title: Hippocampal and frontolimbic function as intermediate phenotype for psychosis: evidence from healthy relatives and a common risk variant in CACNA1C.
abstract: BACKGROUND
  Variation in CACNA1C has consistently been associated with psychiatric disease in genome-wide association studies. We have previously shown that healthy carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate (pgACC) dysfunction during episodic memory recall. To test whether this brain systems-level abnormality is a potential intermediate phenotype for psychiatric disorder, we studied unaffected relatives of patients with bipolar disorder, major depression, and schizophrenia.
  
  
  METHODS
  The study population comprised 188 healthy first-degree relatives of patients with bipolar disorder (n=59), major depression (n=73), and schizophrenia (n=56) and 110 comparison subjects from our discovery study who were genotyped for rs1006737 and underwent functional magnetic resonance imaging while performing an episodic memory task and psychological testing. Group comparisons were analyzed using SPM8 and PASW Statistics 20.
  
  
  RESULTS
  Similar to risk allele carriers in the discovery sample, relatives of index patients exhibited hippocampal and pgACC dysfunction as well as increased scores in depression and anxiety measures, correlating negatively with hippocampal activation. Carrying the rs1006737 risk variant resulted in a stronger decrease of hippocampal and pgACC activation in relatives, indicating an additive effect of CACNA1C variation on familial risk.
  
  
  CONCLUSIONS
  Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte. Electronic address: susanne.erk@charite.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte; Berlin School of Mind and Brain, Humboldt University of Berlin, Berlin.
authors.forename: Phöbe
authors.initials: P
authors.lastname: Schmierer
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Department of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Maria
authors.initials: M
authors.lastname: Garbusow
authors.affiliation: Department of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Lydia
authors.initials: L
authors.lastname: Poehland
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn; Institute of Human Genetics, University of Bonn, Bonn; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.affiliation: Department of Psychology, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Nina
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Björn H
authors.initials: BH
authors.lastname: Schott
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn; Institute of Human Genetics, University of Bonn, Bonn.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte; Berlin School of Mind and Brain, Humboldt University of Berlin, Berlin; Department of Psychiatry, University of Bonn, Bonn.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics / Q000503:physiopathology; D001931:Brain Mapping; D020746:Calcium Channels, L-Type / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics / Q000503:physiopathology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D061212:Memory, Episodic; D010641:Phenotype; D011618:Psychotic Disorders / Q000235:genetics* / Q000503:physiopathology*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: CACNA1C; episodic memory; functional magnetic resonance imaging; hippocampus; imaging genetics; perigenual cingulate cortex