title: Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects.
abstract: Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany. Electronic address: susanne.erk@charite.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.affiliation: Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK.
authors.forename: David E J
authors.initials: DEJ
authors.lastname: Linden
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK; Neuroscience and Mental Health Research Institute, Cardiff University, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lancaster
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pocklington
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Berlin School of Mind and Brain, Humboldt University Berlin, Germany.
authors.forename: Phöbe
authors.initials: P
authors.lastname: Schmierer
authors.affiliation: Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Biomedicine, University of Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Dept. of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Björn H
authors.initials: BH
authors.lastname: Schott
authors.affiliation: Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Dept. of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Berlin School of Mind and Brain, Humboldt University Berlin, Germany; Dept. of Psychiatry, University of Bonn, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D009415:Nerve Net / Q000503:physiopathology*; D011618:Psychotic Disorders / Q000235:genetics*; D018570:Risk Assessment
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: CACNA1C; Dorsolateral prefrontal cortex; Hippocampus; Imaging genetics; Perigenual anterior cingulate; fMRI