Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p<10-6) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L type voltage-gated calcium channel (LTCCs) subunit alpha1 C gene (CACNA1C), that were genome-wide significant (2.0×10 -8 ≤p≤1.0×10 -6 ) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within CACNA1C are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was analyzed. We found CACNA1C had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chip-based microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in chronic mild stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant CACNA1C up-regulation. We concluded that CACNA1C might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.