•Childhood traumatic events increase a risk of psychosis.•Childhood trauma might be associated with a specific psychosis manifestation.•Childhood adversities trigger specific biological alterations ...in psychosis.•Childhood trauma might predict poor prognosis in psychotic disorders.•Psychosis with positive history of childhood trauma might be a distinct phenotype.
There is a growing body of research focused on the relationship between childhood trauma and the risk of developing psychosis. Numerous studies, including many large-scale population-based studies, controlling for possible mediating variables, provide persuasive evidence of a dose-response association and are indicative of a causal relationship. Existing evidence supports the specificity model, showing differential associations between particular adversities and clinical symptoms, with cumulative adversity causing less favorable clinical and functional outcomes in psychotic patients. To date, several psychological and biological models have been proposed to search for underlying developmental trajectories leading to the onset of psychosis, influencing psychopathological manifestation and negative functional outcomes due to a history of childhood trauma. In this article, we provide a unified review on the relationship between childhood trauma and psychosis by integrating results of epidemiological, clinical, neuropsychological and biological studies. The question whether psychosis with a positive history of childhood trauma should be considered as a new psychotic phenotype, requiring specific therapeutic interventions, warrants further investigation.
Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly ...being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-
O
-methyltransferase (
COMT
), brain-derived neurotrophic factor (
BDNF
), and FK506-binding protein 5 (
FKBP5
) have been explored. Almost consistently, these studies revealed that polymorphisms in
COMT
,
BDNF
, and
FKBP5
genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.
Transposable elements (TEs) are highly repetitive DNA sequences in the human genome that are the relics of previous retrotransposition events. Although the majority of TEs are transcriptionally ...inactive due to acquired mutations or epigenetic processes, around 8% of TEs exert transcriptional activity. It has been found that TEs contribute to somatic mosaicism that accounts for functional specification of various brain cells. Indeed, autonomous retrotransposition of long interspersed element-1 (LINE-1) sequences has been reported in the neural rat progenitor cells from the hippocampus, the human fetal brain and the human embryonic stem cells. Moreover, expression of TEs has been found to regulate immune-inflammatory responses, conditioning immunity against exogenous infections. Therefore, aberrant epigenetic regulation and expression of TEs emerged as a potential mechanism underlying the development of various mental disorders, including autism spectrum disorders (ASD), schizophrenia, bipolar disorder, major depression, and Alzheimer's disease (AD). Consequently, some studies revealed that expression of some sequences of human endogenous retroviruses (HERVs) appears only in a certain group of patients with mental disorders (especially those with schizophrenia, bipolar disorder, and ASD) but not in healthy controls. In addition, it has been found that expression of HERVs might be related to subclinical inflammation observed in mental disorders. In this article, we provide an overview of detrimental effects of transposition on the brain development and immune mechanisms with relevance to mental disorders. We show that transposition is not the only mechanism, explaining the way TEs might shape the phenotype of mental disorders. Other mechanisms include the regulation of gene expression and the impact on genomic stability. Next, we review current evidence from studies investigating expression and epigenetic regulation of specific TEs in various mental disorders. Most consistently, these studies indicate altered expression of HERVs and methylation of LINE-1 sequences in patients with ASD, schizophrenia, and mood disorders. However, the contribution of TEs to the etiology of AD is poorly documented. Future studies should further investigate the mechanisms linking epigenetic processes, specific TEs and the phenotype of mental disorders to disentangle causal associations.
The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, ...by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted),
and
genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by
upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation.
Current immunotherapies are effective only in a subset of patients, likely due to several factors including defects in tumor cell antigen presentation, decreased response to immune effectors, and ...molecular heterogeneity of cancers. Recent molecular classifications enable the categorization of many tumor types. However, deregulation of major histocompatibility complex (MHC) gene expression is poorly characterized in the context of molecular cancer subtypes. To suppress the confounding effect of immune infiltrates on expression patterns of immunoregulators, we identified and removed genes with strong correlation to estimated immune compartment levels in each tumor type. Next, we reanalyzed a total of 13 TCGA cancer types encompassing 5651 tumors and 485 normal adjacent tissues by performing unsupervised clustering of 14 MHC genes. Subsequently, resultant clusters were statistically compared in terms of expression of other immune-related genes. Three MHC expression clusters were discovered by unsupervised clustering. We identified concordantly decreased expression of MHC genes (MHC-low) in 26 out of 55 molecular subtypes. Consequently, our study underlines the urgent need for designing strategies to enhance tumor MHC expression that could improve immune cold tumor rejection by cytotoxic T lymphocytes.
