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      Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset.

      The FASEB Journal

      genetics, Adolescent, drug therapy, blood, Schizophrenia, Middle Aged, Male, metabolism, Leukocytes, Humans, therapeutic use, Haloperidol, Female, physiology, Epigenesis, Genetic, DNA Methylation, Catechol O-Methyltransferase, Biological Markers, Antipsychotic Agents, Age of Onset, Adult

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          Abstract

          Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10(-6)) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R(2)=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future.

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          Journal
          10.1096/fj.11-202069
          22426120

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