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

Abstract

Objectives. Intracellular calcium (Ca²⁺) 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 Ca²⁺ concentrations ([Ca²⁺]_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 Ca²⁺ channel α1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca²⁺]_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 [Ca²⁺]_B and Bcl-2 SNP rs956572 genotype measures. Results. SNP rs1006737 was significantly associated with BD-I. The [Ca²⁺]_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 [Ca²⁺]_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.

Key words::

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

Acknowledgements

A preliminary report of this work was presented at the 67th annual meeting of the Society for Biological Psychiatry, Philadelphia, PA, May 2012 and 11th World Congress of Biological Psychiatry; the World Federation of Societies of Biological Psychiatry, Kyoto, Japan, June 2013. This study was supported in part by CIHR operating grants MOP-12851and MOP-69033. We gratefully acknowledge the contributions of the physicians and research staff at CAMH for their assistance in recruiting potential patient subjects for participation in these studies. Bronwen Hughes assisted in recruitment of healthy and patient subjects from whom B lymphoblasts were used in this study.

Statement of Interest

None to declare.

Supplementary material available online

Supplementary Table I. Demographic characteristics of BD-I patients.

Supplementary Table II. Risk genotype frequencies of CACNA1C intronic SNP rs1006737 in mood disorders and comparison healthy subject groups.