title: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Janita
authors.initials: J
authors.lastname: Bralten
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Irwin
authors.initials: I
authors.lastname: Waldman
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.forename: Catharina
authors.initials: C
authors.lastname: Hartman
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ebstein
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Ana
authors.initials: A
authors.lastname: Miranda
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oades
authors.forename: Herbert
authors.initials: H
authors.lastname: Roeyers
authors.forename: Aribert
authors.initials: A
authors.lastname: Rothenberger
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sergeant
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.forename: Edmund
authors.initials: E
authors.lastname: Sonuga-Barke
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Steinhausen
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vásquez
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005060:Europe / Q000453:epidemiology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D006948:Hyperkinesis / Q000453:epidemiology / Q000235:genetics*; D007175:Impulsive Behavior / Q000453:epidemiology / Q000235:genetics*; D007557:Israel / Q000453:epidemiology; D008297:Male; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index
keywords: attention-deficit/hyperactivity disorder symptoms; genetic pathways; neuritic outgrowth; neurotransmitter systems