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

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.

Reviewing the epigenetics of schizophrenia

“…Biological research in schizophrenia has identified differences in multiple neurotransmitter systems, including those for dopamine, GABA and serotonin. Likewise, in this literature Melas et al (2012) and Petronis et al (2003) provided evidence supportive of the dopamine hypothesis of schizophrenia. At the same time, Kundakovic, Chen, Costa, & Grayson (2007) and Ruzicka et al (2007) found evidence associating schizophrenia with epigenetic down-regulation of GABA-ergic neuronal markers; conversely, Carrard et al (2011) found evidence linking schizophrenia with increased DNA methylation of the serotonin receptor (5HTR1A) gene.…”

“…Others investigated brain features such as cerebellar weight and pre-frontal cortex variations, levels of methylation in brain or blood tissues, associations between epigenetic processes and smoking, age, medication use and physical activity, studies of x-chromosome linkage, and paternal age and its association with schizophrenia diagnoses (e.g. DeLisi et al, 2000;Glatt et al, 2011;Melas et al, 2012;Naserbakht, Ahmadkhaniha, Mokri, & Smith, 2011). propensities to receive a schizophrenia diagnosis produced a mixed picture within which the few significant variations identified were attributed throughout to epigenetic processes, but without any direct test of these processes ever being conducted.…”

MB-COMTpromoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

“…The latter is the predominant form found in brain tissue 9 and has a greater affinity for dopamine. 10 Whereas S-COMT promoter methylation appears to be increased in schizophrenia patients, 11 MB-COMT promoter methylation has been shown to be decreased. 12,13 Investigating the relationship between COMT promoter methylation and gene expression in post-mortem brain samples of schizophrenia patients, Abdolmaleky et al 12 found decreased MB-COMT promoter methylation to be associated with increased COMT gene expression.…”

Old Obstacles on New Horizons: The Challenge of Implementing Gene X Environment Discoveries in Schizophrenia Research

“…But each also remains curiously under-represented in mainstream GxE research today. This is despite evidence to suggest they may serve a functional purpose as biomarkers of environmentally-induced pathogenesis, susceptibility, illness progression and treatment outcome [146][147][148][149][150][151][152] . Despite these documented examples, each discipline also faces thematic questions about how to achieve methodological best practice, given their various respective constraints 147,153,154 .…”