[Linguistic distance and psychosis in ethnic minorities]. / Taalachterstand en psychose onder mensen met een migratieachtergrond.

BACKGROUND: Ethnic minorities in the Netherlands face an excess psychosis risk, and understanding of causality remains limited. Linguistic disadvantage and other indicators of societal exclusion might play a role, and offer potential targets for public health interventions. AIM: To establish the contribution of linguistic disadvantage, indicators of social distance and perceived discrimination to the increased risk of psychoses in migrants and ethnic minorities. METHODS: We used the Dutch data from an international case-control study into psychotic disorders (the EU-GEI study). A first episode of psychosis was our outcome variable, and we used well-defined data on established confounders (e.g. age and sex) and indicators of ethnicity, social distance, linguistic disadvantage and perceived discrimination as our predictor variables. RESULTS: Ethnic minorities face an increased psychosis risk. This appears to be the case for both first- and second- generation migrants and so-called ‘Western’ and non-Western migrants. Though confounders and social distance appear to contribute, linguistic disadvantage appears to play a role in the excess psychosis risk in first-generation migrants. CONCLUSION: Reducing the social consequences of linguistic disadvantage or social distance might be a starting point for concrete public health interventions aimed at preventing the increased psychosis risk faced by first-generation migrants.

[Interplay between genetic background and environmental factors in psychiatry: current situation and future prospects]. / Samenspel tussen genetische achtergrond en omgevingsfactoren in de psychiatrie: stand van zaken en toekomstperspectief.

BACKGROUND: The hypothesis that etiopathogeneses of psychiatric disorders are determined by interplay between genetic background and environmental factors, as well their interactions can increasingly be put to direct scientific test, based on a wave of methodological, technological and knowledge developments.
AIM: To provide insight into and to provide perspective on some important scientific developments and facilitate challenges in this area.
METHOD: Narrative overview of the scientific literature and formulation of a concept and future perspective.
RESULTS: The overview points to concrete progress in the fields of genetic epidemiology, environmental analyses, gene-environment interactions and epigenetics in psychiatry. For example, recent studies have provided evidence for the existence of interactions and correlations between genetic and environmental factors, interdependence of risk-influencing effects of environmental factors, and translational neurobiological studies have identified biological processes that influence the impact of (or the response to) environmental influences on individuals mediate. These important steps to translate epidemiological research into testable biological hypotheses are facilitated by new techniques and the availability of large and relevant clinical and biological datasets.
CONCLUSION: Scientific progress on the interplay between genetic background and environmental factors enriches the conceptual framework of the etiopathogenesis of mental disorders and provides a future perspective in which we are likely to receive answers to a number of clinically relevant questions in the coming decade.
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Polygenic liability for schizophrenia and childhood adversity influences daily-life emotion dysregulation and psychosis proneness.

OBJECTIVE: To test whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures. METHODS: The data were retrieved from a general population twin cohort including 593 adolescents and young adults. Childhood adversity was assessed using the Childhood Trauma Questionnaire. Daily-life stressors and momentary mental state domains were measured using ecological momentary assessment. PRS-S was trained on the latest Psychiatric Genetics Consortium schizophrenia meta-analysis. The analyses were conducted using multilevel mixed-effects tobit regression models. RESULTS: Both childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene-environment correlation was detected. There is novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, P = 0.013), positive affect (b = -0.05, P = 0.043), and subtle psychosis expression (b = 0.11, P = 0.007)] and stress-sensitivity measures. CONCLUSION: Exposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotion dysregulation and psychosis proneness.

The association between genome-wide polymorphisms and chronic postoperative pain: a prospective observational study.

Chronic postoperative pain is common and can have a negative impact on quality of life. Recent studies show that genetic risk factors are likely to play a role, although only gene-targeted analysis has been used to date. This is the first genome-wide association study to identify single-nucleotide polymorphisms associated with the development of chronic postoperative pain based on two independent cohorts. In a discovery cohort, 330 women scheduled for hysterectomy were genotyped. A case-control association analysis compared patients without chronic postoperative pain and the 34 who had severe chronic postoperative pain 3 months after surgery. No single-nucleotide polymorphisms reached genome-wide significance, but several showed suggestive associations with chronic postoperative pain (p < 1 × 10-5 ). Single-nucleotide polymorphisms with significance p < 1 × 10-5 were followed up in a replication cohort consisting of 203 men and women scheduled for orthopaedic or abdominal surgery. Ten of these patients developed severe chronic postoperative pain. A single-nucleotide polymorphism in NAV3 was significantly replicated with chronic postoperative pain in the replication cohort (p = 0.009). Meta-analysis revealed that two loci (IQGAP1 and CRTC3) were significantly associated with chronic postoperative pain at 3 months (IQGAP1 p = 3.93 × 10-6 ß = 2.3863, CRTC3 p = 2.26 × 10-6 , ß = 2.4209). The present genome-wide association study provides initial evidence for genetic risk factors of chronic postoperative pain and supports follow-up studies.

