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

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

Uemura T1,2,3, Green M1, Warsh JJ1,2,4,5,6.

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a Laboratory of Cellular and Molecular Pathophysiology, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , Ontario , Canada.
b Department of Psychiatry , University of Toronto , Toronto , Ontario , Canada.
c Department of Neuropsychiatry , Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi , Chuo , Yamanashi , Japan.
d Department of Pharmacology & Toxicology , University of Toronto , Toronto , Ontario , Canada.
e Institute of Medical Science, University of Toronto , Toronto , Ontario , Canada.
f Program in Neuroscience, University of Toronto , Toronto , Ontario , Canada.



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.


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.


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.


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.


Bcl-2; CACNA1C; SNP; bipolar disorder; intracellular calcium homeostasis

[Indexed for MEDLINE]

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