Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD.

Abstract

OBJECTIVE:

Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD.

METHOD:

The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales.

RESULTS:

Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452).

CONCLUSION:

The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder.

• Authors: Janita Bralten, Barbara Franke, Irwin Waldman, Nanda Rommelse, Catharina Hartman, Philip Asherson, Tobias Banaschewski, Richard P Ebstein, Michael Gill, Ana Miranda, Robert D Oades, Herbert Roeyers, Aribert Rothenberger, Joseph A Sergeant, Jaap Oosterlaan, Edmund Sonuga-Barke, Hans-Christoph Steinhausen, Stephen V Faraone, Jan K Buitelaar, Alejandro Arias-Vásquez
• Journal: Journal of the American Academy of Child and Adolescent Psychiatry (J Am Acad Child Adolesc Psychiatry) Vol. 52 Issue 11 Pg. 1204-1212.e1 (Nov 2013) ISSN: 1527-5418 [Electronic] United States
• PMID: 24157394 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Topics

• Adolescent
• Attention Deficit Disorder with Hyperactivity (epidemiology, genetics)
• Child
• Child, Preschool
• Europe (epidemiology)
• Female
• Genetic Association Studies (methods)
• Genotype
• Humans
• Hyperkinesis (epidemiology, genetics)
• Impulsive Behavior (epidemiology, genetics)
• Israel (epidemiology)
• Male
• Phenotype
• Psychiatric Status Rating Scales
• Severity of Illness Index