title: DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder.
abstract: Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 × 10(-5) and 4 × 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.
authors.affiliation: Dr E Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Bjarte
authors.initials: B
authors.lastname: Håvik
authors.forename: Franziska A
authors.initials: FA
authors.lastname: Degenhardt
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Carla P D
authors.initials: CP
authors.lastname: Fernandes
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Helle
authors.initials: H
authors.lastname: Lybæk
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Andrea
authors.initials: A
authors.lastname: Christoforou
authors.forename: Kari M
authors.initials: KM
authors.lastname: Ersland
authors.forename: Sudheer
authors.initials: S
authors.lastname: Giddaluru
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Benno G
authors.initials: BG
authors.lastname: Schimmelmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Renner
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnke
authors.forename: Beate
authors.initials: B
authors.lastname: Herpertz-Dahlmann
authors.forename: Judith
authors.initials: J
authors.lastname: Sinzig
authors.forename: Özgür
authors.initials: Ö
authors.lastname: Albayrak
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Clive R
authors.initials: CR
authors.lastname: Bramham
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Hellard
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics; D000089742:Doublecortin-Like Kinases; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases