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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...
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Context 1
... genetic background of DUSP22 methylation was significantly different between African-American and Caucasian subjects (p < 0.001 in Pearson's χ 2 test). The absence of the low methylation genotype in the African-Americans contributes to the lower variation in DUSP22 DMR methylation levels (see Table 3). This is in line with the stratified analyses for ethnicity that show an association between DUSP22 methylation and schizophrenia in the Caucasians only (B = 0.692, p = 0.002), and not in the African-Americans (B = −0.086, ...Similar publications
Background
Rice (Oryza sativa L.) is a staple food crop worldwide. Its yield and quality are affected by its tillering pattern and spikelet development. Although many genes involved in the vegetative and reproductive development of rice have been characterized in previous studies, the genetic mechanisms that control axillary tillering, spikelet dev...
Citations
... Unfortunately, other datasets in which the abovementioned associations were discovered are not publicly available and thus could not be reanalysed with nc886 methylation treated as a categorical variable. Furthermore, some of the findings are based on a very limited number of individuals, and in the case of prenatal famine, for example, similar studies have not been able to replicate the associations [76][77][78] (Figure 4). Therefore, a reanalysis of the datasets and replication are needed to rule out falsepositive findings. ...
... 5061/dryad.k67kf [14], Chinese (GSE116379 [78] Han Chinese (GSE201287 [123], Taiwanese (GSE78904 [124] and Indonesian (https://figshare.com,10.26188/5e00abd72f581, [67] cohorts were utilized. ...
Non-coding 886 (nc886, vtRNA2–1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNA(s) has been redefined multiple times, and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of the nc886 locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets. Herein, we aim to summarize the existing literature regarding nc886, discuss how the characteristics of nc886 give rise to contradictory results, as well as to reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how the distribution of the nc886 methylation pattern is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.
... Candidate-gene studies were not eligible for meta-analysis Eichenauer and Ehlert Clinical Epigenetics (2023) 15:152 due to the heterogeneity of affected genes and partially unavailable data. Table 4 presents a more recent study by Boks et al. [75], who analyzed changes in DNA methylation in individuals exposed to famine during the first 3 months of prenatal development and their susceptibility to schizophrenia in adulthood. The authors reported that prenatally exposed adults with schizophrenia showed hypermethylation of the DUSP22 gene compared to non-exposed patients and healthy controls [75]. ...
... Table 4 presents a more recent study by Boks et al. [75], who analyzed changes in DNA methylation in individuals exposed to famine during the first 3 months of prenatal development and their susceptibility to schizophrenia in adulthood. The authors reported that prenatally exposed adults with schizophrenia showed hypermethylation of the DUSP22 gene compared to non-exposed patients and healthy controls [75]. ...
... As for the third finding, there is evidence that DUSP family genes are involved in neural functions and play a role in the pathophysiology of mental disorders such as depression, bipolar disorder, and schizophrenia [93]. This supports the involvement of the DUSP22 gene in the etiology of schizophrenia in adults prenatally exposed to famine [75]. In addition, we suggest that altered DNA methylation of the aforementioned IGF2 gene may contribute to an increased risk of mental disorders, as this gene is also involved in neuronal functions. ...
Background
Undernutrition in pregnant women is an unfavorable environmental condition that can affect the intrauterine development via epigenetic mechanisms and thus have long-lasting detrimental consequences for the mental health of the offspring later in life. One epigenetic mechanism that has been associated with mental disorders and undernutrition is alterations in DNA methylation. The effect of prenatal undernutrition on the mental health of adult offspring can be analyzed through quasi-experimental studies such as famine studies. The present systematic review and meta-analysis aims to analyze the association between prenatal famine exposure, DNA methylation, and mental disorders in adult offspring. We further investigate whether altered DNA methylation as a result of prenatal famine exposure is prospectively linked to mental disorders.
Methods
We conducted a systematic search of the databases PubMed and PsycINFO to identify relevant records up to September 2022 on offspring whose mothers experienced famine directly before and/or during pregnancy, examining the impact of prenatal famine exposure on the offspring’s DNA methylation and/or mental disorders or symptoms.
Results
The systematic review showed that adults who were prenatally exposed to famine had an increased risk of schizophrenia and depression. Several studies reported an association between prenatal famine exposure and hyper- or hypomethylation of specific genes. The largest number of studies reported differences in DNA methylation of the IGF2 gene. Altered DNA methylation of the DUSP22 gene mediated the association between prenatal famine exposure and schizophrenia in adult offspring. Meta-analysis confirmed the increased risk of schizophrenia following prenatal famine exposure. For DNA methylation, meta-analysis was not suitable due to different microarrays/data processing approaches and/or unavailable data.
Conclusion
Prenatal famine exposure is associated with an increased risk of mental disorders and DNA methylation changes. The findings suggest that changes in DNA methylation of genes involved in neuronal, neuroendocrine, and immune processes may be a mechanism that promotes the development of mental disorders such as schizophrenia and depression in adult offspring. Such findings are crucial given that undernutrition has risen worldwide, increasing the risk of famine and thus also of negative effects on mental health.
