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.
Highlights
The etiology of human affective disorders is highly multifactorial with the estimated genetic contribution being as high as 85 percent for bipolar disorder (BPD)[1] and around 30 to 40 percent for unipolar major depressive disorder (MDD).[2]
When we unexpectedly observed a cingulate activity during encoding of emotional stimuli complex epistatic interaction of the two risk variants during selfhas been associated with negative recall bias, and this association is modulated by genetic variability of the HPA axis.[21] referential episodic encoding, we aimed to replicate this finding in two additional episodic encoding tasks, conducted in two further
We focused our analyses on the subgenual cingulate/CG25 and on the hippocampus, using the same a priori defined regions of interest (ROIs) in all three experiments
Summary
The etiology of human affective disorders is highly multifactorial with the estimated genetic contribution being as high as 85 percent for bipolar disorder (BPD)[1] and around 30 to 40 percent for unipolar major depressive disorder (MDD).[2] Despite the recent advances in large-scale genomic investigations of the etiology of complex human diseases, including psychiatric disorders, there is a considerable gap between the relative genetic contribution estimated from twin and sibling studies and the actual contribution from identified genetic risk variants This unexplained variance of genetic contributions to human disease is commonly referred to as the missing heritability.[3,4] Several biological processes have been suggested to underlie the phenomenon of missing heritability, including gene–environment interactions, gene–gene interactions, and the heterogeneity of the phenotype of interest itself. An endophenotype is defined as a measurable trait along the pathway from a genotype to a complex disease and commonly shows stronger heritability than the disease phenotype itself.[5]
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