DNA Methylation Pattern of Gene Promoters of MB-COMT, DRD2, and NR3C1 in Turkish Patients Diagnosed with Schizophrenia

Objective We aim to evaluate the methylation status of membrane-bound catechol-O-methyltransferase (MB-COMT) promotor, dopamine receptor D2 (DRD2), and nuclear receptor subfamily 3 group C member 1 (NR3C1) gene in patients with SCZ by comparing healthy controls. Methods A sample of 110 patients with SCZ and 100 age- and sex-matched healthy volunteers was included in the study. The interview was started by filling out data forms that included sociodemographic and clinical information. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to confirming the diagnosis according to DSM-IV-TR criteria. Then the patients were evaluated with the Positive and Negative Symptoms Scale in terms of symptom severity. Methylation-specific polymerase chain reaction was used to determine the methylation status of MB-COMT promotor, DRD2, and NR3C1 gene from DNA material. Results When we compared the percentages of MB-COMT promotor, DRD2, and NR3C1 gene methylation status in SCZ patients with the healthy control group, the percentages of MB-COMT promotor (OR 0.466; 95% CI 0.268−0.809; p = 0.006), DRD2 (OR 0.439; 95% CI 0.375−0.514; p < 0.001), and NR3C1 (OR 0.003; 95% CI 0.001−0.011; p < 0.001) gene methylation status of SCZ was found to be significantly different from the control group. Whereas unmethylation of MB-COMT promotor and NR3C1 genes were associated with SCZ, the partial methylation of the DRD2 gene was related to the SCZ. Conclusion The MB-COMT promotor, DRD2, and NR3C1 gene methylation status may be associated with the SCZ in the Turkish population.

[1]  A. Nursal,et al.  Global and glucocorticoid receptor gene-specific (NR3C1) DNA methylation analysis in patients with cannabinoid or synthetic cannabinoid use disorder , 2021, Psychiatry Research.

[2]  B. Misiak,et al.  Clinical Correlates of the NR3C1 Gene Methylation at Various Stages of Psychosis , 2020, The international journal of neuropsychopharmacology.

[3]  K. Ozdilli,et al.  Tumor Necrosis Factor-alpha (TNF-α) −238 G/A Polymorphism Is Associated with the Treatment Resistance and Attempted Suicide in Schizophrenia , 2020, Immunological investigations.

[4]  T. Burne,et al.  Subcortical Dopamine and Cognition in Schizophrenia: Looking Beyond Psychosis in Preclinical Models , 2020, Frontiers in Neuroscience.

[5]  Ming Yan,et al.  DNA Methylation Analysis of the NR3C1 Gene in Patients with Schizophrenia , 2020, Journal of Molecular Neuroscience.

[6]  S. Lawrie,et al.  Methylation of glucocorticoid receptor (NR3C1), BDNF and oxytocin receptor genes in association with childhood maltreatment in schizophrenia and schizoaffective disorder , 2019, Schizophrenia Research.

[7]  M. Uysal,et al.  Investigation of Catechol-O-Methyltransferase and Cannabinoid Receptor 2 gene variants in tobacco use disorder or tobacco use disorder and schizophrenia comorbidity , 2020 .

[8]  I. Gotlib,et al.  DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis , 2019, Translational Psychiatry.

[9]  E. Grünblatt,et al.  Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use , 2019, Addiction biology.

[10]  S. McDonald.  Understanding the genetics and epigenetics of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD): a systematic review , 2019, Eating and weight disorders : EWD.

[11]  L. Sang-min,et al.  NR3C1 Polymorphisms for Genetic Susceptibility to Schizophrenia , 2019 .

[12]  Abd Rahim Nour El Huda,et al.  DNA methylation of membrane‐bound catechol‐O‐methyltransferase in Malaysian schizophrenia patients , 2018, Psychiatry and clinical neurosciences.

[13]  R. Emsley,et al.  DNA methylation and antipsychotic treatment mechanisms in schizophrenia: Progress and future directions , 2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  A. Mackay-Sim,et al.  DNA methylation in schizophrenia in different patient-derived cell types , 2017, npj Schizophrenia.

[15]  A. Mackay-Sim,et al.  DNA methylation in schizophrenia in different patient-derived cell types , 2017, npj Schizophrenia.

[16]  S. Thiagalingam,et al.  Methamphetamine‐induced psychosis is associated with DNA hypomethylation and increased expression of AKT1 and key dopaminergic genes , 2016, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  S. Ropero,et al.  Epigenetics in Schizophrenia: A Pilot Study of Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions , 2016, Front. Psychol..

[18]  V. Drouet,et al.  Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder , 2016, Translational psychiatry.

[19]  Subin Park,et al.  Associations between the neuron-specific glucocorticoid receptor (NR3C1) Bcl-1 polymorphisms and suicide in cancer patients within the first year of diagnosis , 2016, Behavioral and Brain Functions.

[20]  T. Ohmori,et al.  Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects , 2016, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[21]  S. Beach,et al.  Alcohol and tobacco consumption alter hypothalamic pituitary adrenal axis DNA methylation , 2016, Psychoneuroendocrinology.

[22]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[23]  J. Lieberman,et al.  Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis , 2016, The international journal of neuropsychopharmacology.

[24]  M. Zanetti,et al.  Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission. , 2015, Revista brasileira de psiquiatria.

