TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study

Authors

  • Chun Xu,

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
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  • Peter P Li,

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
    2. Department of Pharmacology
    3. Department of Psychiatry, University of Toronto
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  • Robert G Cooke,

    1. Department of Psychiatry, University of Toronto
    2. Mood Disorders Program, Centre for Addiction and Mental Health
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  • Sagar V Parikh,

    1. Department of Psychiatry, University of Toronto
    2. Mood Disorders Program, Centre for Addiction and Mental Health
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  • KeSheng Wang,

    1. Program in Genetics and Genomic Biology, The Hospital for Sick Children
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  • James L Kennedy,

    1. Department of Psychiatry, University of Toronto
    2. Neurogenetics, Centre for Addiction and Mental Health
    3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Jerry J Warsh

    1. Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health
    2. Department of Pharmacology
    3. Department of Psychiatry, University of Toronto
    4. Mood Disorders Program, Centre for Addiction and Mental Health
    5. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • None of the authors has any involvement, financial or otherwise, that might bias this work.

Jerry J. Warsh, MD, PhD, Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, 250 College Street, Room R20, Toronto, ON, Canada, M5T 1R8. Fax: 416-979-4730;
e-mail: jerry.warsh@utoronto.ca

Abstract

Objective:  Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD.

Methods:  The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using χ2 test, transmission disequilibrium test, and pedigree-based association. SNP rs1556314 was also genotyped in our case-control sample set comprised of 184 BD and 195 healthy Caucasian subjects.

Results:  The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, ppermutation = 0.015) in the case-control dataset and in the family design (p = 0.018, ppermutation = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families.

Conclusion:  Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.

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