RESUMO
In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.
Assuntos
Epigênese Genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Estudos de Coortes , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Estudos Longitudinais , Masculino , Militares/psicologia , Estudos Prospectivos , Proteínas Repressoras , Transtornos de Estresse Pós-Traumáticos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the development of post-deployment psychopathology. GR-1F methylation (52 loci) was quantified using pyrosequencing in whole blood of 92 military men 1 month before and 6 months after a 4-month deployment period to Afghanistan. GR-1F methylation overall (mean methylation and the number of methylated loci) and functional methylation (methylation at loci associated with GR exon 1F expression) measures were examined. We first investigated the effect of exposure to potentially traumatic events during deployment on these measures. Subsequently, changes in GR-1F methylation were related to changes in mental health problems (total Symptom Checklist-90 score) and posttraumatic stress disorder (PTSD) symptoms (Self-Report Inventory for PTSD). Trauma exposure during deployment was associated with an increase in all methylation measures, but development of mental health problems 6 months after deployment was only significantly associated with an increased functional methylation. Emergence of post-deployment PTSD symptoms was not related to increased functional methylation over time. Pre-deployment methylation levels did not predict post-deployment psychopathology. To our knowledge, this is the first study to prospectively demonstrate trauma-related increases in GR-1F methylation, and it shows that only increases at specific functionally relevant sites predispose for post-deployment psychopathology.
Assuntos
Metilação de DNA , Exposição à Violência , Transtornos Mentais/genética , Receptores de Glucocorticoides/genética , Adolescente , Adulto , Campanha Afegã de 2001- , Epigênese Genética , Éxons , Humanos , Estudos Longitudinais , Masculino , Saúde Mental , Pessoa de Meia-Idade , Militares , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Transtornos de Estresse Pós-Traumáticos/genética , Estresse Psicológico , Adulto JovemRESUMO
Can a gene defect be responsible for the occurrence in an individual, at a particular age, of such a muscle twitch followed by relaxation called: "myoclonus" and defined as sudden, brief, shock-like movements? Genetic defects could indeed determine a subsequent cascade of molecular events (caused by abnormal encoded proteins) that would produce new aberrant cellular relationships in a particular area of the CNS leading to re-built "myoclonogenic" neuronal networks. This can be illustrated reviewing some inherited neurological entities that are characterized by a predominant myoclonic picture and among which a clear gene defect has been identified. In the second part of this chapter, we will also propose a new point of view on how some structural genes could, under certain conditions, when altered, produced idiopathic generalized epilepsy with myoclonic jerks, taking juvenile myoclonic epilepsy (JME) and the myoclonin (EFHC-1) gene as examples.