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder.

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.

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer's disease: looking in the correct place at the right time?

Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology.

Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined a continuum of poor to highly functional electrophysiological states of differentiated neurons. The strong correlations between action potentials, synaptic activity, dendritic complexity and gene expression highlight the importance of methods for isolating functionally comparable neurons for in vitro investigations of brain disorders. Although whole-cell electrophysiology is the gold standard for functional evaluation, it often lacks the scalability required for disease modeling studies. Here, we demonstrate a multimodal machine-learning strategy to identify new molecular features that predict the physiological states of single neurons, independently of the time spent in vitro. As further proof of concept, we selected one of the potential neurophysiological biomarkers identified in this study-GDAP1L1-to isolate highly functional live human neurons in vitro.

[Auto-immune disorders as a possible cause of neuropsychiatric syndromes]. / Auto-immuunaandoeningen als mogelijke oorzaak van neuropsychiatrische syndromen.

BACKGROUND: Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. AIM: To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. METHOD: Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. RESULTS: Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. CONCLUSION: Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

[Body dysmorphic disorder in cosmetic surgery - prevalence, psychiatric comorbidity and outcome]. / Stoornis in de lichaamsbeleving bij patiënten binnen de cosmetische chirurgie.

BACKGROUND: Patients suffering from body dysmorphic disorder (bdd) are preoccupied with a slight or imagined defect in appearance. AIM: First of all, to review the literature on the prevalence of bdd in cosmetic surgery and thereafter to review the literature on psychiatric comorbidity and the outcome of surgical interventions. METHOD: We based our search strategy on Embase, Medline and PubMed, using the search terms 'body dysmorphic disorder', 'cosmetic surgery', 'prevalence', 'comorbidity' and 'outcome'. Our search covered English and Dutch literature published after the introduction of bdd in dsm-iii-r and before 1 November, 2013. A study of the relevant articles enabled us to access additional articles mentioned in these texts. RESULTS: Our initial search strategy turned out to be too narrow. It was therefore broadened to include 'body dysmorphic disorder', 'cosmetic surgery', and 'prevalence'. Eventually we included 23 original articles. In 11 of these the prevalence of bdd varied from 3.2 to 53.6%. Twelve articles on psychiatric comorbidity revealed predominantly mood and anxiety disorders on axis I and cluster C personality disorders on axis II. Only two studies reported on the outcome of cosmetic surgery performed on bdd patients; surgical interventions, however, seemed to result in new preoccupations with the prolongation of psychiatric comorbidity. CONCLUSION: bdd is a common psychiatric disorder that can sometimes lead to cosmetic surgery. However, pre-operative screening of bdd patients is vital so that efficient psychiatric treatment can be initiated and patients are not subjected to surgical interventions which may be ineffective or even harmful.

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model.

Investigating and understanding gene-environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

Resilience in mental health: linking psychological and neurobiological perspectives.

OBJECTIVE: To review the literature on psychological and biological findings on resilience (i.e. the successful adaptation and swift recovery after experiencing life adversities) at the level of the individual, and to integrate findings from animal and human studies. METHOD: Electronic and manual literature search of MEDLINE, EMBASE and PSYCHINFO, using a range of search terms around biological and psychological factors influencing resilience as observed in human and experimental animal studies, complemented by review articles and cross-references. RESULTS: The term resilience is used in the literature for different phenomena ranging from prevention of mental health disturbance to successful adaptation and swift recovery after experiencing life adversities, and may also include post-traumatic psychological growth. Secure attachment, experiencing positive emotions and having a purpose in life are three important psychological building blocks of resilience. Overlap between psychological and biological findings on resilience in the literature is most apparent for the topic of stress sensitivity, although recent results suggest a crucial role for reward experience in resilience. CONCLUSION: Improving the understanding of the links between genetic endowment, environmental impact and gene-environment interactions with developmental psychology and biology is crucial for elucidating the neurobiological and psychological underpinnings of resilience.

Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress.

OBJECTIVE: A functional interaction between Catechol-O-Methyltransferase (COMT) Val158Met and methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to differentially affect cognition in patients with schizophrenia and healthy controls; the effect of COMT Val158Met × MTHFR interaction on resilience to stress in patients and controls remains to be examined. METHOD: A total of 98 patients with non-affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met. Daily life reactivity to stress, modelled as the effect of daily life stress on psychotic experiences, was measured using the experience sampling method (ESM). RESULTS: The MTHFR C677T genotype moderated the interaction between COMT Val158Met genotype and stress in patients (P < 0.0001), but not in controls (P = 0.68). Further examination of this interaction revealed that in patients with the MTHFR 677 T-allele, COMT Met/Met individuals displayed the largest increases in psychotic symptoms in reaction to ESM stress [χ(2)(2) = 29.51; P < 0.0001], whereas in patients with the MTHFR 677 C/C genotype no significant COMT Val158Met × ESM stress interaction was apparent [χ(2)(2) = 3.65; P = 0.16]. No moderating effect of MTHFR A1298C was found. CONCLUSION: Stress reactivity associated with COMT Val158Met in patients with psychosis may crucially depend on MTHFR C677T genotype.