... And the effects of GCs only partially explain the stress response and its effects on cells in the central nervous system (CNS) and the development of SRDs. Additionally, inducing cellular stress mechanisms in vitro can be performed beyond treating cells with GCs, and that includes models of oxidative stress, nutrient deprivation, heat shock, treatment with chemicals (e.g., toxins), and mechanical stress, among others (Boks et al., 2018). However, as the literature on this topic is quite expansive in relation to SRDs, we provide an overview of a selected number of critical landmark studies (as opposed to providing a systematic review of the available literature). ...
Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects.
... Dysregulation of gene expression programs both during development and in the adult brain is associated with numerous neuropsychiatric diseases such as addiction [95], depres-sion [96], and SZ [97]. In recent years, epigenetic studies in the postmortem brain in SZ have mainly focused on identifying differentially methylated sites and genes in the cortex and other brain regions [98]. The results of these studies suggest that hypermethylation of the promoter of DUSP22 encoding double specificity phosphatase 22 [98] and differential methylation in the MAD1L1 (Mitotic Arrest Deficient 1-like 1) coding region [99] are SZ risk factors. ...
... In recent years, epigenetic studies in the postmortem brain in SZ have mainly focused on identifying differentially methylated sites and genes in the cortex and other brain regions [98]. The results of these studies suggest that hypermethylation of the promoter of DUSP22 encoding double specificity phosphatase 22 [98] and differential methylation in the MAD1L1 (Mitotic Arrest Deficient 1-like 1) coding region [99] are SZ risk factors. Moreover, the MAD1L1 differential methylation sites colocalize with the transcript quantitative trait loci and the GWAS signal, which strongly suggests the contribution of epigenetic dysregulation of MAD1L1 to the pathogenesis of SZ. ...
The study of diseases of the central nervous system (CNS) at the molecular level is challenging because of the complexity of neural circuits and the huge number of specialized cell types. Moreover, genomic association studies have revealed the complex genetic architecture of schizophrenia and other genetically determined mental disorders. Investigating such complex genetic architecture to decipher the molecular basis of CNS pathologies requires the use of high-throughput models such as cells and their derivatives. The time is coming for high-throughput genetic technologies based on CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)/Cas systems to manipulate multiple genomic targets. CRISPR/Cas systems provide the desired complexity, versatility, and flexibility to create novel genetic tools capable of both altering the DNA sequence and affecting its function at higher levels of genetic information flow. CRISPR/Cas tools make it possible to find and investigate the intricate relationship between the genotype and phenotype of neuronal cells. The purpose of this review is to discuss innovative CRISPR-based approaches for studying the molecular mechanisms of CNS pathologies using cellular models.
... We studied whole-blood DNA methylation datasets generated on patients with Parkinson's disease or schizophrenia. We selected 3 datasets that contain samples from patients with Parkinson's disease and healthy controls-GSE145361 [79], GSE111629 [80][81][82], and GSE72774 [80,81,83]-and 4 datasets that contain samples from patients with schizophrenia and healthy controls: GSE152027 [84], GSE84727 [84,85], GSE80417 [84,85], and GSE116379 (nonfamine participants) [86]. Information about considered datasets is summarized in Table 1, in particular, the number of cases and controls, whether the dataset has been used as a train or test, the original preprocessing type, and the number of CpGs. ...
... The following datasets comprise whole-blood samples from subjects with Parkinson's disease and healthy controls: GSE145361 [79], GSE111629 [80][81][82], and GSE72774 [80,81,83]. The following datasets comprise whole-blood samples from patients with schizophrenia and healthy controls: GSE152027 [84], GSE84727 [84,85], GSE80417 [84,85], and GSE116379 (only nonfamine participants) [86]. We remove from the analysis non-CpG probes [116], single-nucelotide polymorphism-related probes [117], multihit probes [118], and probes on chromosomes X and Y. ...
Background
DNA methylation has a significant effect on gene expression and can be associated with various diseases. Meta-analysis of available DNA methylation datasets requires development of a specific workflow for joint data processing.
Results
We propose a comprehensive approach of combined DNA methylation datasets to classify controls and patients. The solution includes data harmonization, construction of machine learning classification models, dimensionality reduction of models, imputation of missing values, and explanation of model predictions by explainable artificial intelligence (XAI) algorithms. We show that harmonization can improve classification accuracy by up to 20% when preprocessing methods of the training and test datasets are different. The best accuracy results were obtained with tree ensembles, reaching above 95% for Parkinson’s disease. Dimensionality reduction can substantially decrease the number of features, without detriment to the classification accuracy. The best imputation methods achieve almost the same classification accuracy for data with missing values as for the original data. XAI approaches have allowed us to explain model predictions from both populational and individual perspectives.
Conclusions
We propose a methodologically valid and comprehensive approach to the classification of healthy individuals and patients with various diseases based on whole-blood DNA methylation data using Parkinson’s disease and schizophrenia as examples. The proposed algorithm works better for the former pathology, characterized by a complex set of symptoms. It allows to solve data harmonization problems for meta-analysis of many different datasets, impute missing values, and build classification models of small dimensionality.
