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Abstract
Schizophrenia (SCZ) is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.7–0.8%. Elevated plasma total homocysteine has been suggested as a risk factor for SCZ, and various biological effects of hyperhomocysteinemia have been proposed to be relevant to the pathophysiology of SCZ. As increased attention is paid to aberrant DNA methylation in SCZ, homocysteine is attracting additional interest as a potential key substance. Homocysteine is formed in the methionine cycle, which is involved in one-carbon methyl group-transfer metabolism, and it acts as a methyl donor when it is converted to S-adenosyl-methionine. To date, no studies have examined the relationship between homocysteine and genome-wide DNA methylation in SCZ. We examined the relationship between plasma total homocysteine and DNA methylation patterns in the peripheral leukocytes of patients with SCZ (n = 42) using a quantitative high-resolution DNA methylation array (485,764 CpG sites). Significant homocysteine-related changes in DNA methylation were observed at 1,338 CpG sites that were located across whole gene regions, including promoters, gene bodies and 3′-untranslated regions. Of the 1,338 sites, 758 sites (56.6%) were located in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 15.8%; CGI shore: 28.2%; CGI shelf: 12.6%), and positive correlations between plasma total homocysteine and DNA methylation were observed predominantly at CpG sites in the CGIs. Our results suggest that homocysteine might play a role in the pathogenesis of SCZ via a molecular mechanism that involves alterations to DNA methylation.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were dislosed.
Acknowledgments
The authors would like to thank all the volunteers, who understood our study purpose and participated in this study, and the physicians, who helped us to collect clinical data and blood samples at the mental hospitals. The authors would also like to thank Mrs. Akemi Okada and Mrs. Kumiko Kikuchi for their technical assistance. The authors also thank Dr. Jörg Tost for his valuable comments and suggestions on SNP-associated probes in the Illumina HumanMethylation450 platform. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (24791216), SENSHIN Medical Research Foundation and the Research Group For Schizophrenia.
Supplemental Material
Supplementary materials may be found here:
http://www.landesbioscience.com/journals/epigenetics/article/24621
Notes
† These authors contributed equally to this work.