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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 (FBAT) analysis

Robert D Oades1*, Jessica Lasky-Su2, Hanna Christiansen1, Stephen V Faraone3, Edmund JS Sonuga-Barke1216174, Tobias Banaschewski5, Wai Chen6, Richard JL Anney7, Jan K Buitelaar8, Richard P Ebstein9, Barbara Franke108, Michael Gill7, Ana Miranda11, Herbert Roeyers12, Aribert Rothenberger13, Joseph A Sergeant14, Hans-Christoph Steinhausen15, Eric A Taylor16, Margaret Thompson6 and Philip Asherson16

Author Affiliations

1 Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany

2 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA

3 Departments of Psychiatry, Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

4 Developmental Brain-Behavior Unit, School of Psychology, University of Southampton, Southampton, UK

5 Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, J 5, Mannheim, Germany

6 Developmental Brain-Behavior Unit, School of Psychology, University of Southampton, Southampton, UK

7 Department of Psychiatry, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland

8 Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

9 S. Herzog Memorial Hospital, Jerusalem, Israel

10 Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

11 Department of Developmental & Educational Psychology, University of Valencia, Spain

12 Department of Experimental Clinical and Health Psychology, Ghent University, Belgium

13 Department of Child and Adolescent Psychiatry, University of Göttingen, Germany

14 Vrije Universiteit, De Boelelaan 1105 1081 HV, Amsterdam, The Netherlands

15 Department of Child & Adolescent Psychiatry, University of Zurich, Switzerland

16 MRC Social Genetic Developmental & Psychiatry Centre, Institute of Psychiatry, London, UK

17 Child Study Center, New York University, New York, USA

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Behavioral and Brain Functions 2008, 4:48  doi:10.1186/1744-9081-4-48

Published: 20 October 2008

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 impulsive-aggressive 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.