Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population

Schizophrenia (SCZ) is a devastating mental disorder affecting approximately 1% of the worldwide population. Early studies have indicated that genetics plays an important role in the onset and development of SCZ. Accumulating evidence supports that SCZ is linked to abnormalities of synapse transmission and synaptic plasticity. Voltage-gated calcium channel (VGCC) subunits are critical for mediating intracellular Ca^{2 +} influx and therefore are responsible for changing neuronal excitability and synaptic plasticity. To systematically investigate the role of calcium signaling genes in SCZ susceptibility, we conducted a case-control study that included 2518 SCZ patients and 7521 healthy controls with Chinese Han ancestry. Thirty-seven VGCC genes, including 363 tag single nucleotide polymorphisms (SNPs), were examined. Our study replicated the following previously identified susceptible loci: CACNA1C, CACNB2, OPRM1, GRM7 and PDE4B. In addition, several novel loci including CACNA2D1, PDE4D, NALCN, and CACNA2D3 were also identified to be associated with SCZ in our Han Chinese sample. Combined with GTEx eQTL data, we have shown that CASQ2, ITGAV, and TMC2 can be also added into the prioritization list of SCZ susceptible genes. Two-way interaction analyses identified widespread gene-by-gene interactions among VGCC activity and complex-related genes for the susceptibility of SCZ. Further sequencing based studies are still needed to unravel potential contributions of schizophrenia risk from rare or low frequency variants of these candidate genes.