressant drugs such as tranylcypromine, phenelzine or moclobemide. The present mini-review aims at summarizing and critically discussing the growing body of the literature supporting a role of DNA methylation of the MAOA gene promoter/exon I/intron I region and its interaction with environmental factors in several mental disorders, i.e., anxiety disorders, depression, posttraumatic stress disorder, substance use disorder, conduct disorder/antisocial personality disorder, borderline personality disorder and schizophrenia, as well as some pilot data on MAOB methylation in smokers and patients with borderline personality disorder. Furthermore, first evidence for MAOA methylation to be involved in treatment response prediction and as a potential mechanistic correlate of fear extinction is presented. Altered MAOA gene DNA methylation emerges as a possible pathogenetically relevant epigenetic mechanism in mental disorders. Given robust replication and further functional characterization, MAOA methylation patterns might serve as a peripheral biomarker of disease risk and treatment response informing preventive and personalized therapeutic approaches in the future.