Abstract
Introduction The mechanism by which metabolic syndrome occurs in schizophrenia is not completely known; however, previous work suggests that changes in DNA methylation may be involved which is further influenced by sex. Within this study, the DNA methylome was profiled to identify altered methylation associated with metabolic syndrome in a schizophrenia population on atypical antipsychotics. Methods Peripheral blood from schizophrenia subjects was utilized for DNA methylation analyses. Discovery analyses (n = 96) were performed using an epigenome-wide analysis on the Illumina HumanMethylation450K BeadChip based on metabolic syndrome diagnosis. A secondary discovery analysis was conducted based on sex. The top hits from the discovery analyses were assessed in an additional validation set (n = 166) using site-specific methylation pyrosequencing. Results A significant increase in CDH22 gene methylation in subjects with metabolic syndrome was identified in the overall sample. Additionally, differential methylation was found within the MAP3K13 gene in females and the CCDC8 gene within males. Significant differences in methylation were again observed for the CDH22 and MAP3K13 genes, but not CCDC8, in the validation sample set. Conclusions This study provides preliminary evidence that DNA methylation may be associated with metabolic syndrome and sex in schizophrenia.
Highlights
The mechanism by which metabolic syndrome occurs in schizophrenia is not completely known; previous work suggests that changes in DNA methylation may be involved which is further influenced by sex
Treatment of schizophrenia patients with folate may aid in improving some aspects of metabolic syndrome [12]. These findings suggest that a properly functioning folate system may be important to minimizing the risk for atypical antipsychotics (AAPs)-induced metabolic syndrome
Potential subjects interested in participating were invited to the Michigan Clinical Research Center (MCRC) which is supported by the Michigan Institute for Clinical and Translational Research (MiCHR) to undergo full informed consent as approved by the University of Michigan Institutional Review Board
Summary
The mechanism by which metabolic syndrome occurs in schizophrenia is not completely known; previous work suggests that changes in DNA methylation may be involved which is further influenced by sex. This study provides preliminary evidence that DNA methylation may be associated with metabolic syndrome and sex in schizophrenia. Antipsychotics, in particular second-generation or atypical antipsychotics (AAPs), increase the risk of metabolic syndrome 2-3-fold in patients with schizophrenia due to their effects on weight and insulin resistance [1,2,3,4]. The metabolic syndrome consists of a cluster of metabolic disorders that include obesity, dyslipidemia, hypertension, and insulin resistance [5]. Together these risk factors are predictive of cardiovascular disease, type 2 diabetes, and mortality [6, 7]. A better understanding of the molecular mechanisms underlying metabolic syndrome in patients with schizophrenia is necessary so that personalized interventions and/or newer therapies can be developed that will minimize or remove the risk
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