Methylome-wide Association Study of Patients with Recent-onset Psychosis
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Objective: Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls. Methods: The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled. Results: We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed. Conclusion: Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.
Abstract
Objective: Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls. Methods: The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled. Results: We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed. Conclusion: Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.
참고문헌 (68)
- GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, "Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017 : a systematic analysis for the Global Burden of Disease Study 2017", Lancet, 392, pp.1789~1858 (2018)
- Crow TJ, "The emperors of the schizophrenia polygene have no clothes", Psychol Med, 38, pp.1681~1685 (2008)
- Harrison PJ, "Schizophrenia genes, gene expression, and neuropathology : on the matter of their convergence", Mol Psychiatry, 10, pp.40~68 (2005)
- Schizophrenia Working Group of the Psychiatric Genomics Consortium, "Biological insights from 108 schizophrenia-associated genetic loci", Nature, 511, pp.421~427 (2014)
- Brown AS, "The environment and susceptibility to schizophrenia", Prog Neurobiol, 93, pp.23~58 (2011)
- Petronis A, "The origin of schizophrenia : genetic thesis, epigenetic antithesis, and resolving synthesis", Biol Psychiatry, 55, pp.965~970 (2004)
- Funahashi Y, "Analysis of methylation and-141C Ins", Del polymorphisms of the dopamine receptor D2 gene in patients with schizophrenia, 2019, pp.278, 135~140
- Li Y, "Quantitative DNA methylation analysis of DLGAP2 gene using pyrosequencing in schizophrenia with tardive dyskinesia : a linear mixed model approach", Sci Rep, 8, pp.17466~ (2018)
- Gao S, "Catechol-O-methyltransferase gene promoter methylation as a peripheral biomarker in male schizophrenia", Eur Psychiatry, 44, pp.39~46 (2017)
- Luo Y, "Dynamic Alu methylation during normal development, aging, and tumorigenesis", Biomed Res Int, 2014, pp.784706~ (2014)
- Jaffe AE, "Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex", Nat Neurosci, 19, pp.40~47 (2016)
- Mill J, "Epigenomic profiling reveals DNA-methylation changes associated with major psychosis", Am J Hum Genet, 82, pp.696~711 (2008)
- Pidsley R, "Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia", Genome Biol, 15, pp.483~ (2014)
- Wockner LF, "Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients", Transl Psychiatry, 4, pp.e339~ (2014)
- Dempster EL, "Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder", Hum Mol Genet, 20, pp.4786~4796 (2011)
- Kinoshita M, "DNA methylation signatures of peripheral leukocytes in schizophrenia", Neuromolecular Med, 15, pp.95~101 (2013)
- Liu J, "Methylation patterns in whole blood correlate with symptoms in schizophrenia patients", Schizophr Bull, 40, pp.769~776 (2014)
- Montano C, "Association of DNA methylation differences with schizophrenia in an epigenome-wide association study", JAMA Psychiatry, 73, pp.506~514 (2016)
- Nishioka M, "Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia", J Hum Genet, 58, pp.91~97 (2013)
- Li M, "Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population", Mol Psychiatry (2020)[DOI]
- Nie FY, "Methylome-wide association study of first-episode schizophrenia reveals a hypermethylated CpG site in the promoter region of the TNIK susceptibility gene", Prog Neuropsychopharmacol Biol Psychiatry, 106, pp.110081~ (2021)
- Aberg KA, "Methylome-wide association study of schizophrenia : identifying blood biomarker signatures of environmental insults", JAMA Psychiatry, 71, pp.255~264 (2014)
- Bang M, "Reduced DNA methylation of the oxytocin receptor gene is associated with anhedonia-asociality in women with recent-onset schizophrenia and ultra-high risk for psychosis", Schizophr Bull, 45, pp.1279~1290 (2019)
- Burghardt KJ, "The influence of metabolic syndrome and sex on the DNA methylome in schizophrenia", Int J Genomics, 2018, pp.8076397~ (2018)
- Lim U, "Dietary and lifestyle factors of DNA methylation", Methods Mol Biol, 863, pp.359~376 (2012)
- Cordero P, "Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet", Genes Nutr, 8, pp.105~113 (2013)
- Niculescu MD, "Diet, methyl donors and DNA methylation : interactions between dietary folate, methionine and choline", J Nutr, 132(8 Suppl), pp.2333~ (2002)[DOI]
- Wolf EJ, "Traumatic stress and accelerated DNA methylation age : a meta-analysis", Psychoneuroendocrinology, 92, pp.123~134 (2018)
- American Psychiatric Association, "Diagnostic and statistical manual of mental disorders: DSM-5" (2013), American Psychiatric Association
- Kay SR, "The positive and negative syndrome scale(PANSS)for schizophrenia", Schizophr Bull, 13, pp.261~276 (1987)
- 이중서, "한국판 양성 및 음성증후군 척도(Positive and Negative Syndrome Scale)의 신뢰도와 타당도", 신경정신의학, 40(6), pp.1090~1105 (2001), 대한신경정신의학회