[Psychotic disorders: the need for staging]. / Stagering van psychotische stoornissen.

BACKGROUND: In psychotic disorders it is the stage of development of the disease which mainly determines the prognosis and the effectiveness of treatment. AIM: To describe and to refine the current staging and profiling of psychotic disorders and to propose a way in which to describe the course of dimensions of psychoses. METHOD: We searched the literature for articles relating to the staging of psychotic disorders. RESULTS: McGorry e.a. developed a simple classification into stages which is currently applicable to research and clinical practice. We propose a further refinement in the form of a graph from which one can see in a glance the history of clinically relevant variation. CONCLUSION: Research into the prodromal stages of diseases is needed in order to elucidate the pathophysiological mechanisms that the stages have in common and to reveal the pathways of differential development.

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study.

AIMS: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. METHODS: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. RESULTS: There were no genes-environment associations. PRS-SZ was associated with positive dimensions (ß = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. CONCLUSIONS: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus.

Recent studies have suggested that DNA methylation is implicated in age-related changes in gene expression as well as in cognition. DNA methyltransferase 3a (Dnmt3a), which catalyzes DNA methylation, is essential for memory formation and underlying changes in neuronal and synaptic plasticity. Because caloric restriction (CR) and upregulation of antioxidants have been suggested as strategies to attenuate age-related alterations in the brain, we hypothesized that both a diet restricted in calories and transgenic overexpression of normal human Cu/Zn superoxide dismutase 1 (SOD) attenuate age-related changes in Dnmt3a in the aging mouse hippocampus. For this purpose, we performed qualitative and quantitative analyses of Dnmt3a-immunoreactivity (IR) for the hippocampal dentate gyrus (DG), CA3 and CA1-2 regions in 12- and 24-month-old mice from 4 groups, i.e. (1) wild-type (WT) mice on a control diet (WT-CD), (2) SOD-CD mice, (3) WT mice on CR (WT-CR), and (4) SOD-CR. Qualitative analyses revealed two types of Dnmt3a immunoreactive cells: type I cells--present throughout all hippocampal cell layers showing moderate levels of nuclear Dnmt3a-IR, and type II cells--a subpopulation of hippocampal cells showing very intense nuclear Dnmt3a-IR, and colocalization with Bromodeoxyuridine. Quantitative analyses indicated that the age-related increase in Dnmt3a-IR within the CA3 and CA1-2 in type I cells was attenuated by CR, but not by SOD overexpression. In contrast, the density of type II Dnmt3a immunoreactive cells showed an age-related reduction, without significant effects of both CR and SOD. These changes in Dnmt3a levels in the mouse hippocampus may have a significant impact on gene expression and associated cognitive functioning.

No major role for X-inactivation in variations of intelligence and behavioral problems at middle childhood.

Although members of monozygotic (MZ) twin pairs are identical in genomic sequence, epigenetic mechanisms may occasion difference in gene expression and, consequently, twin discordance in complex traits. Recent work suggests that the epigenetic process of X-inactivation in female individuals may impact on intelligence and child behavioral problems. The timing of X-inactivation has been linked to chorionic splitting in MZ twins. Dichorionic monozygotic (DC-MZ) twinning, unlike monochorionic monozygotic (MC-MZ) twinning, occurs prior to the time of X-inactivation in female organisms. Therefore, the hypothesis of a causal role of X-inactivation in intelligence and behavioral problems can be analyzed by modeling the statistical interaction between sex and chorion type for within-pair differences in these traits in MZ twins. In this study, the effect of X-inactivation on childhood behavioral problems, measured with the CBCL, was studied in a sample of 324 MZ twin pairs from the EFPTS and the effect of X-inactivation on IQ was studied in a sample of 272 twin pairs from the same twin survey. Information on chorion type, gestational age, and birth weight was additionally collated. No significant statistical interaction was found between sex and chorion type, indicating that X-inactivation is not likely involved in variations in intelligence or behavioral problems in middle childhood. Further studies are required to replicate these findings and may explore the role of X-inactivation at different ages or at the extreme scores in the spectrum of intelligence and behavioral problems or may focus on other epigenetic mechanisms.

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia.

Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.

Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment.

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.