Abstract
The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders.
Highlights
The heritability of psychiatric illness is high, the genetic mechanisms that confer susceptibility remain relatively unknown.[1,2] Recent genome-wide association studies (GWAS) have repeatedly identified a risk variant in the CACNA1C gene, which encodes an L-type voltage-gated calcium channel
Previous research suggests that the CACNA1C rs1006737 risk variant is associated with heritable neuropsychiatric disorders.[3,4,8,50]
Response bias is blunted in remitted patients, suggesting that reward responsiveness may serve as trait marker.[33]
Summary
The heritability of psychiatric illness is high, the genetic mechanisms that confer susceptibility remain relatively unknown.[1,2] Recent genome-wide association studies (GWAS) have repeatedly identified a risk variant in the CACNA1C gene, which encodes an L-type voltage-gated calcium channel (alpha 1C subunit). The risk variant (rs1006737: A allele) is significantly associated with bipolar disorder[3,4] and schizophrenia,[5,6,7,8] supporting the hypothesis that CACNA1C contributes to the genetic overlap between these psychiatric disorders. Emerging evidence supports a role for rs1006737 in the neural processing of reward[23] and learning.[24] Considering that the CACNA1C variant appears to transcend diagnostic boundaries, we hypothesize that the risk variant may affect intermediate phenotypes that are associated with several psychiatric illnesses. Reward responsiveness initially predicted an anhedonic phenotype,[31] but has since been shown to be diminished in patients with bipolar disorder[32] and more general depressive phenotypes.[33,34,35]
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