title: 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.
authors: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors: H
authors: H
authors: Sugawara
authors: K
authors: K
authors: Iwamoto
authors: M
authors: M
authors: Bundo
authors: J
authors: J
authors: Ueda
authors: T
authors: T
authors: Miyauchi
authors: A
authors: A
authors: Komori
authors: A
authors: A
authors: Kazuno
authors: N
authors: N
authors: Adati
authors: I
authors: I
authors: Kusumi
authors: Y
authors: Y
authors: Okazaki
authors: J
authors: J
authors: Ishigooka
authors: T
authors: T
authors: Kojima
authors: T
authors: T
authors: Kato
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D019175:DNA Methylation / Q000235:genetics*; D004200:Diseases in Twins; D057890:Epigenomics / Q000295:instrumentation / Q000379:methods*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D014430:Twins, Monozygotic
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins