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The influence of serotonin and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): findings from a family-based association test (FVAT) analysis

Oades, Robert D., Lasky-Su, Jessica, Christiansen, Hanna, Faraone, Stephen V., Sonuga-Barke, Edmund J.S., Banaschewski, Tobias, Chen, Wai, Anney, Richard J.L., Buitelaar, Jan K., Ebstein, Richard P., Franke, Barbara, Gill, Michael, Miranda, Ana, Roeyers, Herbert, Rothenberger, Aribert, Sergeant, Joseph A., Steinhausen, Hans-Christoph, Taylor, Eric A., Thompson, Margaret and Asherson, Philip (2008) The influence of serotonin and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): findings from a family-based association test (FVAT) analysis Behavioral and Brain Functions, 4, (48), 14pp. (doi:10.1186/1744-9081-4-48).

Record type: Article


Background: Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).
Methods: Our sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.
Results: In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.
Discussion: A genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsiveaggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.

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Published date: 20 October 2008


Local EPrints ID: 63809
ISSN: 1744-9081
PURE UUID: c3c662f7-427d-4efc-9bff-4db76791b7ec

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Date deposited: 05 Nov 2008
Last modified: 17 Jul 2017 14:15

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Author: Robert D. Oades
Author: Jessica Lasky-Su
Author: Hanna Christiansen
Author: Stephen V. Faraone
Author: Edmund J.S. Sonuga-Barke
Author: Tobias Banaschewski
Author: Wai Chen
Author: Richard J.L. Anney
Author: Jan K. Buitelaar
Author: Richard P. Ebstein
Author: Barbara Franke
Author: Michael Gill
Author: Ana Miranda
Author: Herbert Roeyers
Author: Aribert Rothenberger
Author: Joseph A. Sergeant
Author: Hans-Christoph Steinhausen
Author: Eric A. Taylor
Author: Margaret Thompson
Author: Philip Asherson

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