title: 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: 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.
authors.affiliation: 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.
authors.forename: Takuji
authors.initials: T
authors.lastname: Uemura
authors.affiliation: a Laboratory of Cellular and Molecular Pathophysiology, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , Ontario , Canada.
authors.forename: Marty
authors.initials: M
authors.lastname: Green
authors.affiliation: 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.|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.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002170:Canada; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C000595707:BCL2 protein, human; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium
keywords: Bcl-2; CACNA1C; SNP; bipolar disorder; intracellular calcium homeostasis