User:Neurobsessed/Genetics of post-traumatic stress disorder

Epigenetics
Gene and environment studies alone fail to explain the importance the developmental stressor timing exposure to the phenotypic changes associated with PTSD. Epigenetic modification is the environmentally induced change in DNA that alters the function rather than the structure of the gene. The biological mechanism of epigenetic modification typically involves the methylation of cytosine within a gene that produces decreased transcription of that segment of DNA. The neuroendocrine alteration seen in animal models parallel those of PTSD in which low basal cortisol and enhanced suppression of cortisol in response to synthetic glucocorticoid becomes hereditary. Lower levels of glucocorticoid receptor (GR) mRNA have been demonstrated in the hippocampus of suicide victims with histories of childhood abuse. It has not been possible to monitor the state of methylation over time, however the interpretation is early developmental methylation changes are long-lasting and enduring. It is hypothesized that epigenetic-mediated changes in the HPA axis could be associated with an increased vulnerability to PTSD following traumatic events. These findings support the mechanism in which early life trauma strongly validates as a risk factor for PTSD development in adulthood by recalibrating the set point and stress-responsivity of the HPA axis. Studies have reported an increased risk for PTSD and low cortisol levels in the offspring of female holocaust survivors with PTSD. Epigenetic mechanisms may also be relevant to the intrauterine environment. Mothers with PTSD produced infants with lower salivary cortisol levels only if the traumatic exposure occurred during the third trimester of gestation. These changes occur via transmission of hormonal responses to the fetus leading to a reprogramming of the glucocorticoid responsivity in the offspring.

Proposal 1: Broaden scope of main paragraph
The main paragraph for PTSD Epigenetics above is largely unorganized, sparse, and loosely backed by citations. Edits to this main paragraph should focus on summarized points on the related subsections below. Topic sentences should include information on single nucleotide polymorphisms (SNP's) of candidate genes through genome wide association studies, the effect of childhood trauma on epigenetic alterations in hippocampal neurons, and the role of adrenocorticotropic hormone (ACTH) and glucocorticoid receptors in the HPA axis for stress response. Further details on the regulation of the HPA axis in PTSD patients can be explained in the subsection below.

The background given on DNA methylation is a positive, but can be expanded. For instance, it should be noted that 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) 18 are the two most frequently found types of DNA methylation involved in PTSD, affecting learning and extinction of conditioned fear. Subsequent subsections should be added in terms of the different downstream genes that are affected by DNA methylation. For instance, HDAC4 has been reported to have DNA methylation differences in PTSD patients.

Proposal 2: Add subsection on HPA Axis
The HPA axis regulates stress response and should be expanded on further since it is a key part of PTSD. Genes responsible for modulation of the HPA axis are upregulated in PTSD response, for instance FKBP5, GR, ACDYAP1R1, and SKA2 [Figure 2]. Noncoding RNA and their sub-types such as miRNA, long noncoding RNA (lncRNA), and retrotransposons are involved in regulating the HPA axis as well. The role of miRNA should be focused on, specifically in regards to the HPA axis. One study found that the miRNA miR-34c was upregulated in a stress-dependent manner in mouse amygdala tissue. In terms of glucocorticoid receptor binding regulation, the gene NR3C1 is found to be associated with the HPA axis and traumatic childhood memory formation. It was found that experiencing childhood trauma increased methylation of CpG sites in the noncoding exon regions of NR3C1, impairing HPA regulation.

Proposal 3: Other potential subsections with limited research
Other genes and regulators in PTSD response include MAOA gene, HTR genes for 5-HT receptors, BDNF, and TET in traumatic memory formation.