... PM20D1 (Ensink et al., 2021), DUSP22 (Rutten et al., 2018), and ZFP57 (Nöthling et al., 2018;Rutten et al., 2018;Vinkers et al., 2021) were related to post-traumatic stress disorder. DUSP22 was also related to schizophrenia (Boks et al., 2018), ZFP57 (Ladd-Acosta et al., 2014) with autism, and FGFR2 (Carboni et al., 2020) with depression. Maternal and child vulnerability to psychopathologies is one of the prominent features of the neglect phenotype due to their high exposure to early social stress (Dias et al., 2017;Conway et al., 2018). ...
Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the “biologically embedding” of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with (n = 51), versus those without (n = 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected (n = 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer’s disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.
... SZ-associated SNPs often alter local DNA methylation (DNAm) [6][7][8]. DNAm, the addition of a methyl group to a cytosine in DNA, stably affects gene expression via interaction with transcription factor binding [9]. DNAm is associated with both increased and decreased gene expression as well as other forms of gene regulation, including splicing and alternative promoter usage [9][10][11]. ...
DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 ( MAD1L1 ), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1 -containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.
... GSE152027 [78], GSE84727 [78,79], GSE80417 [78,79], GSE116379 (non-famine participants) [80]. Information about considered datasets is summarized in Table 1, in particular, the number of cases and controls, whether the dataset has been used as train or test, the original preprocessing type, the number of CpGs. ...
... The following datasets comprise whole blood samples from subjects with Parkinson's disease and healthy controls: GSE145361 [73], GSE111629 [74][75][76], GSE72774 [74,75,77]. The following datasets comprise whole blood samples from subjects with schizophrenia and healthy controls: GSE152027 [78], GSE84727 [78,79], GSE80417 [78,79], GSE116379 (only non-famine participants) [80]. We remove from the analysis non-CpG probes [104], SNP-related probes [105], multi-hit probes [106], probes on chromosomes X and Y. ...
Background
DNA methylation has a significant effect on gene expression and can be associated with various diseases. Meta-analysis of available DNA methylation datasets requires development of a specific pipeline for joint data processing.
Results
We propose a comprehensive approach of combined DNA methylation datasets to classify controls and patients. The solution includes data harmonization, construction of machine learning classification models, dimensionality reduction of models, imputation of missing values, and explanation of model predictions by explainable artificial intelligence (XAI) algorithms. We show that harmonization can improve classification accuracy by up to 20% when preprocessing methods of the training and test datasets are different. The best accuracy results were obtained with tree ensembles, reaching above 95% for Parkinson’s disease. Dimensionality reduction can substantially decrease the number of features, without detriment to the classification accuracy. The best imputation methods achieve almost the same classification accuracy for data with missing values as for the original data. Explainable artificial intelligence approaches have allowed us to explain model predictions from both populational and individual perspectives.
Conclusions
We propose a methodologically valid and comprehensive approach to the classification of healthy individuals and patients with various diseases based on whole blood DNA methylation data using Parkinson’s disease and schizophrenia as examples. The proposed algorithm works better for the former pathology, characterized by a complex set of symptoms. It allows to solve data harmonization problems for meta-analysis of many different datasets, impute missing values, and build classification models of small dimensionality.
... Although we could only investigate brain-blood correlation in adulthood, we expect some correlation to be present at earlier ages. Moreover, methylation at the DUSP22 gene in brain tissue has been previously implicated in schizophrenia, Parkinson's and Alzheimer's disease, albeit in different directions depending on the brain region investigated [54][55][56]. More generally, dual-specific phosphatases, including DUSP22, are implicated in a number of neural functions, as shown by several in vivo and in vitro preclinical studies across species, and in a range of mental and neurological disorders (see for review An et al. [57]). ...
Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22 .
... Prenatal exposure to famine was also shown to be able to induce epigenetic changes in pathways other than those involved in metabolic regulation. For example, significant hypermethylation in the promoter of the schizophrenia candidate gene, such as DUSP22, was observed in the Chinese famine-exposed schizophrenia patients [43]. There is convincing evidence about an increased risk of schizophrenia in adult life caused by prenatal exposure to famine. ...
Numerous human chronic pathological conditions depend on epigenetic modifications induced by environmental triggers throughout sensitive stages early in development. Developmental malnutrition is regarded as one of the most important risk factors in these processes. We present an overview of studies that the initiation and progression of many diseases are largely dependent on persisting epigenetic dysregulation caused by environmental insults early in life. For particular disorders, candidate genes were identified that underlie these associations. The current study assessed the most convincing evidence for the epigenetic link between developmental malnutrition and adult-life disease in the human population. These findings were obtained from quasi-experimental studies (so-called ‘natural experiments’), i.e. naturally occurring environmental conditions in which certain subsets of the population have differing levels of exposure to a supposed causal factor. Most of this evidence was derived on the DNA methylation level. We discussed DNA methylation as a key player in epigenetic modifications that can be inherited through multiple cell divisions. In this Perspective article, an overview of the quasi-experimental epidemiological evidence for the role of epigenetic mechanisms in the developmental programming by early-life undernutrition is provided.
