Evidence for epigenetic alterations in PTSD

Rationale/statement of the problem : Neuropeptide Y (NPY) is a peptide with behaviorally relevant effects on the hippocampus and is thought to function as an endogenous anxiolytic. In prior work, we reported that veterans who had recovered from combat-related post-traumatic stress disorder (PTSD) had higher levels than those who were not combat exposed. NPY levels were significantly associated with the extent of symptom improvement, suggesting that plasma NPY levels may represent a biological correlate of resilience to, and/or recovery from, the adverse effects of trauma exposure. Cytosine methylation of the glucocorticoid gene (GR methylation) has been associated with PTSD risk and/or symptom expression. GR methylation is influenced by environmental factors that can result in enduring differences in function, including neuroendocrine regulation. As the NPY gene has glucocorticoid response elements, levels of circulating NPY represent a potential indicator of alterations in GR responsivity. Methods : The relationship of NPY to PTSD and GR methylation was examined in two samples. In the first sample, veterans who developed PTSD following combat exposure were compared to those who did not develop PTSD. In a second sample, veterans with combat-related PTSD were assessed prior to and following a course of prolonged exposure (PE). Results : In the cross-sectional study, veterans with PTSD had higher NPY levels than those who never developed PTSD (t (62) = − 1.99, p=0.05; 95.8±45.6 pm/l vs. 73.9±41.5 pm/l). NPY associated with number of GR methylated sites in the full sample (r=0.35, n=64, p=0.005), but not with average percent methylation (r= − 0.05). When the associations were examined separately by PTSD group status, results showed a positive association between NPY and number of methylated sites (r=0.36) as well as percent methylation (r=0.38) in veterans with PTSD. However, NPY was only associated with the number of methylated sites (r = 0.35) in the subjects who did not develop PTSD following combat exposure. In the treatment study, plasma NPY levels increased among veterans who responded to treatment (who no longer met diagnostic criteria for PTSD following PE), compared to treatment non-responders, as indicated by a significant group æ time interaction (F1,14 = 5.48, p=0.035). While plasma NPY was comparable in the two groups at pretreatment (responders: 71.4±20.3 pm/l, non-responders: 71.0±16.0 pm/l), responders had higher plasma NPY (84.0±24.2 pm/l) relative to non-responders (61.0±15.4 pm/l). Both pretreatment number of GR methylated sites (r=0.53, n=16, p=0.04) and average percent GR methylation (r=0.75, n=15, p=0.001) were associated with higher plasma NPY at post-treatment. Conclusion : To the extent that improvement from symptomatic PTSD may involve a mobilization of endogenous mechanisms to reduce hyperarousal and other post-trauma sequellae, the results of these studies are consistent in suggesting a role for NPY. NPY was elevated in a sample of combat veterans with PTSD, and increased in association with PTSD improvement in response to trauma-focused treatment. GR methylation was associated with combat-related PTSD in a cross-sectional study, and with treatment associated improvement in PTSD. These findings suggest that epigenetic modification of the GR gene may be associated with resilience in PTSD