title: Brain function in carriers of a genome-wide supported bipolar disorder variant.
abstract: BACKGROUND
  The neural abnormalities underlying genetic risk for bipolar disorder, a severe, common, and highly heritable psychiatric condition, are largely unknown. An opportunity to define these mechanisms is provided by the recent discovery, through genome-wide association, of a single-nucleotide polymorphism (rs1006737) strongly associated with bipolar disorder within the CACNA1C gene, encoding the alpha subunit of the L-type voltage-dependent calcium channel Ca(v)1.2.
  
  
  OBJECTIVE
  To determine whether the genetic risk associated with rs1006737 is mediated through hippocampal function.
  
  
  METHODS
  Functional magnetic resonance imaging study.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  A total of 110 healthy volunteers of both sexes and of German descent in the Hardy-Weinberg equilibrium for rs1006737.
  
  
  METHODS
  Blood oxygen level-dependent signal during an episodic memory task and behavioral and psychopathological measures.
  
  
  RESULTS
  Using an intermediate phenotype approach, we show that healthy carriers of the CACNA1C risk variant exhibit a pronounced reduction of bilateral hippocampal activation during episodic memory recall and diminished functional coupling between left and right hippocampal regions. Furthermore, risk allele carriers exhibit activation deficits of the subgenual anterior cingulate cortex, a region repeatedly associated with affective disorders and the mediation of adaptive stress-related responses. The relevance of these findings for affective disorders is supported by significantly higher psychopathology scores for depression, anxiety, obsessive-compulsive thoughts, interpersonal sensitivity, and neuroticism in risk allele carriers, correlating negatively with the observed regional brain activation.
  
  
  CONCLUSIONS
  Our data demonstrate that rs1006737 or genetic variants in linkage disequilibrium with it are functional in the human brain and provide a neurogenetic risk mechanism for bipolar disorder backed by genome-wide evidence.
authors.affiliation: Division of Medical Psychology, University of Bonn, Bonn, Germany. susanne.erk@charite.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Knut
authors.initials: K
authors.lastname: Schnell
authors.forename: Carola
authors.initials: C
authors.lastname: Opitz von Boberfeld
authors.forename: Christine
authors.initials: C
authors.lastname: Esslinger
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.forename: Claudia
authors.initials: C
authors.lastname: Arnold
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D015220:Calcium Channels / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C425903:CACNA2D1 protein, human; D015220:Calcium Channels