While diagnosis of PTSD is based on behavioral symptom clusters that are most directly associated with brain function, epigenetic studies of PTSD in humans to date have been limited to peripheral tissues. Animal models of PTSD have been key for understanding the epigenetic alterations in the brain most directly relevant to endophenotypes of PTSD, in particular those pertaining to fear memory and stress response. This chapter provides an overview of neuroepigenetic studies based on animal models of PTSD, with an emphasis on the effect of stress on fear memory. Where relevant, we also describe human-based studies with relevance to neuroepigenetic insights gleaned from animal work and suggest promising directions for future studies of PTSD neuroepigenetics in living humans that combine peripheral epigenetic measures with measures of central nervous system activity, structure and function.
by
Naomi Sadeh;
Jeffrey M. Spielberg;
Mark W. Logue;
Erika J. Wolf;
Alicia K Smith;
Joanna Lusk;
Jasmeet P. Hayes;
Emily Sperbeck;
William P. Milberg;
Regina E. McGlinchey;
David H. Salat;
Weleetka C. Carter;
Annjanette Stone;
Steven A. Schichman;
Donald E. Humphries;
Mark W. Miller
Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation adj). Specifically, DNA methylation adj was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation adj and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation adj of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.
Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Genetic association studies of the BDNF Val66Met polymorphism (rs6265) in geriatric depression have produced inconsistent results. A meta-analysis of studies was conducted to compare the frequency of the BDNF Val66Met variant between cases with geriatric depression and age-matched controls. A total of five studies involving 523 cases with geriatric depression and 1,220 psychiatrically healthy controls was included. Met allele carriers had an increased risk for geriatric depression when compared to Val/Val homozygotes (P=0.004, OR=1.48, 95% CI=1.13-1.93). Our findings suggest the BDNF Met allele may confer increased risk for depression as individual age.