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Bipolar Disorders

Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder

Authors

  • Takuji Uemura,

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
    2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • Marty Green,

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
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  • Timothy W Corson,

    1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA
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  • Tatiana Perova,

    1. Department of Medical Biophysics
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  • Peter P Li,

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
    2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    3. Department of Pharmacology and Toxicology
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  • Jerry J Warsh

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
    2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    3. Department of Pharmacology and Toxicology
    4. Institute of Medical Science
    5. Program in Neuroscience, University of Toronto, Toronto, Ontario, Canada
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  • A preliminary report of this work was presented at the 65th Annual Meeting of the Society for Biological Psychiatry, May 20–22, 2010, New Orleans, LA, USA.

  • The authors of this paper declare that, except for income received from the primary employer or trainee award, no financial support or compensation has been received from any individual or corporate entity for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Corresponding author:
Jerry J. Warsh, M.D., Ph.D.
Laboratory of Cellular and Molecular Pathophysiology
Centre for Addiction and Mental Health
250 College Street, Room R20
Toronto, Ontario, Canada M5T 1R8
Fax: +1-416-979-4730
E-mail: jerry.warsh@utoronto.ca

Abstract

Uemura T, Green M, Corson TW, Perova T, Li PP, Warsh JJ. Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder.
Bipolar Disord 2011: 13: 41–51. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S.

Objectives:  Disrupted intracellular calcium (Ca2+) 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-Ca2+ 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 Ca2+ concentrations ([Ca2+]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 Ca2+ responses.

Results:  Although rs956572 variation was not significantly associated with BD, BD-I, or BD-II, BLCL [Ca2+]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 Ca2+ 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.

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