User:Methyliodide/Epigenetics of Personality Disorders

Epigenetics of Borderline Personality Disorder
While epigenetic mechanisms have been studied in many psychiatric disorders, the epigenetic mechanisms contributing to personality disorders, such as BPD, are less understood. Epigenetic studies showed that histone modifications have not been found to be associated with BPD--only studies on methylation pattern deviations in relation to the epigenetics of personality disorders were found. Therefore, DNA methylation is an important factor in the epigenetic mechanisms behind BPD and is useful in understanding the interactions or risk factors that influence the disorder. There are no epigenetic studies of other common personality disorders, such as narcissistic, histrionic, anankastic, avoidant, paranoid, and schizoid personality disorder.

DNA Methylation
Individual development and phenotypic characteristics of bipolar personality disorder were found to involve methylation of the genes BDNF, NR3C1, DRD2, HTFR2A, HTR3A, COMT, MAOA, and PRIMA1 in various studies.

NR3C1 Methylation, Stress, and the HPA axis
It does not appear that any single set of epigenetic modifications are uniquely associated with BPD, as other comorbid mental illnesses appear to share similar epigenetics profiles. In a study on the relationship between the severity/type of trauma and NR3C1 methylation, it was found that repetition of abuse and sexual abuse and penetrative sexual abuse were correlated with higher methylation levels. A comparison of individuals with BPD (n=101) to those with major depressive disorder (n=99) revealed that subjects with BPD had higher NR3C1 exon 1F methylation levels specifically in peripheral blood leucocytes, suggesting that peripheral blood may be a means by which environmental factors affect these epigenetic processes. The hypothalamic-pituitary-adrenal axis (HPA axis) is impacted by epigenetic modifications of NR3C1, which may explain the mechanism by which childhood trauma leads to adulthood psychopathology. In addition to this, increased NR3C1 methylation in newborns is linked to prenatal exposure to the mother's stress as a fetus.

The HPA axis is a key stress response system; its dysfunction is prevalent in the BPD patient population and mirrors that of PTSD. When contextualizing BPD as a stress-related disorder, the Trier Social Stress Test (TSST) has been found to be the most useful and appropriate standardized method to study HPA function and stress hormone reactivity. The TSST consists of a 3-minute anticipatory period, a 5-minute public speaking task, and a 5-minute mental arithmetic task; these three activities are all done in front of a team of "experts". Before, after, and during the TSST, subjective mood ratings, salivary cortisol, heart rate, and skin conductance levels were assessed. Several studies conducted using the TSST have concluded that female individuals with BPD had reduced cortisol levels, compared to subjects with Cluster C personality disorders and/or healthy controls. However, another study reported contradictory findings of increased cortisol reactivity in females with BPD and reduced cortisol levels in males with BPD after the TSST challenge. It is fair to say that sex and sex hormones are confounding variables when assessing HPA activity in individuals with BPD. While the mechanisms are unknown, testosterone has been found to have an inhibitory effect on HPA activity, while estradiol appears to enhance it. Epigenetic modifications of genes linked to BPD are generally more common in females than males, and have been shown to influence the X chromosome as well.

Collectively, these data on stress and HPA axis dysfunction provide strong evidence confirming that BPD development is largely due to environmental and gene interactions. BPD not only mirrors the HPA dysfunction of PTSD, but also has additional similarities at the etiological, neurobiological, and clinical level. The key difference lies in the timing of trauma exposure--BPD diagnoses are the more likely outcome of early life trauma, while PTSD diagnoses are mainly the outcome of trauma exposure in adulthood. In this context, modulation of stress response may prevent the onset of BPD.

In a study conducted by Dammann et al., elevated methylation levels were found in the genes HTR2A, NR3C1, and s-COMT for subjects with BPD (n=26), compared to healthy controls (n=11). In addition to this, methylation of MAOA and MAOB in female subjects were higher in BPD. CpG sites of MAOA (CpG4), MAOB (CpG5), NR3C1 (CpG1 and 5) and s-COMT (CpG1 and 2) were significantly higher methylated in BPD patients.

Other Relevant Genes
Since DBT is an established treatment for BPD, its effects on epigenetic regulation have also been studied in analyzing other potential biomarkers, such as the genes APBA3 and MCF2. Prior to DBT treatment, both of these genes were much higher methylated in individuals with BPD. The mechanistic role of APBA3 and MCF2 in BPD is unknown. It is known that APBA3 plays a role in normal neuronal processes, as it is an amyloid beta precursor binding protein. Thus, normal neuronal and synaptic functions may be disturbed by differential DNA methylation of APBA3, making this a potential influencing factor for the development of BPD. Similarly, MCF2 plays a role in neuronal development and has been found to be linked to schizophrenia and autism. More studies are needed to clarify the exact roles of APBA3 and MCF2 in BPD.

BPD Treatments and Associated Research
Research shows that there has been some success in treating self-harm behaviors with opioid antagonists but its application to BPD is vague due to the retrospective study designs used and subject demographics. Other research points to the use of vasopressin antagonists as a potential treatment for personality disorders. Researchers found that, for BPD subjects, elevated vasopressin concentrations in CSF were positively correlated with enhanced social behaviors such as aggression.