Abstract
BackgroundOxytocin is one of the key hormones involved in human social and emotional processing. In this regard, abnormal functioning of the oxytocin system has been suggested to influence on the clinical manifestation of schizophrenia, especially negative symptoms. The aim of the present study was to investigate epigenetic modification of the oxytocin receptor gene (OXTR) and its association with negative symptoms in individuals with recent-onset schizophrenia (SCZ) and at ultra-high risk (UHR) for psychosis.MethodsSixty-four SCZ patients (< 5 years of duration of illness; 25 men, 39 women), 46 UHR individuals (27 men, 19 women), and 98 healthy controls (HCs; 46 men, 52 women) participated in the present study. DNA methylation was quantified from peripheral blood using pyrosequencing at CpG sites in OXTR intron 1 (hg19, chr3: 8,810,729–8,810,845) and exon 3 (hg19, chr3: 8,809,281–8,809,534). The severity of negative symptoms in clinical groups was measured using the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS).ResultsA multivariate analysis of covariance revealed significant differences in OXTR methylation between groups (F = 16.00, p < 0.001) and gender (F = 2.84, p = 0.025). Compared to HCs, both UHR and SCZ participants showed lower levels of OXTR intron 1 methylation, particularly at CpG site -934 upstream of the OXTR start codon (HCs = 47.3 ± 4.1 [mean ± SD], UHR = 38.8 ± 4.8, SCZ = 40.2 ± 5.3; F = 73.74, p < 0.001). Besides, female participants showed higher OXTR intron 1 methylation at CpG site -934 than male participants (male = 42.3 ± 6.1, female = 44.1 ± 5.8, F = 9.08, p = 0.003). Multiple linear regression analysis with clinical symptoms demonstrated that the degree of DNA methylation at CpG site -934 was significantly associated with the SANS anhedonia-asociality subscale scores in the entire group of female UHR and SCZ participants (beta = -0.44, p = 0.001).DiscussionThe present study demonstrated decreased OXTR methylation in both UHR and SCZ individuals compared to HCs. Furthermore, the severity of anhedonia-asociality was significantly associated with the degree of OXTR methylation in female UHR and SCZ individuals. These findings suggest that epigenetic aberration of OXTR may confer susceptibility to schizophrenia spectrum psychosis and influence the early pathogenesis of schizophrenia prior to the onset of overt psychosis, particularly in females.
Highlights
Transcription at enhancers is a widespread phenomenon, which produces so-called enhancer RNA and occurs in an activity dependent manner
The aim of this study is to clarify the contribution of polymorphisms of the neuregulin 1 (NRG1) with schizophrenia Methods: After informed consent was obtained, 100 schizophrenia patients and 100 control subjects were enrolled in this study
The NRG1gene was originally identified as a susceptibility gene for schizophrenia by using a combination of a linkage and association approaches based on microsatellite markers and using SNPs after microsatellite at risk haplotypes were identified
Summary
Oxytocin is one of the key hormones involved in human social and emotional processing. Multiple linear regression analysis with clinical symptoms demonstrated that the degree of DNA methylation at CpG site -934 was significantly associated with the SANS anhedonia-asociality subscale scores in the entire group of female UHR and SCZ participants (beta = -0.44, p = 0.001). Discussion: The present study demonstrated decreased OXTR methylation in both UHR and SCZ individuals compared to HCs. the severity of anhedonia-asociality was significantly associated with the degree of OXTR methylation in female UHR and SCZ individuals. The severity of anhedonia-asociality was significantly associated with the degree of OXTR methylation in female UHR and SCZ individuals These findings suggest that epigenetic aberration of OXTR may confer susceptibility to schizophrenia spectrum psychosis and influence the early pathogenesis of schizophrenia prior to the onset of overt psychosis, in females
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