[25]  A. Martín-Blanco,et al.  Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder. , 2014, Journal of psychiatric research.

[26]  T. Elbert,et al.  Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors , 2014, The Journal of Neuroscience.

[27]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[28]  F. Jiménez-Jiménez,et al.  COMT gene and risk for Parkinson’s disease: a systematic review and meta-analysis , 2014, Pharmacogenetics and genomics.

[29]  Anne G E Collins,et al.  Opponent actor learning (OpAL): modeling interactive effects of striatal dopamine on reinforcement learning and choice incentive. , 2014, Psychological review.

[30]  V. Calhoun,et al.  MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls , 2014, Epigenetics.

[31]  A. Cardno,et al.  Genetics of Schizophrenia and other Psychotic Disorders , 2014 .

[32]  E P Noble,et al.  Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients , 2014, Translational Psychiatry.

[33]  D. Kordi-Tamandani,et al.  Analysis of association between dopamine receptor genes’ methylation and their expression profile with the risk of schizophrenia , 2013, Psychiatric genetics.

[34]  Simon C. Potter,et al.  Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia , 2013, Nature Genetics.

[35]  Kiyoto Kasai,et al.  Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia , 2012, Journal of Human Genetics.

[36]  Marisa O. Hollinshead,et al.  Identification of common variants associated with human hippocampal and intracranial volumes , 2012, Nature Genetics.

[37]  Janice M. Fullerton,et al.  Glucocorticoid Receptor 1B and 1C mRNA Transcript Alterations in Schizophrenia and Bipolar Disorder, and Their Possible Regulation by GR Gene Variants , 2012, PloS one.

[38]  Y. Zou,et al.  Association of DRD2 gene polymorphisms with mood disorders: a meta-analysis. , 2012, Journal of affective disorders.

[39]  S. Thiagalingam,et al.  DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. , 2011, Journal of psychiatric research.

[40]  M. R. Salleh,et al.  A Nested Allele-Specific Multiplex Polymerase Chain Reaction Method for the Detection of DRD2 Polymorphisms. , 2011, The Malaysian journal of medical sciences : MJMS.

[41]  R. Murray,et al.  Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder , 2011, Human molecular genetics.

[42]  C. Weickert,et al.  Abnormal Glucocorticoid Receptor mRNA and Protein Isoform Expression in the Prefrontal Cortex in Psychiatric Illness , 2011, Neuropsychopharmacology.

[43]  L. Teh,et al.  Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia , 2011, Psychiatric genetics.

[44]  Alain Malafosse,et al.  Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. , 2011, Journal of affective disorders.

[45]  S. Thiagalingam,et al.  Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder , 2011, Schizophrenia Research.

[46]  A. Caspi,et al.  Childhood trauma and children's emerging psychotic symptoms: A genetically sensitive longitudinal cohort study. , 2011, The American journal of psychiatry.

[47]  A. Malhotra,et al.  D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. , 2010, The American journal of psychiatry.

[48]  T. Myöhänen,et al.  Distribution of catechol‐O‐methyltransferase (COMT) proteins and enzymatic activities in wild‐type and soluble COMT deficient mice , 2010, Journal of neurochemistry.

[49]  Alan S. Brown,et al.  Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. , 2010, The American journal of psychiatry.

[50]  A. Lajtha,et al.  An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes , 2009, Schizophrenia Research.

[51]  J. McGrath,et al.  Schizophrenia: a concise overview of incidence, prevalence, and mortality. , 2008, Epidemiologic reviews.

[52]  S. Sponheim,et al.  Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder , 2008, Schizophrenia Research.

[53]  Sun-Chong Wang,et al.  Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. , 2008, American journal of human genetics.

[54]  S. Akbarian,et al.  Thomas Vicary and the Anatomie of Mans Body , 2006, Medical History.

[55]  Jingde Zhu,et al.  The DNA methylation profile within the 5′-regulatory region of DRD2 in discordant sib pairs with schizophrenia , 2007, Schizophrenia Research.

[56]  R. Lothe,et al.  ADAMTS1, CRABP1, and NR3C1 Identified as Epigenetically Deregulated Genes in Colorectal Tumorigenesis , 2006, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[57]  S. Faraone,et al.  Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. , 2006, Human molecular genetics.

[58]  M C O'Donovan,et al.  The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons , 2006, Molecular Psychiatry.

[59]  Vladimír Znojil,et al.  Polymorphism of DRD2 gene and ADHD. , 2006, Neuro endocrinology letters.

[60]  S. Faraone,et al.  Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[61]  Shiva M. Singh,et al.  Site‐specific cytosine methylation in S‐COMT promoter in 31 brain regions with implications for studies involving schizophrenia , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[62]  D. Rujescu,et al.  Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene , 2004 .

[63]  G. Hutchinson,et al.  Migration and schizophrenia , 2004, Social Psychiatry and Psychiatric Epidemiology.

[64]  Christiane,et al.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , 2004, Journal international de bioethique = International journal of bioethics.

[65]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[66]  S. Aksoy,et al.  Catechol O-methyltransferase pharmacogenetics: photoaffinity labelling and western blot analysis of human liver samples. , 1993, Pharmacogenetics.

[67]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[68]  R T Borchardt,et al.  Catechol O-methyltransferase. , 1981, Methods in enzymology.