Genetic Variants of Voltage-Gated Ca+2 Channel Genes, cacna1c and cacnb2, Conferring the Risk of Schizophrenia in Patients from Pakistan

Schizophrenia (SCZ) is a chronic mental disorder with a lifetime risk of approximately 1%. It is characterized by a profound disruption in cognition, behavior, and sensation with heritability estimated at up to 80%. It is a disorder with a complex etiology that involves multiple and heterogeneous genetic factors. The polygenic model of genetic susceptibility of psychiatric diseases explains that genetic variants of multiple genes determine the overall risk of disease because of their multiplicative effect. Two subunits of voltage-gated calcium channels, cacna1c and cacnb2 genes, play important roles in balancing calcium in brain cells, and their single-nucleotide polymorphisms (SNPs) have been associated differently with schizophrenia risk in different ethnicities. Two SNPs (rs1006737 & 4765913) of the cacna1c gene and a SNP (rs12257556) of the cacnb2 gene have been associated with schizophrenia. In this study, confirmed diagnosed schizophrenia patients and age-matched healthy control subjects were analyzed for the association of SNPs (rs1006737, 4765913 & rs12257556) with schizophrenia risk in Pakistani patients. Both SNPs of the cacna1c gene (rs1006737 and rs4765913) showed significant association with schizophrenia risk in this population. Moreover, two haplotypes (AT and GA) out of four for SNPs (rs1006737, rs4765913) of cacna1c further verified their significant association with the risk of schizophrenia. For cacnb2 , no significant association with the risk of schizophrenia in the SNP (rs12257556) was observed. The results of this study offer compelling evidence of a strong link between cacna1c polymorphisms (individual variant & haplotypes) and schizophrenia risk in the Pakistani population. Keywords: single-nucleotide polymorphisms, rs1006737, rs4765913, rs12257556. https://doi.org/10.55463/issn.1674-2974.50.12.10