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.

Figure 1

Effects of CACNA1C and PCLO depression risk variants on self-referential memory encoding (Experiment 1). (a) Experimental paradigm. Participants studied adjectives describing personality traits and performed either a self-reference task (‘Self'), an other-reference task (‘Merkel') or a control task (syllable counting). Stimuli were presented in a pseudo-randomized order with a near-exponential temporal jitter to optimize estimation of trial-specific BOLD responses. (b) Interaction of CACNA1C and PCLO depression risk variants on subgenual cingulate activation. Carriers of both high-risk alleles (CACNA1C rs1006737 A and PCLO rs2522833 C) exhibited comparable CG25 activation as participants homozygous for both low-risk alleles (CACNA1C rs1006737 G and PCLO rs2522833 A), whereas CG25 activity was drastically reduced in carriers of either one high-risk allele. The activation difference in CG25 was significant after family-wise error (FWE) correction for the ROI volume. Bar plots depict contrasts of parameter estimates (SPM betas) scaled to the global mean, ±s.e. ROI, region of interest; SPM, statistical parametric mapping.

Figure 2

Effects of CACNA1C and PCLO depression risk variants on associative memory encoding (Experiment 2). (a) Experimental paradigm. The task was divided into three phases (encoding, recall, recognition). During encoding, participants studied face–profession associations (left). In the recall task, participants were asked to recall the profession associated with the face and decide whether this profession required academic studies or vocational training (center). During recognition, participants performed a two-alternative forced choice task deciding which profession had been presented with the face (right). Translations: Architektin—architect; Studium—academic studies; Lehre—vocational training; Apothekerin—pharmacist. Stimuli were presented as blocked design. (b) Interaction of CACNA1C and PCLO depression risk variants on subgenual cingulate activation. Carriers of both high-risk alleles exhibited comparable CG25 activation as participants homozygous for both low-risk alleles, whereas CG25 activation was lower in carriers of either one high-risk allele. The CACNA1C by PCLO genotype interaction in CG25 was significant after family-wise error (FWE) correction for the ROI volume. Bar plots depict contrasts of parameter estimates (SPM betas), ±standard error.

Figure 3

Effects of CACNA1C and PCLO depression risk variants on encoding of novel scenes (Experiment 3). (a) Experimental paradigm. Participants studied novel scenes intermixed with previously familiarized ‘master' scenes and were asked to respond via button press whether an indoor or outdoor scene was shown. Stimuli were presented in a pseudo-randomized order with a near-exponential temporal jitter to optimize estimation of trial-specific BOLD responses. (b) Interaction of CACNA1C and PCLO depression risk variants on subgenual cingulate activation. Carriers of both high-risk alleles exhibited comparable CG25 activation as participants homozygous for both low-risk alleles, whereas CG25 activation was lower in carriers of either one high-risk allele. The CACNA1C by PCLO genotype interaction in CG25 was significant after family-wise error (FWE) correction for the ROI volume. Bar plots depict contrasts of parameter estimates (SPM betas), ±s.e. ROI, region of interest; SPM, statistical parametric mapping.