ABSTRACT
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.
Subject(s)
Epigenesis, Genetic , Stress Disorders, Post-Traumatic/genetics , Adult , Cohort Studies , DNA Methylation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genetic Predisposition to Disease , Genetic Testing/methods , Humans , Immediate-Early Proteins/genetics , Immediate-Early Proteins/metabolism , Longitudinal Studies , Male , Military Personnel/psychology , Prospective Studies , Repressor Proteins , Stress Disorders, Post-Traumatic/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.
Subject(s)
DNA Methylation/genetics , Genome-Wide Association Study/statistics & numerical data , Prenatal Exposure Delayed Effects/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Stress, Physiological/genetics , Stress, Psychological/genetics , Animals , Behavior, Animal , Female , Gene Expression/genetics , Hippocampus , Mice , Mice, Inbred C57BL , PregnancyABSTRACT
The gene encoding the neuronal nicotinic acetylcholine receptor alpha7 subunit (CHRNA7) is located on chromosome 15q13.2. This region was suggested to be involved in the etiopathogenesis of: (a) schizophrenia combined with a neurophysiological deficit; (b) lithium-responsive bipolar disorder; and (c) familial catatonic schizophrenia (periodic catatonia). Therefore, members of a large family with periodic catatonia strongly supporting the chromosome 15q13-22 region were genotyped with polymorphic markers localized around the CHRNA7 locus. A recombination event distally of marker D15S144 leading to the exclusion of the CHRNA7 locus from this candidate region was detected in one branch of the pedigree. This result provides strong evidence that a gene located telomeric to CHRNA7 is causative for the pathogenesis of catatonic schizophrenia in this family.
