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Ozburn AR, Purohit K, Parekh PK, et al. Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism. Front Psychiatry. 2016;7:67doi: 10.3389/fpsyt.2016.00067.
Ozburn, A. R., Purohit, K., Parekh, P. K., Kaplan, G. N., Falcon, E., Mukherjee, S., Cates, H. M., & McClung, C. A. (2016). Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism. Frontiers in psychiatry, 767. https://doi.org/10.3389/fpsyt.2016.00067
Ozburn, Angela R, et al. "Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism." Frontiers in psychiatry vol. 7 (2016): 67. doi: https://doi.org/10.3389/fpsyt.2016.00067
Ozburn AR, Purohit K, Parekh PK, Kaplan GN, Falcon E, Mukherjee S, Cates HM, McClung CA. Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism. Front Psychiatry. 2016 Apr 21;7:67. doi: 10.3389/fpsyt.2016.00067. eCollection 2016. PMID: 27148095; PMCID: PMC4838618.
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Front Psychiatry. 2016 Apr 21;7:67. doi: 10.3389/fpsyt.2016.00067. eCollection 2016.

Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

Frontiers in psychiatry

Angela R Ozburn, Kush Purohit, Puja K Parekh, Gabrielle N Kaplan, Edgardo Falcon, Shibani Mukherjee, Hannah M Cates, Colleen A McClung

Affiliations

  1. Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; Portland Alcohol Research Center, VA Medical Center, Portland, OR, USA.
  2. Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine , Pittsburgh, PA , USA.
  3. Department of Pharmacology, University of Pennsylvania , Philadelphia, PA , USA.
  4. Department of Psychiatry, University of Texas Southwestern Medical Center , Dallas, TX , USA.
  5. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

PMID: 27148095 PMCID: PMC4838618 DOI: 10.3389/fpsyt.2016.00067

Abstract

Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) is a genetic variation of the human CLOCK gene that is significantly associated with increased frequency of manic episodes in BD patients (2). The 3111T/C SNP is located in the 3'-untranslated region of the CLOCK gene. In this study, we sought to examine the functional implications of the human CLOCK 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock(-/-) knockout mice) with pcDNA plasmids containing the human CLOCK gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24-h time period. We found that the CLOCK3111C SNP resulted in higher mRNA levels than the CLOCK 3111T SNP. Furthermore, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with CLOCK 3111C expression, indicating that the 3'-UTR SNP affects the expression, function, and stability of CLOCK mRNA.

Keywords: bipolar disorder; cell culture; circadian; clock; gene expression; single-nucleotide polymorphism

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