title: Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder.
abstract: OBJECTIVE
  Disrupted intracellular calcium (Ca(2+) ) homeostasis (ICH) related to mitochondrial and/or endoplasmic reticulum (ER) dysfunction has been implicated in bipolar disorder (BD). The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2), encoded in a putative BD susceptibility locus, modulates ER-Ca(2+) dynamics. Recently, an intronic single-nucleotide polymorphism (SNP) in the Bcl-2 gene, rs956572, was suggested as a functionally active SNP that influences its messenger RNA (mRNA) and protein level as well as human gray matter volume. We sought to evaluate the impact of this variant on ICH in BD.
  
  
  METHODS
  Basal intracellular Ca(2+) concentrations ([Ca(2+) ](B) ) and rs956572 genotypes were determined in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) (n=150), bipolar II disorder (BD-II) (n=65), and major depressive disorder (n=30) patients, and from healthy subjects (n=70). Bcl-2 mRNA and protein levels were determined by quantitative reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Functional interactions of rs956572 with ICH were assessed by thapsigargin- and lysophosphatidic acid (LPA)-stimulated Ca(2+) responses.
  
  
  RESULTS
  Although rs956572 variation was not significantly associated with BD, BD-I, or BD-II, BLCL [Ca(2+) ](B) was significantly higher in BD-I G/G patients compared with other genotypes and with healthy subjects. Bcl-2 mRNA and protein levels were lowest in BD-I G/G patients. Compared with A carriers, BD-I patients with G/G variants showed a modest enhancing effect on thapsigargin- and LPA-stimulated Ca(2+) responses.
  
  
  CONCLUSIONS
  These findings support the notion that genetic variation in Bcl-2 affecting its expression impacts ICH in BD. Moreover, we show here for the first time that this interactive effect is diagnostically specific to BD-I.
authors.affiliation: Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Takuji
authors.initials: T
authors.lastname: Uemura
authors.forename: Marty
authors.initials: M
authors.lastname: Green
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
authors.forename: Tatiana
authors.initials: T
authors.lastname: Perova
authors.forename: Peter P
authors.initials: PP
authors.lastname: Li
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D002118:Calcium