Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients

Abstract

Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1, AKT1, DTNBP1, DNMT1, PPP3CC and SOX10, which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27 000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls (P=1.74 × 10−4). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia.

Stress, Schizophrenia and Bipolar Disorder

“…Notably, increased methylation of this site has also been recently associated with the number and severity of childhood maltreatment (sexual, physical, emotional) in patients with bipolar disorder (Perroud et al 2014). Evidence for aberrant DNA methylation patterns in schizophrenia patients have been reported for genes implicated in molecular genetic and neurobiological investigations of this disorder (Wockner et al 2014). Interestingly, there has also been recent demonstration of common genomic sites of hypomethylation among twins with bipolar disorder and schizophrenia (Dempster et al 2013); although this study did not examine associations with childhood trauma, their results imply common biological features of schizophrenia and bipolar disorder that likely result from common environmental effects on existing neurobiological vulnerabilities.…”

The Genome-Wide DNA Methylation Profile of Peripheral Blood Is Not Systematically Changed by Short-Time Storage at Room Temperature

“…Previous studies examining whole blood stored for twelve months at RT in a DNA-protecting solution [17] or placenta tissue stored for two days at RT [33] identified no major DNA methylation changes. Moreover, the feasibility of genome-wide DNA methylation studies using DNA from post-mortem brains [34], as well as archived dried blood spots has also been described before [15,35,36]. To our knowledge this is the first report of a genome-wide interrogation of the DNA methylome in matched whole blood samples stored at RT.…”

Epigenetic Dysregulation in the Schizophrenic Brain

“…SOX10 is a transcription factor gene that is important for oligodendrocyte maturation and myelination [48]. Some of the promoter DNA methylation changes that were found to be associated with corresponding alterations in gene expression in the cerebral cortex from small cohorts of SCZ subjects were independently replicated [49]. There is a general consensus that between-group differences (SCZ vs. control) show at best only subtle changes between cases and controls [50•, 51, 52].…”