CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis

World J Biol Psychiatry. 2016 Oct;17(7):525-34. doi: 10.3109/15622975.2015.1019360. Epub 2015 Apr 5.


Objectives: Intracellular calcium (Ca(2+)) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca(2+) concentrations ([Ca(2+)]B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca(2+) channel α1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca(2+)]B in BD-I.

Methods: CACNA1C SNP rs1006737 was genotyped in 150 BD-I, 65 BD-II, 30 major depressive disorder patients, and 70 healthy subjects with available BLCL [Ca(2+)]B and Bcl-2 SNP rs956572 genotype measures.

Results: SNP rs1006737 was significantly associated with BD-I. The [Ca(2+)]B was significantly higher in BD-I rs1006737 A compared with healthy A allele carriers and also in healthy GG compared with A allele carriers. There was no significant interaction between SNP rs1006737 and SNP rs956572 on [Ca(2+)]B.

Conclusions: Our study further supports the association of SNP rs1006737 with BD-I and suggests that CACNA1C SNP rs1006737 and Bcl-2 SNP rs956572, or specific causal variants in LD with these proxies, act independently to increase risk and ICDH in BD-I.

Keywords: Bcl-2; CACNA1C; SNP; bipolar disorder; intracellular calcium homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Bipolar Disorder / genetics*
  • Calcium / metabolism*
  • Calcium Channels, L-Type / genetics*
  • Canada
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heterozygote
  • Homeostasis*
  • Humans
  • Male
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Young Adult


  • BCL2 protein, human
  • CACNA1C protein, human
  • Calcium Channels, L-Type
  • Proto-Oncogene Proteins c-bcl-2
  • Calcium