Methylation Patterns in Whole Blood Correlate With Symptoms in Schizophrenia Patients

Abstract

DNA methylation, one of the main epigenetic mechanisms to regulate gene expression, appears to be involved in the development of schizophrenia (SZ). In this study, we investigated 7562 DNA methylation markers in blood from 98 SZ patients and 108 healthy controls. A linear regression model including age, gender, race, alcohol, nicotine and cannabis use status, and diagnosis was implemented to identify C-phosphate-G (CpG) sites significantly associated with diagnosis. These CpG sites were further validated using an independent data set. Sixteen CpG sites were identified with hyper-or hypomethylation in patients. A further verification of expression of the corresponding genes identified 7 genes whose expression levels were also significantly altered in patients. While such altered methylation patterns showed no correlation with disorganized symptoms and negative symptoms in patients, 11 CpG sites significantly correlated with reality distortion symptoms. The direction of the correlations indicates that methylation changes possibly play a protective mechanism to lessen delusion and hallucination symptoms in patients. Pathway analyses showed that the most significant biological function of the differentially methylated CpGs is inflammatory response with CD224, LAX1, TXK, PRF1, CD7, MPG, and MPO genes directly involved in activations of T cells, B cells, and natural killer cells or in cytotoxic reaction. Our results suggest that such methylation changes may modulate aspects of the immune response and hence protect against the neurobiological substrate of reality distortion symptoms in SZ patients.

Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

“…For instance, CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4) genes, which modulate T-cell activity were significantly associated with schizophrenia risk (Frydecka et al 2013;Liu et al 2011). Epigenetic studies also indicated that genes regulating activation of T cells were found to be differentially methylated in schizophrenia (Liu et al 2014). Importantly, a meta-analysis on lymphocytes suggested CD4/CD8 ratio as a state-related marker of schizophrenia as significantly increased ratio was reported in first episode patient, while the ratio diminished following anti-psychotic treatment .…”

Peripheral Biomarker Candidates in Schizophrenia

“…Receptor binding assay [40] Aberrant DNA damage response signalling in dividing lymphoblasts 28 schizophrenia patients Flow cytometry [43] Hypermethylated region of S-COMT 177 patients with schizophrenia Luminometric methylation assay [45] Altered DNA-methylation patterns of C-phosphate-G dinucleotides 98 patients with schizophrenia Luminometric methylation assay [44] Chronic olanzapine treatment alters methylation in genes encoding for dopamine receptors, transporter, synthesis and metabolism 2 olanzapine-treated rats Rat-specific methylation arrays [46] Lipidomic markers Increased levels of multiple fatty acids and ketone bodies in serum and urine 112 schizophrenic patients GC-TOF mass spectrometry, 1 H-NMR [48] Decreased level of n-3 class PUFA in drug-naïve patients with a first episode of schizophrenia 20 drug-naïve patients with a first episode of schizophrenia; 20 patients with chronic schizophrenia non-adherent to prescribed medications Chromatography [49] Higher levels of pregnenolone sulphate, sulphated 5α-and 5β-saturated metabolites of C21 steroids; lowered levels of 5β-reduced metabolites of C19 steroids markers, the development of assays with sufficient sensitivity and specificity for clinical use is conceivable. Although, for the patients concerned, individual psychiatric-clinical care will remain the basis of the management of schizophrenia, these 'marker assays' might, in the near future, prove to be of considerable help with diagnostic and prognostic processes, not only from a research perspective but also from a clinical point of view.…”

“…Epigenetic phenomena have also been proposed in order to explain non-Mendelian characteristics of schizophrenic heritability and the intricate interaction between genes and the environment [42]. Interestingly, recent studies have suggested a dysregulated epigenome in schizophrenia, a notion which might lead to the discovery of biomarker candidates as DNA methylation signatures and modifications to histone variants are detectable in peripheral blood and peripheral blood cell preparation, respectively [43][44][45]. Furthermore, antipsychotic drugs might influence epigenetic processes; hence, markers for DNA methylation might also be useful as predictors of therapy response [46].…”

Schizophrenia Prediction Using Integrated Imaging Genomic Networks

“…After a series of quality controls, we selected 184 subjects, including 80 SZ cases (age: 34 ± 11, 20 females and 60 males) and 104 healthy controls (age:32 ± 11, 38 females and 66 males). After pre-processing, 27,508 DNA methylation sites, 41,s236 fMRI voxels and 722,177 SNP loci were obtained for the subsequent biomarker selections [22,23,24,25,26,27].…”