Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

Schott, Björn H. and Assmann, Anne and Schmierer, Phöbe and Soch, Joram and Erk, Susanne and Garbusow, Maria and Mohnke, Sebastian and Pohland, Lydia and Romanczuk-Seiferth, Nina and Barman, Adrian and Wustenberg, Torsten and Haddad, Linda and Grimm, Oliver and Witt, Stephanie H. and Richter, Sylvia and Klein, Marieke and Schutze, Hartmut and Muhleisen, Thomas W. and Cichon, Sven and Rietschel, Marcella and Noethen, Markus M. and Tost, H. and Gundelfinger, Eckart D. and Duzel, Emrah and Heinz, Andreas and Meyer-Lindenberg, Andreas and Seidenbecher, Constanze I. and Walter, Henrik . (2014) Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding. Translational Psychiatry, 4. e372.

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Official URL: https://edoc.unibas.ch/61580/

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Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the 'missing heritability' of complex phenotypes.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Jul 2020 13:46
Deposited On:20 Jul 2020 15:10

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