Monoamine Oxidase A Gene Methylation and Its Role in Posttraumatic Stress Disorder: First Evidence from the South Eastern Europe (SEE)-PTSD Study

Abstract

BackgroundPosttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity.MethodsMonoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters.ResultsIn the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D).ConclusionsThe present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

“…The mitochondrial enzyme monoamine oxidase A (MAOA) is responsible for the degradation of serotonin as well as epinephrine and NE and a meta‐analysis found an association between a variable number of tandem repeats polymorphism (uVNTR) in the MAOA promoter region and MDD, but limited to Asians (Fan et al, ). In addition, epigenetic modifications by DNA methylation of the MAOA gene have been associated with PTSD (increased methylation status) and panic disorder (decreased methylation status) as well as the occurrence of positive and negative life events (Domschke et al, ; Ziegler et al, ). Another enzyme in the serotonin metabolism is tryptophan hydroxylase 2 ( TPH2 ), the rate‐limiting enzyme in the synthesizing pathway for brain serotonin (Invernizzi, ).…”

Post-Traumatic Stress Disorder Chronification via Monoaminooxidase and Cortisol Metabolism

“…Clinical data revealed the implications of MAO activity to psychotic features in patients with PTSD [14]. MAO-A is one of the key enzymes mediating the turnover of biogenic amines, such as norepinephrine (NE), and is thus to be considered a major candidate molecule in PTSD and potentially, enhanced NE signaling via MAO-A gene hypermethylation, as discussed recently in order to make personalized treatment decisions [15]. Moreover, an activation of MAO-A expression in neurons via higher ability to receptor binding was described for glucocorticoids [10].…”

The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

“…For uncovering the individual methylation profiles, quantitative analysis of CpG site specific methylation (relative peak heights C/C + T) was performed with Epigenetic Sequencing Methylation analysis software (ESME) as recommended (Lewin, Schmitt, Adorjan, Hildmann, & Piepenbrock, ) and described previously (Domschke et al, ; Schartner et al, ; Tadić et al, ; Ziegler et al, ; Ziegler et al, ). This included quality control, correction for incomplete bisulfite conversions, normalization of signals, and alignment of own generated sequence trace files and reference sequences (public databases).…”