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).

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Original Publication URL: http://dx.doi.org/10.1186/1744-9081-4-48

Description/Abstract

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.

Item Type: Article
ISSNs: 1744-9081 (print)
Related URLs:
Subjects: H Social Sciences > HQ The family. Marriage. Woman
Q Science > QH Natural history > QH426 Genetics
B Philosophy. Psychology. Religion > BF Psychology
Divisions: University Structure - Pre August 2011 > School of Psychology > Division of Clinical Neuroscience
ePrint ID: 63809
Date Deposited: 05 Nov 2008
Last Modified: 27 Mar 2014 18:45
URI: http://eprints.soton.ac.uk/id/eprint/63809

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