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Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.

ABSTRACT: Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case-control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology.

SUBMITTER: Sugawara H

PROVIDER: S-EPMC3309511 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.

Sugawara H H Iwamoto K K Bundo M M Ueda J J Miyauchi T T Komori A A Kazuno A A Adati N N Kusumi I I Okazaki Y Y Ishigooka J J Kojima T T Kato T T

Translational psychiatry 20110726

Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variat ...[more]

PMID: 22832526

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Project description:Although monozygotic (MZ) twins share the majority of their genetic makeup, they can be phenotypically discordant on several traits and diseases. DNA methylation is an epigenetic mechanism that can be influenced by genetic, environmental and stochastic events and may have an important impact on individual variability. In this study we explored epigenetic differences in peripheral blood samples in three MZ twin studies on major depressive disorder (MDD). Epigenetic data for twin pairs were collected as part of a previous study using 8.1-K-CpG microarrays tagging DNA modification in white blood cells from MZ twins discordant for MDD. Data originated from three geographical regions: UK, Australia and the Netherlands. Ninety-seven MZ pairs (194 individuals) discordant for MDD were included. Different methods to address non independently-and-identically distributed (non-i.i.d.) data were evaluated. Machine-learning methods with feature selection centered on support vector machine and random forest were used to build a classifier to predict cases and controls based on epivariations. The most informative variants were mapped to genes and carried forward for network analysis. A mixture approach using principal component analysis (PCA) and Bayes methods allowed to combine the three studies and to leverage the increased predictive power provided by the larger sample. A machine-learning algorithm with feature reduction classified affected from non-affected twins above chance levels in an independent training-testing design. Network analysis revealed gene networks centered on the PPAR-γ (NR1C3) and C-MYC gene hubs interacting through the AP-1 (c-Jun) transcription factor. PPAR-γ (NR1C3) is a drug target for pioglitazone, which has been shown to reduce depression symptoms in patients with MDD. Using a data-driven approach we were able to overcome challenges of non-i.i.d. data when combining epigenetic studies from MZ twins discordant for MDD. Individually, the studies yielded negative results but when combined classification of the disease state from blood epigenome alone was possible. Network analysis revealed genes and gene networks that support the inflammation hypothesis of MDD.

Dataset Information

Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.

Publications

Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.

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