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Cellular genome-wide association study identifies common genetic variation influencing lithium induced neural progenitor proliferation

  • Author Footnotes
    # These authors contributed equally to this work.
    Justin M. Wolter
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Author Footnotes
    # These authors contributed equally to this work.
    Brandon D. Le
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Nana Matoba
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Michael J. Lafferty
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Nil Aygün
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Dan Liang
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Kenan Courtney
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Juan Song
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Joseph Piven
    Affiliations
    Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Mark J. Zylka
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Jason L. Stein
    Correspondence
    Correspondence should be addressed to: Jason Stein, Associate Professor, The University of North Carolina at Chapel Hill, Department of Genetics and Neuroscience Research Center, 7202A Mary Ellen Jones Building, Chapel Hill, NC 27599
    Affiliations
    UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.

      Abstract

      Background

      Bipolar disorder (BD) is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with BD. Lithium is clinically effective in roughly half of treated individuals, where genetic background is known to influence treatment outcomes. While the mechanism of lithium’s therapeutic action is unclear, it stimulates adult neural progenitor cell (NPC) proliferation, similar to some antidepressant drugs.

      Methods

      To identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU-incorporation assay in a library of 80 genotyped human NPCs treated with lithium. This data was used to perform a genome-wide association study (GWAS) to identify common genetic variants that influence lithium induced NPC proliferation. We manipulated expression of a putatively causal gene using CRISPRi/a constructs to experimentally verify lithium induced proliferation effects.

      Results

      We identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with BD risk, schizophrenia risk, and inter-individual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased following lithium in an allele-specific fashion. Experimentally increasing expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium induced proliferation.

      Conclusions

      Our experiments reveal that common genetic variation modulates lithium induced neural progenitor proliferation and that GNL3 expression is necessary for lithium’s full proliferation-stimulating effects. These results suggest that performing genome wide associations in genetically diverse human cell lines is a useful approach to discover context specific pharmacogenomic effects.

      Keywords

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