Previous transcriptome analyses of brain samples provided several insights into the pathophysiology of schizophrenia. In this study, we aimed to re-investigate gene expression datasets from seven ...brain regions of patients with schizophrenia and healthy controls by adopting a unified approach. After adjustment for confounding factors, we detected gene expression changes in 2 out of 7 brain regions – the dorsolateral prefrontal cortex (DLPFC) and parietal cortex (PC). We found relatively small effect sizes, not exceeding absolute log fold changes of 1. Gene-set enrichment analysis revealed the following alterations: 1) down-regulation of GABAergic signaling (in DLPFC and PC); 2) up-regulation of interleukin-23 signaling together with up-regulation of transcription mediated by RUNX1 and RUNX3 as well as down-regulation of RUNX2 signaling (in DLPFC) and 3) up-regulation of genes associated with responses to metal ions and RUNX1 signaling (PC). The number of neurons was significantly lower and the number of astrocytes was significantly higher at both brain regions. In turn, the index of microglia was increased in DLPFC and decreased in PC. Finally, our unsupervised analysis demonstrated that cellular composition of the samples was a major confounding factor in the analysis of gene expression across all datasets. In conclusion, our analysis provides further evidence that small but significant changes in the expression of genes related to GABAergic signaling, brain development, neuroinflammation and responses to metal ions might be involved in the pathophysiology of schizophrenia. Cell sorting techniques need to be used by future studies to dissect the effect of cellular content.
Highlights • Reduced number of NK cells might occur in schizophrenia but not in bipolar disorder. • Longitudinal studies addressing these alterations should be recommended. • Deconvolution might ...reliably measure counts of peripheral lymphocytes. • Future studies should compare results obtained from deconvolution and flow cytometry.
Dysregulation of innate and adaptive immunity is increasingly being recognized as one of core characteristics of schizophrenia pathophysiology. Several studies have revealed that patients with ...schizophrenia present various alterations in the levels of distinct leukocyte subpopulations. However, studies addressing this point have provided mixed results. Therefore, in this study we translated a computational deconvolution algorithm in order to estimate counts of distinct leukocyte subpopulations in peripheral blood of patients with schizophrenia. Our analysis was based on publicly available data from peripheral blood DNA methylation profiling in 711 schizophrenia patients and 713 healthy controls (2 independent samples). In both datasets, there were significantly lower levels of CD8 and NK cells together with significantly higher levels of granulocytes. However, the levels of CD8 cells were insignificant after controlling for age and sex differences in one dataset. Our results indicate that patients with schizophrenia present innate immunity dysregulation in terms of NK cells depletion and increased levels of granulocytes. Longitudinal studies of various clinical subgroups of schizophrenia patients are required in order to disentangle whether our findings reflect trait- or state-dependent alterations.
Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases ...remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5–14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.
•Lower levels of HERV-K methylation were found in first-episode schizophrenia compared to controls.•Multiple-episode schizophrenia patients and controls had similar levels of HERV-K ...methylation.•Deficit and non-deficit schizophrenia patients and controls had similar levels of HERV-K methylation.•There was a significant positive correlation between chlorpromazine equivalent dosage and HERV-K methylation in multiple-episode schizophrenia patients.
Human endogenous retroviruses (HERV) have been widely associated with schizophrenia etiology. Aberrant epigenetic processes may play a role in the etiology of schizophrenia. In this study, we tested whether schizophrenia patients at different stages of illness might present alterations in the levels of HERV-K methylation. We recruited 49 first-episode schizophrenia (FES) patients with 47 age- and sex-matched healthy controls (HCs), and 100 multi-episode schizophrenia (MES) patients with 50 age- and sex-matched HCs. Based on the Schedule for Deficit Schizophrenia, patients with MES were also divided into two subgroups: deficit (D-SCZ) and non-deficit schizophrenia (ND-SCZ). DNA methylation levels of HERV-K sequences were examined in peripheral blood leukocytes. We found significantly lower levels of HERV-K methylation in FES patients compared to HCs. Patients with MES and matched HCs had similar levels of HERV-K methylation. There was a significant positive correlation between chlorpromazine equivalent dosage and HERV-K methylation levels in MES patients, but not in FES individuals. No significant differences in HERV-K methylation levels between D-SCZ and ND-SCZ as well as HCs were found. Our results indicate lower HERV-K methylation levels at early stages of schizophrenia. This difference might normalize with subsequent exacerbations of schizophrenia, likely due to the effects of antipsychotics.
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