RESUMO
OBJECTIVE: Epigenetic modifications such as DNA methylation may play a key role in the aetiology and serve as biomarkers for post-traumatic stress disorder (PTSD). We performed a genomewide analysis to identify genes whose DNA methylation levels are associated with PTSD. METHOD: A total of 211 individuals comprising Australian male Vietnam War veterans (n = 96) and males from a general population belonging to the Grady Trauma Project (n = 115) were included. Genomewide DNA methylation was performed from peripheral blood using the Illumina arrays. Data analysis was performed using generalized linear regression models. RESULTS: Differential DNA methylation of 17 previously reported PTSD candidate genes was associated with PTSD symptom severity. Genomewide analyses revealed CpG sites spanning BRSK1, LCN8, NFG and DOCK2 genes were associated with PTSD symptom severity. We replicated the findings of DOCK2 in an independent cohort. Pathway analysis revealed that among the associated genes, genes within actin cytoskeleton and focal adhesion molecular pathways were enriched. CONCLUSION: These data highlight the role of DNA methylation as biomarkers of PTSD. The results support the role of previous candidates and uncover novel genes associated with PTSD, such as DOCK2. This study contributes to our understanding of the biological underpinnings of PTSD.
Assuntos
Distúrbios de Guerra/genética , Metilação de DNA/genética , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos , Idoso , Austrália , Biomarcadores/metabolismo , Proteínas Ativadoras de GTPase , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Guerra do VietnãRESUMO
This corrects the article DOI: 10.1038/mp.2016.204.
RESUMO
The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3ß phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.
Assuntos
Transtornos de Ansiedade/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Negro ou Afro-Americano/genética , Animais , Ansiedade/diagnóstico por imagem , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/farmacologia , Citocromo P-450 CYP2C19/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/genética , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Homeostase/genética , Homeostase/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Neurogênese/genética , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Our understanding of major depressive disorder (MDD) has focused on the influence of genetic variation and environmental risk factors. Growing evidence suggests the additional role of epigenetic mechanisms influencing susceptibility for complex traits. DNA sequence within discordant monozygotic twin (MZT) pairs is virtually identical; thus, they represent a powerful design for studying the contribution of epigenetic factors to disease liability. The aim of this study was to investigate whether specific methylation profiles in white blood cells could contribute to the aetiology of MDD. Participants were drawn from the Queensland Twin Registry and comprised 12 MZT pairs discordant for MDD and 12 MZT pairs concordant for no MDD and low neuroticism. Bisulphite treatment and genome-wide interrogation of differentially methylated CpG sites using the Illumina Human Methylation 450 BeadChip were performed in WBC-derived DNA. No overall difference in mean global methylation between cases and their unaffected co-twins was found; however, the differences in females was significant (P=0.005). The difference in variance across all probes between affected and unaffected twins was highly significant (P<2.2 × 10⻹6), with 52.4% of probes having higher variance in cases (binomial P-value<2.2 × 10⻹6). No significant differences in methylation were observed between discordant MZT pairs and their matched concordant MZT (permutation minimum P=0.11) at any individual probe. Larger samples are likely to be needed to identify true associations between methylation differences at specific CpG sites.
