Balkan Journal of Medical Genetics

GENOME-WIDE METHYLATION PROFILING OF SCHIZOPHRENIA
Rukova B1, Staneva R1, Hadjidekova S1, Stamenov G2, Milanova V3, Toncheva D1,
*Corresponding Author: Professor Draga Toncheva, Department of Medical Genetics, Medical University of Sofia, 1431 2 Zdrave Str., Sofia, Bulgaria. Tel./Fax: +35929520357. Email: dragatoncheva@ gmail.com
page: 15

DISCUSSION

The aim of our study was to perform microarraybased genome-wide methylation analysis of blood DNA samples to search for new specific biomarkers for schizophrenia in the Bulgarian population. There are very few articles regarding whole-genome methylation analysis [26,27]. Most of the differentially methylated genes in our study were involved in synaptic transmission and nervous system development. The HRH1 and FGFR1 genes have been implicated in schizophrenia, whereas the remaining genes were novel candidates [28-31]. The MYLIP, CRMP1 and FGFR1 genes are involved in nervous system development [32-37]. A comparison between the general and male pool found three genes in common: GABRA2, LIN7B, CASP3, while the comparison of the general and female pool found two common genes (CASP3, MACF1) but one was methylated in the opposite direction (MACF1). These could represent candidate genes and biomarkers for schizophrenia. All of them are involved in synaptic transmission. Among the top 10 genes from the three pools, one is common to all three: CASP3. The CASP3 gene participates in cell apoptosis. It is hypermethylated inside, so we propose that it is activated. Thus, our results can explain the apoptotic mechanism in schizophrenia pathophysiology [38-40]. The CASP3 gene participates in serotonin and glutamate neurotransmission regulation [41,42]. For finding gender-specific differences, we compared the top 10 genes in gender-specific pools and corresponding individual samples. We found all of the top 10 genes being differentially methylated in at least some of the individual patients. The most convincing candidates were those found in around half or more of the patients. The top 10 genes from the female pool were involved in apoptosis, synaptic transmission, neuron development and axon guidance. Four of them showed different methylation regions in more than half of the patients: XIAP, GABDR, OXT and KRT7. In our study, the CpG island of the XIAP gene was hypermethylated in the promoter region and maybe it was suppressed. Inactivation of the XIAP gene activates CASP3 and apoptosis [43]. The GABRD gene is of known relation to schizophrenia [25]. We found hypermethylation in the promoter region, which was a possible mechanism for involvement of GABRD inactivation in the disease pathogenesis. The CpG island of OXT was hypermethylated intragenically. Previous findings showed significantly increased mRNA in melancholic patients [44]. We supposed that OXT hypermethylation activates the gene and could play a role in schizophrenia. It is difficult to interpret the connection between KRT7 expression and downstream hypermethylation, moreover data in the literature were insufficient. Four genes from the top 10 in the male pool were found to be differentially methylated in over 50.0% of individual male patients: DHX37, MAP2K2, FNDC4 and GIPC1, therefore these were considered the best candidates. They had CpG islands with different methylation regions that were hypomethylated. Their methylation status was difficult to interpret. The function of FNDC4 is still unknown. The MAP2K2 gene belongs to the MAP kinase kinase family. It activates MAPK1/ERK2 and MAPK2/ERK3 that are related to synaptic plasticity, cell survival, learning and memory [45]. The DHX37 gene showed helicase activity [21]. The GIPC1 gene participates in BDNF-mediated neurotransmission and neurite outgrowth [46,47]. There are no data in the literature about the role of these four genes in schizophrenia. We hypothesized that they are new candidate genes for schizophrenia in males due to their different methylation profiles.

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