DNA methylation changes related to nutritional deprivation : A genome-wide analysis of population and in vitro data

Background: DNA methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits. However, genome-wide analyses are scarce and cross-sectional analyses are hampered by many potential confounding factors. Moreover, causal relations are hard to identify due to the lack of controlled experimental designs. In the current study, we therefore combined a comprehensive assessment of genome-wide DNA methylation differences in people exposed to the great Chinese famine in utero with an in vitro study in which we deprived fibroblasts of nutrition. Methods: We compared whole blood DNA methylation differences between 25 individuals in utero exposed to famine and 54 healthy control individuals using the HumanMethylation450 platform. In vitro, we analyzed DNA methylation changes in 10 fibroblast cultures that were nutritionally deprived for 72 h by withholding fetal bovine serum. Results: We identified three differentially methylated regions (DMRs) in four genes (ENO2, ZNF226, CCDC51, and TMA7) that were related to famine exposure in both analyses. Pathway analysis with data from both Chinese famine samples and fibroblasts highlighted the nervous system and neurogenesis pathways as the most affected by nutritional deprivation. Conclusions: The combination of cross-sectional and experimental data provides indications that biological adaptation to famine leads to DNA methylation changes in genes involved in the central nervous system

DNA methylation changes related to nutritional deprivation : A genome-wide analysis of population and in vitro data

Background: DNA methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits. However, genome-wide analyses are scarce and cross-sectional analyses are hampered by many potential confounding factors. Moreover, causal relations are hard to identify due to the lack of controlled experimental designs. In the current study, we therefore combined a comprehensive assessment of genome-wide DNA methylation differences in people exposed to the great Chinese famine in utero with an in vitro study in which we deprived fibroblasts of nutrition. Methods: We compared whole blood DNA methylation differences between 25 individuals in utero exposed to famine and 54 healthy control individuals using the HumanMethylation450 platform. In vitro, we analyzed DNA methylation changes in 10 fibroblast cultures that were nutritionally deprived for 72 h by withholding fetal bovine serum. Results: We identified three differentially methylated regions (DMRs) in four genes (ENO2, ZNF226, CCDC51, and TMA7) that were related to famine exposure in both analyses. Pathway analysis with data from both Chinese famine samples and fibroblasts highlighted the nervous system and neurogenesis pathways as the most affected by nutritional deprivation. Conclusions: The combination of cross-sectional and experimental data provides indications that biological adaptation to famine leads to DNA methylation changes in genes involved in the central nervous system

Successful treatment of post-traumatic stress disorder reverses DNA methylation marks

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = −0.84, t = −2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD

DNA methylation differences in cortical grey and white matter in schizophrenia

Aim: Identify grey- and white-matter-specific DNA-methylation differences between schizophrenia (SCZ) patients and controls in postmortem brain cortical tissue. Materials & methods: Grey and white matter were separated from postmortem brain tissue of the superior temporal and medial frontal gyrus from SCZ (n = 10) and control (n = 11) cases. Genome-wide DNA-methylation analysis was performed using the Infinium EPIC Methylation Array (Illumina, CA, USA). Results: Four differentially methylated regions associated with SCZ status and tissue type (grey vs white matter) were identified within or near KLF9, SFXN1, SPRED2 and ALS2CL genes. Gene-expression analysis showed differential expression of KLF9 and SFXN1 in SCZ. Conclusion: Our data show distinct differences in DNA methylation between grey and white matter that are unique to SCZ, providing new leads to unravel the pathogenesis of SCZ

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD