Manuel Mattheisen

Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects

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  • Susanne Erk, 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.
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  • Andreas Meyer-Lindenberg, Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • David Linden, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom.
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  • Thomas Lancaster, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom; Neuroscience and Mental Health Research Institute, Cardiff University, United Kingdom.
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  • Sebastian Mohnke, Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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  • Oliver Grimm, Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • Franziska Degenhardt, Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany.
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  • Peter Holmans, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom.
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  • Andrew Pocklington, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom.
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  • Phöbe Schmierer, 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.
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  • Leila Haddad, Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • Thomas W Mühleisen, 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.
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  • Manuel Mattheisen
  • Stephanie H Witt, Dept. of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • Nina Seiferth, Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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  • Heike Tost, Dept. of Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • Björn H Schott, Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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  • Sven Cichon, 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.
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  • Markus M Nöthen, Dept. of Genomics, Life & Brain Center, University of Bonn, Germany; Institute of Human Genetics, University of Bonn, Germany.
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  • Marcella Rietschel, Dept. of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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  • Andreas Heinz, Dept. of Psychiatry, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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  • Henrik Walter, 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.
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 analysed 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 systems-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.
Original languageEnglish
JournalNeuroImage
ISSN1053-8119
DOIs
Publication statusPublished - 15 Mar 2014

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