Male-Specific Association between Dopamine Receptor D4 Gene Methylation and Schizophrenia
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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.
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Studies examining DNAm in the blood of patients with SCZ compared with controls have shown both higher and lower DNAm levels in different DA receptor genes, with decreased DNAm in DRD3 and DRD4.
“Studies examining DNAm in the blood of patients with SCZ as compared with controls have showed both higher and lower DNAm levels in different DA receptor's genes; with decreased DNAm in DRD3 (Dai et al., 2014) and DRD4 (Cheng et al., 2014)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Cheng et al., 2014
The citation to Cheng et al. is attached to the claim of decreased DRD4 methylation in patients with schizophrenia. The Results report the opposite: DRD4 methylation was higher in patients than controls, with a significant difference in males and no significant difference in females. (LLM, conf=0.94)
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- Authors
- Cheng, J., Wang, Y., Zhou, K., Wang, L., Li, J., Zhuang, Q., Xu, X., Xu, L., Zhang, K., Dai, D., Zheng, R., Li, G., Zhang, A., Gao, S., & Duan, S.
- Affiliations
- Ningbo University (CN)
- Ningbo No. 2 Hospital (CN)
- Shanghai Jiao Tong University (CN)
- Ningbo Kangning Hospital (CN)
- Corresponding author
- Wang, Yunliang
- Gao, Shugui
- Duan, Shiwei
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-19
- Volume
- 9
- Issue
- 2
- Pages
- e89128
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3929639
- OpenAlex
- W2078382337
- Cited by
- 60
- References
- 38
- Citations by year
- 2025: 3 · 2024: 9 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 9 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 4
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (81371469, 2012C50032, 31100919, LR13H020003)
- Ningbo University (LR13H020003, 2012C50032, 81371469, 31100919)
- Natural Science Foundation of Ningbo (2013A610249, 81371469, 31100919, 2012C50032, LR13H020003)
- K. C. Wong Magna Fund in Ningbo University
- Natural Science Foundation of Zhejiang Province (LR13H020003, 2012C50032, 81371469, 31100919)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, DRD4, dopamine D4 receptor, DNA methylation, CpG islands, sex differences, genetic susceptibility, paranoid schizophrenia, undifferentiated schizophrenia, P300, gene expression, epigenetics, Han Chinese
- MeSH terms
- Adolescent, Adult, Child, Female, Humans, Male, Promoter Regions, Genetic, Schizophrenia, Sex Factors, Linkage Disequilibrium, DNA Methylation, Genetic Predisposition to Disease, Receptors, Dopamine D4, Young Adult, Genetic Association Studies
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