CACNA1C Risk Allele for Psychotic Disorders is Related to the Activation of the AKT-Pathway

To the Editor: Genome-wide association studies have revealed a significant relationship between mood disorders, schizophrenia, and a variant in the CACNA1C gene (rs1006737, A/G) (1). This gene encodes the alpha subunit of the L-type voltage-dependent calcium channel (CAv1.2), and the risk variant is related to gray matter volume (2) and brain activation (3) in healthy individuals. However, the molecular correlates of the polymorphism are unknown. Recent evidence suggests that signals stemming from calcium channels modulate the activation of the phosphatidylinositol 3 kinase- protein kinase B (PI3K-PKB/Akt) intracellular messenger pathway (4), which may be an important convergence point of several molecular factors in the pathophysiology of mood disorders and schizophrenia (5–7).

In the present study, we investigated the relationship between rs1006737 and the activation of the PI3K-PKB/Akt pathway. Participants were 100 healthy volunteers of Central-Eastern European descent with a negative family history for schizophrenia and major mood disorders (mean age: 43.1 years [SD=6.7]; mean education: 12.2 years [SD=4.6]; female: N=47). The rs1006737 genotype was determined by a TaqMan assay (Applied Biosystems, Foster City, Calif.), as described previously (1). The activation of the PI3K-PKB/Akt pathway was determined from peripheral lymphoblasts by measuring phosphorylation at Ser473 using an immunoblot assay (6). The phosphorylated form/total ratio of Akt (pAkt/Akt) was analyzed as a function of genotype (AA, AG, and GG; no significant deviation from Hardy-Weinberg equilibrium).

Results revealed a significant effect of genotype on the pAkt/Akt ratio, which was lowest in the AA risk variant and highest in the GG nonrisk variant (AA [N=9]: 0.16 [SD=0.10]; AG [N=38]: 0.19 [SD=0.12]; GG [N5=3]: 0.32 [SD=0.19]). A oneway analysis of variance revealed a significant main effect of genotype (F=8.55, df=1, 97, p<0.001; Scheffé's test: AA<GG, AG<GG, p<0.05). This suggests that the CACNA1C risk geno-type is associated with the lowest level of Akt-pathway activation. Intracellular calcium may be involved in Akt activation, and functional polymorphisms of the CACNA1C gene may have an influence on this process. Both mechanisms may be included in memory processes and synaptic plasticity in the hippocampus (5, 8). However, at this time it is not known how rs1006737 affects CAv1.2 functions and whether this polymorphism is causally linked to mental disorders.