title: Male-specific association between dopamine receptor D4 gene methylation and schizophrenia.
abstract: 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.
  
  
  CONCLUSIONS
  The gender disparity in the DRD4 DNA methylation provides novel insights into the pathogenesis of SCZ.
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China ; Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Neurology Department of the 148th Hospital of PLA, Zibo, Shandong, China.
authors.forename: Yunliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Kena
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Bank of Blood Products, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Neurology Department of the 148th Hospital of PLA, Zibo, Shandong, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Qidong
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Xuting
authors.initials: X
authors.lastname: Xu
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Leiting
authors.initials: L
authors.lastname: Xu
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Dai
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Rongjiong
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China ; Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China.
authors.forename: Guangxue
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China.
authors.forename: Shugui
authors.initials: S
authors.lastname: Gao
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Duan
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D011401:Promoter Regions, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D012737:Sex Factors; D055815:Young Adult
chemical_list: C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4