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GENOME-WIDE METHYLATION PROFILING of SCHIZOPHRENIA Rukova B1, Staneva R1, Hadjidekova S1, Stamenov G2, Milanova V3, Toncheva D1,*

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GENOME-WIDE METHYLATION PROFILING of SCHIZOPHRENIA Rukova B1, Staneva R1, Hadjidekova S1, Stamenov G2, Milanova V3, Toncheva D1,* 17 (2), 2014 l 15-24 DOI: 10.2478/bjmg-2014-0070 ORIGINAL ARTICLE 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 ABSTRACT CASP3). Methylation profiles differed between the genders. In females, the most important genes par- Schizophrenia is one of the major psychiatric ticipate in apoptosis and synaptic transmission (XIAP, disorders. It is a disorder of complex inheritance, GABRD, OXT, KRT7), whereas in the males, the involving both heritable and environmental factors. implicated genes in the molecular pathology of the DNA methylation is an inheritable epigenetic modifi- disease were DHX37, MAP2K2, FNDC4 and GIPC1. cation that stably alters gene expression. We reasoned Data from the individual methylation analyses con- that genetic modifications that are a result of envi- firmed, the gender-specific pools results. ronmental stimuli could also make a contribution. Our data revealed major differences in meth- We have performed 26 high-resolution genome- ylation profiles between schizophrenia patients and wide methylation array analyses to determine the controls and between male and female patients. The methylation status of 27,627 CpG islands and com- dysregulated activity of the candidate genes could pared the data between patients and healthy controls. play a role in schizophrenia pathogenesis. Methylation profiles of DNAs were analyzed in six Keywords: DNA methylation, Schizophrenia, pools: 220 schizophrenia patients; 220 age-matched Whole genome arrays. healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizo- INTRODUCTION phrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 Schizophrenia is a severe psychiatric disorder, individual patient DNA samples (eight females and characterized by debilitating behavioral abnormali- 12 males. ties, delusions, hallucinations and negative symptoms We found significant differences in the methyla- [1]. It is an etiologically complex disorder, involving tion profile between schizophrenia and control DNA both heritable and non heritable factors, with heri- pools. We found new candidate genes that princi- tability estimates of up to 81.0% [2]. It is believed pally participate in apoptosis, synaptic transmission that the disorder is due to early neurodevelopmental and nervous system development (GABRA2, LIN7B, factors, imbalances in neurotransmitter signaling, to- gether with obstetric complications, infections, stress and trauma [3,4]. In the absence of established diag- 1 Department of Medical Genetics, Medical University of Sofia, Sofia, nostic biological markers, diagnosis of schizophrenia Bulgaria relies on examination of mental state by a clinical 2 Woman Health Hospital “Nadezda”, Sofia, Bulgaria interview [5]. DNA methylation is a basic epigenetic 3 Department of Psychiatry, Medical University of Sofia, Sofia, Bulgaria modification, important for normal development in 15 METHYLATION IN SCHIZOPHRENIA higher organisms. It alters the gene expression with- of its mechanisms is very important for clinical psy- out modification of the primary DNA sequence and is chiatry and for identifying new targets for prevention heritable through the cell [6]. It involves conversion and intervention. The aim of our study was to inves- of the cytosine to 5-methylcytosine by means of DNA tigate the whole genome methylation profile to find methyltransferases [6]. In eukaryotes, methylation specific differentially methylated regions (DMRs) is most commonly found in CG rich areas of DNA, for schizophrenia patients. We tried to find gender- called CpG islands [7]. The epigenetic processes are specific differences in methylation pattern. Here we dynamic and allow the cells to respond reversibly and report our best candidate genes with DMRs for as- in a precise way to environmental stimuli, but also sociation with schizophrenia. preserve cell type specific gene programs. Epigenetic changes over time display familial clustering [8]. MATERIALS AND METHODS This could explain the clustering of some common diseases in families, so the epigenetic pattern could We have examined the methylation status of be implicated in transmitting “predisposition” over Bulgarian patients with schizophrenia compared to generations. sex - and age-matched healthy controls. We analyzed DNA methylation can be associated with the methylation profiles of DNAs in six pools, consisting transcription start sites of genes or can be found in of: 1) general pool of 220 schizophrenia