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Objective  The goal of our study was to investigate whether  DRD4  gene DNA methylation played an important role in the susceptibility of Han Chinese SCZ.    Methods  Using the bisulphite pyrosequencing technology, DNA methylation levels of 6 CpG dinucleotides in  DRD4  CpG island were measured among 30 paranoid SCZ patients, 30 undifferentiated SCZ patients, and 30 age- and gender-matched healthy controls.    Results  Strong correlation was observed among the six CpG sites (r>0.5, P<0.01), thus average methylation levels were applied thereafter. Our results indicated that there was a significant association between  DRD4  methylation and the risk of SCZ (P = 0.003), although there was no significant difference in  DRD4  methylation between the two SCZ subtypes (P = 0.670). A breakdown analysis by gender showed that the significant association of  DRD4  methylation and SCZ was driven by males (P<0.001) but not by females (P = 0.835).  DRD4  methylation was significantly associated with p300 in male SCZ patients (r = −0.543, P = 0.005) but not in female SCZ patients (r = 0.110, P = 0.599). Moreover, receiver operating characteristic (ROC) curves showed  DRD4  methylation was able to predict the status of SCZ in males [area under curve (AUC) = 0.832, P = 0.002] but not in females (AUC = 0.483, P = 0.876). Finally, a further expression experiment showed that  DRD4  methylation in the gene body was positively associated with gene expression, although the exact mechanism of gene regulation remained unknown for this interesting  DRD4  methylation.    Conclusion  The gender disparity in the  DRD4  DNA methylation provides novel insights into the pathogenesis of SCZ.

Male-Specific Association between Dopamine Receptor D4 Gene Methylation and Schizophrenia