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

Abstract

ObjectiveThe goal of our study was to investigate whether DRD4 gene DNA methylation played an important role in the susceptibility of Han Chinese SCZ.MethodsUsing 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.ResultsStrong 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.ConclusionThe gender disparity in the DRD4 DNA methylation provides novel insights into the pathogenesis of SCZ.

Genetic analysis of common variants in the HDAC2 gene with schizophrenia susceptibility in Han Chinese

“…14 Previous studies reported that abnormal gene methylation has a key role in the development of SCZ. 15,16 For the covalent modification of histones, histone acetylation/deacetylation is the primary epigenetic mechanism regulating gene expression, which is catalyzed by two key enzymes, histone acetyltransferase and histone deacetylase (HDAC). 17 HDACs may increase the expression of several key genes in the brain and may also be associated with susceptibility to SCZ.…”

Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

“…Hypomethylation of genes promoters [77] 98/108 Peripheral blood CpG genome-wide islands Significant differences in DNA methylation at multiple loci [78] 60/30 Peripheral blood DRD4 Hypermethylation in male patients [79] 24/23 2 pairs of discordant twins…”

“…So far, few studies have examined the epigenetic effects of antipsychotics directly in humans and results are far from being clear, as detailed in Table 3 [65,78,82,86]. Patients treated with haloperidol showed a level of global methylation almost normal (control-like), as if the drug may partially rescue global hypomethylation reported in schizophrenia [65].…”

“…Brain tissue Saliva 5-HTT No statistically significant difference between methylation in the controls and those patients who were under antipsychotic drugs Risperidone [78] 60/30 Peripheral blood DRD4 No significant different methylation between pre-therapy and post-therapy of risperidone, after 8 weeks Haloperidol [65] 177/171 Peripheral blood leukocytes…”

Dopamine receptor D4 promoter hypermethylation increases the risk of drug addiction

“…The dopamine receptor D4 gene (DRD4) encodes the D4 subtype of the dopamine receptor, which belongs to the dopaminergic system (18). The alternative methylation of DRD4 is associated with various mental illnesses (19) and a male-specific association between DRD4 methylation and schizophrenia has been identified (20). It has been reported that the DRD4 promoter is hypermethylated in patients addicted to alcohol (21).…”