Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated.
RNA-sequencing analyses of cortical and striatal micropunches from Brd1<sup>+/-</sup> and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D<sub>2</sub> [Drd2], and transcription factor 4 [Tcf4]).
Genetic variation in CACNA1C, which codes for the L-type calcium channel (LTCC) Ca<sub>v</sub> 1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia.
Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common.
The CACNA1C gene that encodes the L-type Ca<sup>2+</sup> channel (LTCC) Ca<sub>v</sub>1.2 subunit has emerged as a candidate risk gene for multiple neuropsychiatric disorders including bipolar disorder, major depressive disorder, and schizophrenia, all marked with depression-related symptoms.
The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology.
In conclusion, polymorphisms in CACNA1C and SYNE1 could confer a greater risk of developing SZ and BD in individuals who are already at high risk because of their family history.
Specifically, genome wide association studies (GWAS) have repeatedly identified the single nucleotide polymorphism (SNP) rs1006737 in intron 3 of CACNA1C to be strongly associated with schizophrenia and bipolar disorder.
Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ.
We performed a comprehensive meta-analysis of all available samples from existing studies of East Asian populations, including a total of 9,432 cases and 10,661 controls, to further confirm whether CACNA1Crs1006737 is an authentic risk SNP for schizophrenia in East Asian populations.
Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations.
On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1Crs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder.
Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
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.