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


CONCLUSIONS
These data present DCLK1 as a functionally pertinent gene involved in human memory and cognitive functions.
Bergen Mental Health Research Center, Department of Clinical Medicine, University of Bergen, Bergen, Norway. stephanie.hellard@med.uib.no
Stéphanie
S
Le Hellard
Bjarte
B
Håvik
Thomas
T
Espeseth
Harald
H
Breilid
Roger
R
Løvlie
Michelle
M
Luciano
Alan J
AJ
Gow
Sarah E
SE
Harris
John M
JM
Starr
Karin
K
Wibrand
Astri J
AJ
Lundervold
David J
DJ
Porteous
Clive R
CR
Bramham
Ian J
IJ
Deary
Ivar
I
Reinvang
Vidar M
VM
Steen
D000368:Aged; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism*; D003071:Cognition; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007361:Intelligence Tests; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008568:Memory; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism*; D009664:Norway; D051381:Rats; D015854:Up-Regulation
D019208:Brain-Derived Neurotrophic Factor; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1