DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Bjarte Håvik; Franziska A Degenhardt; Stefan Johansson; Carla P D Fernandes; Anke Hinney; André Scherag; Helle Lybæk; Srdjan Djurovic; Andrea Christoforou; Kari M Ersland; Sudheer Giddaluru; Michael C O'Donovan; Michael J Owen; Nick Craddock; Thomas W Mühleisen; Manuel Mattheisen; Benno G Schimmelmann; Tobias Renner; Andreas Warnke; Beate Herpertz-Dahlmann; Judith Sinzig; Özgür Albayrak; Marcella Rietschel; Markus M Nöthen; Clive R Bramham; Thomas Werge; Johannes Hebebrand; Jan Haavik; Ole A Andreassen; Sven Cichon; Vidar M Steen; Stéphanie Le Hellard

doi:10.1371/journal.pone.0035424

DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Bjarte Håvik, Franziska A Degenhardt, Stefan Johansson, Carla P D Fernandes, Anke Hinney, André Scherag, Helle Lybæk, Srdjan Djurovic, Andrea Christoforou, Kari M Ersland, Sudheer Giddaluru, Michael C O'Donovan, Michael J Owen, Nick Craddock, Thomas W Mühleisen, Manuel Mattheisen, Benno G Schimmelmann, Tobias Renner, Andreas Warnke, Beate Herpertz-DahlmannJudith Sinzig, Özgür Albayrak, Marcella Rietschel, Markus M Nöthen, Clive R Bramham, Thomas Werge, Johannes Hebebrand, Jan Haavik, Ole A Andreassen, Sven Cichon, Vidar M Steen, Stéphanie Le Hellard

15 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	P L o S One
Vol/bind	7
Udgave nummer	4
Sider (fra-til)	e35424
Antal sider	12
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0035424
Status	Udgivet - 23 apr. 2012

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10.1371/journal.pone.0035424

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Håvik, B., Degenhardt, F. A., Johansson, S., Fernandes, C. P. D., Hinney, A., Scherag, A., Lybæk, H., Djurovic, S., Christoforou, A., Ersland, K. M., Giddaluru, S., O'Donovan, M. C., Owen, M. J., Craddock, N., Mühleisen, T. W., Mattheisen, M., Schimmelmann, B. G., Renner, T., Warnke, A., ... Le Hellard, S. (2012). DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder. P L o S One, 7(4), e35424. https://doi.org/10.1371/journal.pone.0035424

Håvik, B, Degenhardt, FA, Johansson, S, Fernandes, CPD, Hinney, A, Scherag, A, Lybæk, H, Djurovic, S, Christoforou, A, Ersland, KM, Giddaluru, S, O'Donovan, MC, Owen, MJ, Craddock, N, Mühleisen, TW, Mattheisen, M, Schimmelmann, BG, Renner, T, Warnke, A, Herpertz-Dahlmann, B, Sinzig, J, Albayrak, Ö, Rietschel, M, Nöthen, MM, Bramham, CR, Werge, T, Hebebrand, J, Haavik, J, Andreassen, OA, Cichon, S, Steen, VM & Le Hellard, S 2012, 'DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder', P L o S One, bind 7, nr. 4, s. e35424. https://doi.org/10.1371/journal.pone.0035424

@article{657d95ad169e4cc9ba75068a4febc1f2,

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.",

author = "Bjarte H{\aa}vik and Degenhardt, {Franziska A} and Stefan Johansson and Fernandes, {Carla P D} and Anke Hinney and Andr{\'e} Scherag and Helle Lyb{\ae}k and Srdjan Djurovic and Andrea Christoforou and Ersland, {Kari M} and Sudheer Giddaluru and O'Donovan, {Michael C} and Owen, {Michael J} and Nick Craddock and M{\"u}hleisen, {Thomas W} and Manuel Mattheisen and Schimmelmann, {Benno G} and Tobias Renner and Andreas Warnke and Beate Herpertz-Dahlmann and Judith Sinzig and {\"O}zg{\"u}r Albayrak and Marcella Rietschel and N{\"o}then, {Markus M} and Bramham, {Clive R} and Thomas Werge and Johannes Hebebrand and Jan Haavik and Andreassen, {Ole A} and Sven Cichon and Steen, {Vidar M} and {Le Hellard}, St{\'e}phanie",

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TY - JOUR

T1 - DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

AU - Håvik, Bjarte

AU - Degenhardt, Franziska A

AU - Johansson, Stefan

AU - Fernandes, Carla P D

AU - Hinney, Anke

AU - Scherag, André

AU - Lybæk, Helle

AU - Djurovic, Srdjan

AU - Christoforou, Andrea

AU - Ersland, Kari M

AU - Giddaluru, Sudheer

AU - O'Donovan, Michael C

AU - Owen, Michael J

AU - Craddock, Nick

AU - Mühleisen, Thomas W

AU - Mattheisen, Manuel

AU - Schimmelmann, Benno G

AU - Renner, Tobias

AU - Warnke, Andreas

AU - Herpertz-Dahlmann, Beate

AU - Sinzig, Judith

AU - Albayrak, Özgür

AU - Rietschel, Marcella

AU - Nöthen, Markus M

AU - Bramham, Clive R

AU - Werge, Thomas

AU - Hebebrand, Johannes

AU - Haavik, Jan

AU - Andreassen, Ole A

AU - Cichon, Sven

AU - Steen, Vidar M

AU - Le Hellard, Stéphanie

PY - 2012/4/23

Y1 - 2012/4/23

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0035424

DO - 10.1371/journal.pone.0035424

M3 - Journal article

C2 - 22539971

SN - 1932-6203

VL - 7

SP - e35424

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

ER -

DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

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