patients [110 the gene bodies, intergenic or in distant regulatory males with a mean age of 42 years, standard devia- regions. The position of the methylation affects its tion (SD) = 11, and 110 females, aged 45, SD = 11 relationship to gene expression level. Methylation in years]; 2) general pool of 220 healthy controls (110 the immediate vicinity of the transcription start site males aged 50 years, SD = 14 and 110 females aged blocks initiation, while methylation inside the gene 51 years. SD = 14); 3) a pool of 110 female cases stimulates transcription elongation. So it is suggested (the same female patients from the general pool); 4) a that gene body methylation may have an effect on pool of 110 healthy females (the same female controls splicing. It is supposed that the methylation in repeti- from the general pool); 5) a pool of 110 male cases tive regions is important for chromosomal and ge- (the same male patients from the general pool); 6) a nomic stability, and probably represses transposable pool of 110 healthy males (the same male controls element expression. Yet the role of DNA methylation from the general pool). in modifying the action of regulatory elements such We also investigated methylation status of 20 as enhancers is not well established [9,10]. individual schizophrenia patient DNA samples (eight There is evidence of DNA methylation aber- females and 12 males). Informed consent was ob- rations in a wide variety of brain disorders such as tained from all investigated subjects and the relevant mental retardation, Angelman and Prader-Willi syn- Ethics Committees of the hospitals where subjects dromes, fragile X syndrome, gliomas and neuroec- were recruited gave approval for the use of these todermal tumors. Yet there are no conclusive studies samples in genetic studies. The diagnosis of schizo- about DNA methylation in major psychotic disorders phrenia was made by experienced psychiatrists, such as schizophrenia and bipolar disorder [11,12]. according to Diagnostic and Statistical Manual of Studies of the Bulgarian schizophrenia popula- Mental Disorders, 4th Edition (DSM-IV) criteria on tion have implicated common and rare genetic factors the basis of extensive clinical interviews [15]. [13-16]. Here we use the same large clinical cohort Genomic DNA was extracted from peripheral and propose a role of epigenetic modifiers of gene blood by the phenol-chloroform extraction method. expression in the development and progression of Concentration and purity were determined on all the disease and use cohort. DNA samples (NanoDrop 2000C; Thermo Scien- Epidemiological data as variable age of onset tific, Wilmington, DE, USA). All samples were tested between males and females, advanced paternal age, electrophoretically to verify the integrity of DNA. in utero nutritional deficiency, viral exposure and Six DNA pools were constructed using equal amount hypoxia, support the importance of “epigenetic” of DNA (at 100 ng/µL) from each patient/ control modifications. Because of the dynamic nature and samples and placing them in a single tube-pool [17]. potential reversibility of DNA methylation, the study We based our DNA methylation profiling strategy on 16 BALKAN JOURNAL OF MEDICAL GENETICS Rukova B, Staneva R, Hadjidekova S, Stamenov G, Milanova V, Toncheva D a recently developed technique, methylated DNA im- analysis of all genes with DMRs revealed from pool munoprecipitation (MeDIP), which utilizes a mono- analysis (726) we used online data mining service clonal antibody against 5-methylcytosine to enrich (Biograph; http:// biograph.be/). It was very helpful in the methylated fraction of a genomic DNA sample identification of susceptibility genes, because it used [18,19]. different databases and analyses functional relations Genome-wide DNA methylation was assessed in order to rank the genes according to their relevance using the Agilent Human DNA Methylation Microar- in disease etiopathogenesis [21]. There are literature ray (Agilent Technologies, Santa Clara, CA, USA) data for some of the genes about association with the platform. We used oligonucleotide microarrays (1 × disease so they are defined as “known.” For other 244K, density 237,227 sequences covering 27,627 genes, the relation to the disease was not proved, so CpG). All included arrays passed standard quality they were defined as “inferred.” control metrics. Agilent methylation microarrays were scanned, using Agilent High-Resolution Mi- RESULTS croarray Scanner G2505 with a resolution of 2 µm. Scans were performed with 532 nm wavelength of The threshold between hypo - or hypermethyl- green laser and 635 nm for red laser. The resulting ated islands was 60.0% of the oligonucleotide se- .tif images were processed with the Agilent
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