title: Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL.
abstract: The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ between bipolar disorder (BD) and controls.
  
  
  
  The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5' region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls.
  
  
  
  Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073).
  
  
  
  Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Bengesser
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Eva Z
authors.initials: EZ
authors.lastname: Reininghaus
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Lackner
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Birner
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Frederike T
authors.initials: FT
authors.lastname: Fellendorf
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Platzer
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Nora
authors.initials: N
authors.lastname: Kainzbauer
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Tropper
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Christa
authors.initials: C
authors.lastname: Hörmanseder
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Queissner
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kapfhammer
authors.affiliation: b Institute of Pathophysiology and Immunology , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Wallner-Liebmann
authors.affiliation: b Institute of Pathophysiology and Immunology , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Fuchs
authors.affiliation: c Institute of Human Genetics , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Erwin
authors.initials: E
authors.lastname: Petek
authors.affiliation: c Institute of Human Genetics , Medical University of Graz (MUG) , Graz , Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: d Institute of Economics , JKU Linz , Leonding, Linz , Austria.|e Cubido business solutions , Leonding, Linz , Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Schnalzenberger
authors.affiliation: a Department of Psychiatry , Medical University of Graz (MUG) , Graz , Austria.|f Justuspark Bad Hall , Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reininghaus
authors.affiliation: g Department of Neurology , University of Bonn , Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Evert
authors.affiliation: h Institute of Neuropathology , University of Bonn , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000627:therapeutic use; D001317:Austria; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008094:Lithium / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D000927:Anticonvulsants; D008094:Lithium
keywords: ARNTL; Bipolar affective disorder; PS2; cg05733463; methylation