DNA methylation in peripheral tissue of schizophrenia and bipolar disorder: a systematic review.

Nina Teroganova,Melissa J Green,Catherine M Suter,Leah Girshkin

doi:10.1186/s12863-016-0332-2

Abstract

BackgroundIncreasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications (specifically DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls.MethodsOriginal research articles using humans were identified using electronic databases. There were 33 included studies for which data were extracted and graded in duplicate on 22 items of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, to assess methodological precision and quality of reporting.ResultsThere were 15 genome-wide and 18 exclusive candidate gene loci investigations for DNA methylation studies. A number of common genes were identified as differentially methylated in schizophrenia/bipolar disorder, which were related to reelin, brain-derived neurotrophic factor, dopamine (including the catechol-O-methyltransferase gene), serotonin and glutamate, despite inconsistent findings of hyper-, hypo-, or lack of methylation at these and other loci. The mean STROBE score of 59 % suggested moderate quality of available evidence; however, wide methodological variability contributed to a lack of consistency in the way methylation levels were quantified, such that meta-analysis of the results was not possible.ConclusionsModerate quality of available evidence shows some convergence of differential methylation at some common genetic loci in schizophrenia and bipolar disorder, despite wide variation in methodology and reporting across studies. Improvement in the clarity of reporting clinical and other potential confounds would be useful in future studies of epigenetic processes in the context of exposure to environmental and other risk factors.

Highlights

Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue
Study quality assessment The STROBE ratings suggested that the available evidence for differential methylation in SZ and bipolar disorder (BD) ranged from low (29.5 % minimum) to high quality (77 % maximum) with the mean of all scores at 59 % (SD: 2.36), suggesting moderate quality of available evidence and moderate probability of reporting bias
Differential methylation converged on five candidate genes (RELN, brain-derived neurotrophic factor (BDNF), COMT, Serotonin neurotransmitter transporter (5-HTT) and glutamate receptor genes) which have each been previously implicated in the neuropathology of SZ and/or BD

Summary

Introduction

Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications ( DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls. The most widely studied epigenetic modification is DNA methylation, characterised by covalent linking of a methyl (CH3) group to a cytosine residue [11], almost exclusively occurring at cytosines within CpG dinucleotides. This review instead focused on the growing evidence base for differential DNA methylation in peripheral (i.e. blood and saliva) samples, which may minimise confounding effects related to tissue quality and stability [16], and importantly allow the study of epigenetic processes in living humans. Recent comparison of within-subject methylation patterns across blood and brain suggest the utility of peripheral blood in human epigenetic studies [17]

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