title: Studies in humans and mice implicate neurocan in the etiology of mania.
abstract: OBJECTIVE
  Genome-wide association has been reported between the NCAN gene and bipolar disorder. The aims of this study were to characterize the clinical symptomatology most strongly influenced by NCAN and to explore the behavioral phenotype of Ncan knockout (Ncan(-/-)) mice.
  
  
  METHODS
  Genotype/phenotype correlations were investigated in patients with bipolar disorder (N=641) and the genetically related disorders major depression (N=597) and schizophrenia (N=480). Principal components and genotype association analyses were used to derive main clinical factors from 69 lifetime symptoms and to determine which of these factors were associated with the NCAN risk allele. These analyses were then repeated using the associated factor(s) only in order to identify the more specific clinical subdimensions that drive the association. Ncan(-/-) mice were tested using diverse paradigms, assessing a range of behavioral traits, including paradigms corresponding to bipolar symptoms in humans.
  
  
  RESULTS
  In the combined patient sample, the NCAN risk allele was significantly associated with the "mania" factor, in particular the subdimension "overactivity." Ncan(-/-) mice were hyperactive and showed more frequent risk-taking and repetitive behaviors, less depression-like conduct, impaired prepulse inhibition, amphetamine hypersensitivity, and increased saccharin preference. These aberrant behavioral responses normalized after the administration of lithium.
  
  
  CONCLUSIONS
  NCAN preferentially affected mania symptoms in humans. Ncan(-/-) mice showed behavioral abnormalities that were strikingly similar to those of the human mania phenotype and may thus serve as a valid mouse model.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Miró
authors.forename: Sandra
authors.initials: S
authors.lastname: Meier
authors.forename: Marie Luise
authors.initials: ML
authors.lastname: Dreisow
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.forename: René
authors.initials: R
authors.lastname: Breuer
authors.forename: Christine
authors.initials: C
authors.lastname: Schmäl
authors.forename: Önder
authors.initials: Ö
authors.lastname: Albayram
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Pardo-Olmedilla
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.forename: Franziska A
authors.initials: FA
authors.lastname: Degenhardt
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Iris
authors.initials: I
authors.lastname: Reinhard
authors.forename: Andras
authors.initials: A
authors.lastname: Bilkei-Gorzo
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Constanze
authors.initials: C
authors.lastname: Seidenbecher
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001714:Bipolar Disorder / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods / Q000706:statistics & numerical data*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058580:Neurocan / Q000235:genetics* / Q000502:physiology*; D025341:Principal Component Analysis / Q000379:methods; D012559:Schizophrenia / Q000235:genetics
chemical_list: D058580:Neurocan; D008094:Lithium