Epigenome-wide Association Study for Tic Disorders in Children: A Preliminary Study in Korean Population (original) (raw)
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Research Square (Research Square), 2022
Tic disorders can affect the quality of life in both childhood and adolescence. Many factors are involved in the etiology of tic disorders, and the genetic and epigenetic factors of tic disorders are considered complex and heterogeneous. In this study, the differentially methylated regions (DMRs) between normal controls (n = 24; aged 6-15; 7 females) and patients with tic disorders (n = 16; aged 6-15; 5 females) were analyzed. We performed an epigenome-wide association study (EWAS) of tic disorders in Korean children. The severity of the tics was measured using a self-report version of the YGTSS. The DNA methylation data consisted of 726,945 CpG sites, assessed using the Illumina In nium MethylationEPIC (850k) BeadChip. The DNA methylation data of the 40 participants were retrieved, and DMRs between the four groups based on sex and tic disorder were identi ed. From 28 male and 16 female samples, 37 and 38 DMRs were identi ed, respectively. We analyzed the enriched terms and visualized the network, heatmap, and upset plot. In male, KEGG enrichment analysis revealed hypomethylated patterns in the ligand, receptor, and second signal transductors of the MAPK, Ras, Rap1, and PI3K-Akt signaling pathway, and in female, the opposite patterns were revealed. Five mental disorder-related enriched terms were identi ed in the network analysis. Here, we provide insights into the epigenetic mechanisms of tic disorders. Abnormal DNA methylation patterns are associated with mental disorder-related symptoms.
DNA methylation signature as a biomarker of major neuropsychiatric disorders
Journal of Psychiatric Research, 2021
DNA methylation is a broadly-investigated epigenetic modification that has been considered as a heritable and reversible change. Previous findings have indicated that DNA methylation regulates gene expression in the central nervous system (CNS). Also, disturbance of DNA methylation patterns has been associated with destructive consequences that lead to human brain diseases such as neuropsychiatric disorders (NPDs). In this review, we comprehensively discuss the mechanism and function of DNA methylation and its most recent associations with the pathology of NPDsincluding Major depressive disorder (MDD), schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and attention/deficit hyperactivity disorder (ADHD). We also discuss how heterogeneous findings demand further investigations. Finally, based on the recent studies we conclude that DNA methylation status may have implications in clinical diagnostics and therapeutics as a potential epigenetics biomarker of NPDs.
The DNA Methylome and Transcriptome of Different Brain Regions in Schizophrenia and Bipolar Disorder
PLoS ONE, 2014
Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-regiondependent aberrant DNA methylation in the pathogenesis of these two disorders.
EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder
Genes
Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified (TSC1 and CRYZ/TYW3) and the enriched pathways and components (phosphoinosides and PTEN pathway...
Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study
JAMA psychiatry, 2016
DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls. Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases an...
Translational Psychiatry
Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value o10 − 6 , we identified cg23546855 (P-value = 2.15 × 10 − 7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value o 0.05 after Benjamini-Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value = 5.37 × 10 − 8) to be associated with intellectual disability (F70-79), in TOP1 (P-value = 1.86 × 10 − 7) with behavioral disorders (F90-98), in NOSIP (P-value = 5.12 × 10 − 8) with disorders of psychological development (F80-89) and in SEMA4B (P-value = 4.02 × 10 − 7) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals.
Genome-Wide DNA Methylation Scan in Major Depressive Disorder
PLOS ONE, 2012
While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences .10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, nonsignificant at p = 0.08. While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.