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

Erk, Susanne, Meyer-Lindenberg, Andreas, Linden, David Edmund Johannes, Lancaster, Thomas, Mohnke, Sebastian, Grimm, Oliver, Degenhardt, Franziska, Holmans, Peter Alan, Pocklington, Andrew, Schmierer, Phöbe, Haddad, Leila, Mühleisen, Thomas W., Mattheisen, Manuel, Witt, Stephanie H., Romanczuk-Seiferth, Nina, Tost, Heike, Schott, Björn H., Cichon, Sven, Nöthen, Markus M., Rietschel, Marcella, Heinz, Andreas and Walter, Henrik 2014. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. NeuroImage 94 , pp. 147-154. 10.1016/j.neuroimage.2014.03.007

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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 CACNA1Crs1006737 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 CACNA1Cgene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1Cvariants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 1053-8119
Last Modified: 18 May 2019 23:02
URI: http://orca.cf.ac.uk/id/eprint/67583

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