title: Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.
abstract: 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.
authors.affiliation: 1] Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Leibniz Institute for Neurobiology, Magdeburg, Germany [3] Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany [4] Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
authors.forename: B H
authors.initials: BH
authors.lastname: Schott
authors.affiliation: 1] Leibniz Institute for Neurobiology, Magdeburg, Germany [2] Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Assmann
authors.affiliation: 1] Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Berlin School of Mind and Brain, Humboldt University Berlin, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schmierer
authors.affiliation: 1] Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Leibniz Institute for Neurobiology, Magdeburg, Germany [3] Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Soch
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Garbusow
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Pöhland
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Barman
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wüstenberg
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Witt
authors.affiliation: 1] Leibniz Institute for Neurobiology, Magdeburg, Germany [2] University of Salzburg, Salzburg, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Richter
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.affiliation: Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schütze
authors.affiliation: 1] University of Bonn, Bonn, Germany [2] Research Center Jülich, Jülich, Germany.
authors.forename: T W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: 1] University of Bonn, Bonn, Germany [2] Research Center Jülich, Jülich, Germany [3] University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Noethen
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Tost
authors.affiliation: 1] Leibniz Institute for Neurobiology, Magdeburg, Germany [2] Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany [3] Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
authors.forename: E D
authors.initials: ED
authors.lastname: Gundelfinger
authors.affiliation: 1] Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany [2] Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany [3] Helmholtz Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Düzel
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: 1] Leibniz Institute for Neurobiology, Magdeburg, Germany [2] Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
authors.forename: C I
authors.initials: CI
authors.lastname: Seidenbecher
authors.affiliation: Department of Psychiatry, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Walter
mesh_terms: D000328:Adult; D020746:Calcium Channels, L-Type / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics*; D059907:Functional Neuroimaging; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D061212:Memory, Episodic; D009479:Neuropeptides / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D003598:Cytoskeletal Proteins; D009479:Neuropeptides; C498630:PCLO protein, human