The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes

Thissen, Andrieke J. A. M.; Bralten, Janita; Rommelse, Nanda; Vasquez, Alejandro Arias; Greven, Corina U.; Heslenfeld, Dirk J.; Luman, Marjolein; Oosterlaan, Jaap; Hoekstra, Pieter J.; Hartman, Catharina A.; Franke, Barbara; Buitelaar, Jan K.

doi:10.1002/ajmg.b.32290

Cited by 22 publications

(16 citation statements)

References 77 publications

(101 reference statements)

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“…Such differential effects were found in each of the reported two- and three-way interactions. In agreement, our group has shown that associations between the 5-HTT , DAT1 , DRD4 and neurocognitive functioning, such as inhibition and working memory, depended on age as well [ 82 ]. These findings highlight the importance of including age when studying genetic and environmental effects on the neural architecture of children, adolescents and young adults, as the direction of associations likely depend on developmental stage.…”

Section: Discussionsupporting

confidence: 63%

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes

et al. 2016

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Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

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Section: Discussionsupporting

confidence: 63%

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes

et al. 2016

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“…However, specific genetic factors differentiating childhood and persistent ADHD into adulthood are not well understood due to the lack of longitudinal studies. Molecular studies, including the most recent GWAS-MA of ADHD [6], have been performed in children and adults either separately or jointly [6,[31][32][33][34][35][36][37][38][39][40], but large-scale analyses comparing their genetic basis are yet to be conducted.…”

Section: Introductionmentioning

confidence: 99%

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Rovira¹,

Demontis²,

Sánchez-Mora³

et al. 2020

Neuropsychopharmacol.

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Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.Neuropsychopharmacology (2020) 0:1-10; https://doi.

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“…Genotyping of candidate polymorphisms (DRD4 exon 3 VNTR; 5‐HTTLPR) was performed at the SGDP laboratories in London or at the Human Genetics department of the Radboudumc in Nijmegen, the Netherlands. Standard PCR protocols were used, as previously described [Brookes et al, ; Thissen et al, ].…”

Section: Methodsmentioning

confidence: 99%

Gene‐set and multivariate genome‐wide association analysis of oppositional defiant behavior subtypes in attention‐deficit/hyperactivity disorder

Aebi

Donkelaar

Poelmans

et al. 2015

American J of Med Genetics Pt B

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Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention‐deficit‐hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5‐HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome‐wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for “parental ability to cope with disruptive behavior.” None of the hypothesis‐driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome‐wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top‐ranked genes functionally interact in a molecular landscape centered around Beta‐catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes

Cited by 22 publications

References 77 publications

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Gene‐set and multivariate genome‐wide association analysis of oppositional defiant behavior subtypes in attention‐deficit/hyperactivity disorder

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