- Bremner JD, "Psychometric properties of the Early Trauma Inventory-Self Report", J Nerv Ment Dis, 195, pp.211~218 (2007)
- Heatherton TF, "The Fagerström Test for Nicotine Dependence : a revision of the Fagerström Tolerance Questionnaire", Br J Addict, 86, pp.1119~1127 (1991)
- Kim JS, "Screening criteria of alcoholism by alcohol use disorders identification test(AUDIT)in Korea", J Korean Acad Fam Med, 20, pp.1152~1159 (1999)
- Jhon M, "Gender-specific risk factors for low bone mineral density in patients taking antipsychotics for psychosis", Hum Psychopharmacol, 33, pp.e2648~ (2018)
- Jackson AS, "Prediction of functional aerobic capacity without exercise testing", Med Sci Sports Exerc, 22, pp.863~870 (1990)
- Dietary reference intakes for Koreans, "Ministry of Health and Welfare", Ministry of Health and Welfare, ~ (2010)
- Mansell G, "Guidance for DNA methylation studies : statistical insights from the Illumina EPIC array", BMC Genomics, 20, pp.366~ (2019)
- Ball MP, "Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells", Nat Biotechnol, 27, pp.361~368 (2009)
- Illingworth RS, "Orphan CpG islands identify numerous conserved promoters in the mammalian genome", PLoS Genet, 6, pp.e1001134~ (2010)
- Maunakea AK, "Conserved role of intragenic DNA methylation in regulating alternative promoters", Nature, 466, pp.253~257 (2010)
- Deaton AM, "Cell type-specific DNA methylation at intragenic CpG islands in the immune system", Genome Res, 21, pp.1074~1086 (2011)
- Weber M, "Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome", Nat Genet, 39, pp.457~466 (2007)
- Szymona K, "Analysis of the expression of BAX, BCL2, BIRC6, CASP3, CASP9 apoptosis genes during the first episode of schizophrenia", Psychiatr Pol, 53, pp.1293~1303 (2019)
- Kumar A, "Altered expression of a unique set of genes reveals complex etiology of schizophrenia", Front Psychiatry, 10, pp.906~ (2019)
- Horesh Y, "Gene expression signature is shared by patients with Alzheimer's disease and schizophrenia at the superior temporal gyrus", Eur J Neurol, 18, pp.410~424 (2011)
- Schneider JL, "Autophagy and schizophrenia : a closer look at how dysregulation of neuronal cell homeostasis influences the pathogenesis of schizophrenia", Einstein J Biol Med, 31, pp.34~39 (2016)
- Vitale AM, "DNA methylation in schizophrenia in different patient-derived cell types", NPJ Schizophr, 3, pp.6~ (2017)
- Vucicevic L, "Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs", Cell Stress, 2, pp.282~291 (2018)
- Wang L, "A methionine-induced animal model of schizophrenia : face and predictive validity", Int J Neuropsychopharmacol, 18, pp.pyv054~ (2015)
- Grayson DR, "From trans-methylation to cytosine methylation : evolution of the methylation hypothesis of schizophrenia", Epigenetics, 4, pp.144~149 (2009)
- Akbarian S, "The molecular pathology of schizophrenia--focus on histone and DNA modifications", Brain Res Bull, 83, pp.103~107 (2010)
- Chase KA, "Histone methylation at H3K9 : evidence for a restrictive epigenome in schizophrenia", Schizophr Res, 149, pp.15~20 (2013)
- Lavratti C, "Exercise-induced modulation of histone H4acetylation status and cytokines levels in patients with schizophrenia", Physiol Behav, 168, pp.84~90 (2017)
- Schubert KO, "Hypothesis review : are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?", Mol Psychiatry, 17, pp.669~681 (2012)
- Montag C, "Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia : a case-control study", World J Biol Psychiatry, 14, pp.500~508 (2013)
- Wang Z, "Axon guidance pathway genes are associated with schizophrenia risk", Exp Ther Med, 16, pp.4519~4526 (2018)
- Melka MG, "Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia", J Mol Psychiatry, 3, pp.7~ (2015)
- Pensold D, "DNA methylation-mediated modulation of endocytosis as potential mechanism for synaptic function regulation in murine inhibitory cortical interneurons", Cereb Cortex, 30, pp.3921~3937 (2020)
- Grinberg I, "Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation", Nat Genet, 36, pp.1053~1055 (2004)
- Stevens SJ, "Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms", Genome Med, 8, pp.131~ (2016)
- Al-Naama N, "C2H2-type zinc finger proteins in brain development, neurodevelopmental, and other neuropsychiatric disorders : systematic literature-based analysis", Front Neurol, 11, pp.32~ (2020)
- Takase K, "Association of ZNF74 gene genotypes with age-at-onset of schizophrenia", Schizophr Res, 52, pp.161~165 (2001)
- Zhang Y, "Replication of association between schizophrenia and chromosome 6p21-6p22.1 polymorphisms in Chinese Han population", PLoS One, 8, pp.e56732~ (2013)
- Melka MG, "The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum", Clin Epigenetics, 6, pp.1~ (2014)
- Kinoshita M, "Effect of clozapine on DNA methylation in peripheral leukocytes from patients with treatment-resistant schizophrenia", Int J Mol Sci, 18, pp.632~ (2017)
- Jaffe AE, "Accounting for cellular heterogeneity is critical in epigenome-wide association studies", Genome Biol, 15, pp.R31~ (2014)
- Zhou W, "Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes", Nucleic Acids Res, 45, pp.e22~ (2017)
