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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

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 significan...

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Autores principales: Oades, Robert D, Lasky-Su, Jessica, Christiansen, Hanna, Faraone, Stephen V, Sonuga-Barke, Edmund JS, Banaschewski, Tobias, Chen, Wai, Anney, Richard JL, 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, Asherson, Philip
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577091/
https://www.ncbi.nlm.nih.gov/pubmed/18937842
http://dx.doi.org/10.1186/1744-9081-4-48
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author Oades, Robert D
Lasky-Su, Jessica
Christiansen, Hanna
Faraone, Stephen V
Sonuga-Barke, Edmund JS
Banaschewski, Tobias
Chen, Wai
Anney, Richard JL
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
Asherson, Philip
author_facet Oades, Robert D
Lasky-Su, Jessica
Christiansen, Hanna
Faraone, Stephen V
Sonuga-Barke, Edmund JS
Banaschewski, Tobias
Chen, Wai
Anney, Richard JL
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
Asherson, Philip
author_sort Oades, Robert D
collection PubMed
description 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.
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spelling pubmed-25770912008-11-01 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 Oades, Robert D Lasky-Su, Jessica Christiansen, Hanna Faraone, Stephen V Sonuga-Barke, Edmund JS Banaschewski, Tobias Chen, Wai Anney, Richard JL 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 Asherson, Philip Behav Brain Funct Research 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. BioMed Central 2008-10-20 /pmc/articles/PMC2577091/ /pubmed/18937842 http://dx.doi.org/10.1186/1744-9081-4-48 Text en Copyright © 2008 Oades et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Oades, Robert D
Lasky-Su, Jessica
Christiansen, Hanna
Faraone, Stephen V
Sonuga-Barke, Edmund JS
Banaschewski, Tobias
Chen, Wai
Anney, Richard JL
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
Asherson, Philip
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577091/
https://www.ncbi.nlm.nih.gov/pubmed/18937842
http://dx.doi.org/10.1186/1744-9081-4-48
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