cytidylyl-3--5--guanosine and Schizophrenia

DNA methylation, which is the transference of a methyl group to the 5'-carbon position of the cytosine in a CpG dinucleotide, is one of the major mechanisms of epigenetic modifications. A number of studies have demonstrated altered DNA methylation of peripheral blood cells in schizophrenia (SCZ) in previous studies. However, most of these studies have been limited to the analysis of the CpG sites in CpG islands in gene promoter regions, and cell-type proportions of peripheral leukocytes, which may be one of the potential confounding factors for DNA methylation, have not been adjusted in these studies. In this study, we performed a genome-wide DNA methylation profiling of the peripheral leukocytes from patients with SCZ and from non-psychiatric controls (N = 105; 63 SCZ and 42 control subjects) using a quantitative high-resolution DNA methylation microarray which covered across the whole gene region (485,764 CpG dinucleotides). In the DNA methylation data analysis, we first estimated the cell-type proportions of each sample with a published algorithm. Next, we performed a surrogate variable analysis to identify potential confounding factors in our microarray data. Finally, we conducted a multiple linear regression analysis in consideration of these factors, including estimated cell-type proportions, and identified aberrant DNA methylation in SCZ at 2,552 CpG loci at a 5% false discovery rate correction. Our results suggest that altered DNA methylation may be involved in the pathophysiology of SCZ, and cell heterogeneity adjustments may be necessary for DNA methylation analysis.

Topics: Adult; Confounding Factors, Epidemiologic; CpG Islands; Dinucleoside Phosphates; DNA Methylation; Female; Genome-Wide Association Study; Granulocytes; Humans; Leukocyte Count; Leukocytes; Linear Models; Lymphocyte Subsets; Male; Middle Aged; Monocytes; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Receptors, Androgen; Schizophrenia

Suicide is the act of intentionally causing one's own death. The lifetime suicide risk in schizophrenia is 4.9% and 20% to 50% of patients with SCZ will attempt suicide during their life. The other risk factors for suicidal behavior in schizophrenia include prior history of suicide attempts, active psychosis, depression and substance abuse. To date, there are no robust genetic or epigenetic predictors of suicide or suicide attempt in this specific population.. We collected detailed clinical information and DNA samples from 241 schizophrenia patients and performed the genetic analyses in suicide attempters and non-attempters, among these patients. Using the structured research interview, we determined the presence of suicide attempt lifetime and then we tested 384 DNA variants in candidate genes supposed to be involved in the neurobiology of schizophrenia. We applied a novel mapping analysis using a specific bioinformatic tool that analyzed only the polymorphic CpG sites in our SNP panel. This analysis looked at the presence or absence of methylation sites affected by the SNP allele. The SNPs in the candidate genes were studied under a different perspective considering their direct contribution to the availability of methylation sites within the gene of interest. The level of potential methylation was compared using a linear model in attempters and non-attempters.. Among the 384 SNPs selected from the Illumina Bead Chip only the rs2661319 in the RGS4 gene was significantly associated with suicide attempt (p = 0.002). There were 119 CpG SNPs in the aforementioned panel. The gene-wise potential methylation level of RGS4 was 55% in the attempters and 65% in the non-attempters with a p-value of 0.005. The total level of potential metylation in the overall panel (119 SNPs combined) was not associated with suicide attempt. However, when considering the potential methylation at chromosome 1, we found that suicide attempt (p = 0.036) was associated with lower methylation.. The overall results showed no strong association between CpG SNPs and suicide attempt but the information regarding the CpG SNP potential methylation could be used as covariate in future methylation analysis.

Topics: Adolescent; Adult; Aged; Dinucleoside Phosphates; DNA Methylation; Female; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Principal Component Analysis; Schizophrenia; Schizophrenic Psychology; Suicide, Attempted; Young Adult