Tests of linkage and allelic association between markers in the 1p36 PRKCZ (Protein Kinase C Zeta) gene region and bipolar affective disorder

Authors

  • Radhika Kandaswamy,

    1. Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, Rockefeller Building, University College London, London, UK
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  • Andrew McQuillin,

    1. Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, Rockefeller Building, University College London, London, UK
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  • David Curtis,

    1. Department of Psychological Medicine, Queen Marys University of London, London, UK
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  • Hugh Gurling

    Corresponding author
    1. Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, Rockefeller Building, University College London, London, UK
    • Molecular Psychiatry Laboratory, Rockefeller Building, University College London, London WC1E 6BT, UK.
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  • How to Cite this Article: Kandaswamy R, McQuillin A, Curtis D, Gurling H. 2012. Tests of Linkage and Allelic Association Between Markers in the 1p36 PRKCZ (Protein Kinase C Zeta) Gene Region and Bipolar Affective Disorder. Am J Med Genet Part B 159B:201–209.

Abstract

Three linkage studies of families with multiple cases of bipolar disorder and/or unipolar affective disorder have confirmed the involvement of the chromosome 1p36 region in the etiology of affective disorders with LOD scores of 2.7, 3.6, and 3.97. We investigated the protein kinase C zeta gene (PRKCZ) as a susceptibility locus for bipolar disorder because it is highly brain expressed and is localized close to the marker D1S243 which was linked to affective disorder in a single large UCL bipolar disorder family with a LOD of 3.1. PRKCZ encodes an unusual type of protein kinase which affects axonal differentiation through Wnt-signaling. We genotyped four microsatellite markers and nine single nucleotide polymorphism (SNP) markers within or near the PRKCZ gene in the UCL case–control sample of 600 bipolar disorder patients and up to 605 supernormal controls. Markers D1S243 and rs3128396 were significantly associated with bipolar disorder (empirical P = 0.037 and P = 0.040, respectively). We also included data from eight SNPs which were genotyped as part of our GWA study on bipolar disorder for association analysis. Tests of haplotypic association found that a haplotype block comprising markers rs3128296, rs2503706, and rs3128309 was associated with bipolar disorder (empirical P = 0.004). A previous linkage study had shown greater evidence for linkage within female cases compared to males. Therefore, to assess if the association was sex-specific, we performed a female-only allelic-association analysis, which resulted in SNPs rs3128296 and rs3128309 becoming associated with bipolar disorder (P = 0.004 and P = 0.016, respectively). PRKCZ may play a role in susceptibility to bipolar affective disorder. © 2012 Wiley Periodicals, Inc.

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