Candidate Genetic Pathways for Attention-Deficit/Hyperactivity Disorder (ADHD) Show Association to Hyperactive/Impulsive Symptoms in Children With ADHD

Abstract

Objective: As multiple genes with small effect size are assumed to play a role in attentiondeficit/hyperactivity disorder (ADHD) disease etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. We investigated whether pathway-based analysis could bring us closer to unraveling the biology of ADHD. Method:We describe pathway as a pre-defined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/noradrenaline and serotonin neurotransmission and genes involved in neurite outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. We performed multivariable analysis 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 Rating Scales (n=916).Results: Summing genetic effects of common genetic variants within the pathways showed significant association with hyperactive/impulsive (p empirical =0.007), but not inattentive symptoms (p empirical =0.73).Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result (p empirical =0.0018). Teacher-rated Conners scores were not associated. Post-hoc analyses showed significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/noradrenaline p empirical =0.0004, serotonin p empirical =0.0149, neurite outgrowth p empirical =0.0452). Conclusion:The current analysis shows association between common variants in three genetic pathways with the hyperactive/impulsive component of ADHD. This study demonstrates that pathwaybased association analyses, using quantitative measures of ADHD symptom domains may increase the power of genetic analyses to identify biological risk factors involved in this disease. 2 IntroductionAttention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterized by developmentally inappropriate inattentiveness and/or increased impulsivity and hyperactivity . Medications used to treat ADHD affect these systems 18,19 and reduce behavioral symptoms 20,21 . In the current study we used a case-only design to investigate whether pathway-based analyses of dopamine, noradrenaline and serotonin neurotransmission and genes involved in neurite outgrowth moderate the underlying behavioral components and severity of ADHD. Common genetic variants within these pathways were included into the same analysis. Method 4 SampleThe present study is part of the International Multicentre ADHD Genetics (IMAGE) study [31][32][33] , an international collaborative study in seven European countries (Belgium, Germany, Ireland, Spain, Switzerland, the Netherlands and the United Kingdom) and Israel aiming at identifying genes that increase ADHD susceptibility. Participants were aged ...

Common prefrontal cortical gene expression profiles between adolescent SHR/NCrl and WKY/NCrl rats which showed inattention behavior

“…Identifying dimension-specific genetic risk variants is key to discovering biological risk factors for ADHD [4]. Further, it is important to explore unique domain-specific genetic risk factors as the developmental course and relationship to co-occurring disorders have been shown to vary across the two ADHD symptom domains (inattention and the combination of hyperactivity and impulsivity) (for review see [31]).…”

“…It is a highly heritable disorder, with heritability estimated at about 76% [2]. Nevertheless, identifying genetic risk variants associated with ADHD has proven difficult, in part, because of the clinically heterogeneous nature of the disorder [3,4].…”

“…Further, these symptom dimensions are expressed at varying levels in children, leading to individual differences in the balance of symptoms, reflected in the DSM-IV ADHD diagnoses of primarily inattentive (ADHD-PI), primarily hyperactive-impulsive (ADHD-HI) and combined type ADHD (ADHD-C). A key strategy suggested to increase the likelihood of identifying biological risk factors for ADHD is to investigate domain-specific genetic risk variants, as it could potentially decrease phenotypic heterogeneity and increase the power of genetic association studies [4]. Nevertheless, in comparison with data available on genetic influences of hyperactivity and impulsivity domains, little is known about the genes involved in the inattentive subtype.…”

Hat die Häufigkeit elternberichteter Diagnosen einer Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) in Deutschland zwischen 2003–2006 und 2009–2012 zugenommen?

“…Die Ursachen der Störung sind komplex und noch nicht völlig verstanden. Ätiol-ogisch wird die ADHS zu einem Groß-teil auf genetische Faktoren zurückge-führt [18][19][20][21]. Nach den Ergebnissen einiger [22,23], jedoch nicht aller [24,25] Studien sind umweltbezogene Risikofaktoren wie pränatale Alkohol-und Nikotinexposition, geringes Geburtsgewicht und perinatale Komplikationen sowie psychosoziale Problemkonstellationen ebenfalls mit dem Vorliegen von ADHS assoziiert [26][27][28].…”

COMT and DAT1 genes are associated with hyperactivity and inattention traits in the 1993 Pelotas Birth Cohort: evidence of sex-specific combined effect

“…45 Recently, it was demonstrated that common variants of the dopamine/norepinephrine, serotonin and neurite outgrowth pathways are associated with quantitative measurements of hyperactivity/impulsivity symptoms in children with ADHD. 46 In studies involving the general popu lation, polygenic risk scores derived from common molecular variants for categorical ADHD were found to predict attentional and hyperactive/impulsive traits in the general population. 47 On the other hand, polygenic risk scores derived from ADHD traits in the general population sample predicted ADHD categorical diagnosis and symptom severity.…”