title: Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII.
abstract: The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.
authors.affiliation: Department of Biomedical Sciences, University of Teramo, Teramo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dell'Osso
authors.forename: Maria Carlotta
authors.initials: MC
authors.lastname: Palazzo
authors.forename: Beatrice
authors.initials: B
authors.lastname: Benatti
authors.forename: Licia
authors.initials: L
authors.lastname: Lietti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.forename: Francesca
authors.initials: F
authors.lastname: Cortini
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Beatrice
authors.initials: B
authors.lastname: Arosio
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Francesco
authors.forename: Manuela
authors.initials: M
authors.lastname: Di Benedetto
authors.forename: Patrizia
authors.initials: P
authors.lastname: Romualdi
authors.forename: Sanzio
authors.initials: S
authors.lastname: Candeletti
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.forename: Luigi
authors.initials: L
authors.lastname: Bergamaschini
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: A Carlo
authors.initials: AC
authors.lastname: Altamura
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor