Variants in doublecortin- and calmodulin kinase like 1, a gene up-regulated by BDNF, are associated with memory and general cognitive abilities

Stephanie Le Hellard, Bjarte Havik, Thomas Espeseth, Harald Breilid, Roger Lovlie, Michelle Luciano, Alan J. Gow, Sarah E. Harris, John M. Starr, Karin Wibrand, Astri J. Lundervold, David J. Porteous, Clive R. Bramham, Ian J. Deary, Ivar Reinvang, Vidar M. Steen

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    25 Citations (Scopus)

    Abstract

    Background: Human memory and general cognitive abilities are complex functions of high heritability and wide variability in the population. The brain-derived neurotrophic factor (BDNF) plays an important role in mammalian memory formation.

    Methodology / Principal Finding: Based on the identification of genes markedly up-regulated during BDNF-induced synaptic consolidation in the hippocampus, we selected genetic variants that were tested in three independent samples, from Norway and Scotland, of adult individuals examined for cognitive abilities. In all samples, we show that markers in the doublecortin-and calmodulin kinase like 1 (DCLK1) gene, are significantly associated with general cognition (IQ scores) and verbal memory function, resisting multiple testing. DCLK1 is a complex gene with multiple transcripts which vary in expression and function. We show that the short variants are all up-regulated after BDNF treatment in the rat hippocampus, and that they are expressed in the adult human brain (mostly in cortices and hippocampus). We demonstrate that several of the associated variants are located in potential alternative promoter-and cis-regulatory elements of the gene and that they affect BDNF-mediated expression of short DCLK1 transcripts in a reporter system.

    Conclusion: These data present DCLK1 as a functionally pertinent gene involved in human memory and cognitive functions.

    Original languageEnglish
    Article numberARTN e7534
    Number of pages11
    JournalPLoS ONE
    Volume4
    Issue number10
    DOIs
    Publication statusPublished - 2009

    Keywords

    • LONG-TERM POTENTIATION
    • COPY-NUMBER VARIATION
    • BIPOLAR-DISORDER
    • DEPENDENT PROTEIN-KINASE
    • EPISODIC MEMORY
    • CONVERGENT FUNCTIONAL GENOMICS
    • GYRUS IN-VIVO
    • HIPPOCAMPAL ACTIVITY
    • SPLICE VARIANTS
    • SYNAPTIC PLASTICITY

    Cite this

    Le Hellard, S., Havik, B., Espeseth, T., Breilid, H., Lovlie, R., Luciano, M., Gow, A. J., Harris, S. E., Starr, J. M., Wibrand, K., Lundervold, A. J., Porteous, D. J., Bramham, C. R., Deary, I. J., Reinvang, I., & Steen, V. M. (2009). Variants in doublecortin- and calmodulin kinase like 1, a gene up-regulated by BDNF, are associated with memory and general cognitive abilities. PLoS ONE, 4(10), [ARTN e7534]. https://doi.org/10.1371/journal.pone.0007534