TY - JOUR
T1 - Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins
AU - Kuratomi, G.
AU - Iwamoto, K.
AU - Bundo, M.
AU - Kusumi, I.
AU - Kato, N.
AU - Iwata, N.
AU - Ozaki, N.
AU - Kato, T.
N1 - Funding Information:
This study was supported by grant-in-aid from Japanese Ministry of Health, Welfare and Labor. We thank all the patients and volunteers who participated in this study. We are grateful to Dr Yuji Okazaki, who has inspired us for this research strategy of discordant twins, and encouraged us continuously. We are grateful to Dr Toshikazu Ushijima, who provided the detailed protocol of MS-RDA and gave us valuable advice. We are very grateful to Dr Tatsuyo Suzuki and Dr Tsuyoshi Kitajima (Fujita Health University) for generous help for providing the lymphoblastoid cell lines. We also thank Dr Chihiro Kakiuchi, Ms Mizuho Ishiwata, Ms Atsuko Komori and Mizue Kametani for their assistance in cell culture and DNA extraction.
PY - 2008/4
Y1 - 2008/4
N2 - To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5′ region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.
AB - To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5′ region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.
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U2 - 10.1038/sj.mp.4002001
DO - 10.1038/sj.mp.4002001
M3 - Article
C2 - 17471289
AN - SCOPUS:40849116456
SN - 1359-4184
VL - 13
SP - 429
EP - 441
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 4
ER -