Dataset Information

Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population.

ABSTRACT: Importance:Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder that shows clinical and genetic overlap with other childhood neurodevelopmental disorders. Levels of ADHD symptoms typically decline across childhood and adolescence, although they remain elevated for some individuals. The determinants of symptom persistence and decline are not yet fully understood. Objectives:To test the hypothesis that genetic risk variant load for ADHD (indexed by polygenic risk scores [PRS]), but not for other psychiatric disorders, is associated with population-based ADHD symptom trajectories across childhood and adolescence, and to examine whether higher genetic liability for ADHD is correlated with total number of additional neurodevelopmental disorders (multimorbidity) in childhood. Design, Setting, and Participants:The Avon Longitudinal Study of Parents and Children, an ongoing prospective population-based cohort study, has been collecting data on 14?701 children, including 9757 with data on symptoms of ADHD at multiple time points, since September 6, 1990. The primary exposure variables, PRS, were generated using results of a genome-wide association study from the Psychiatric Genomics Consortium. Childhood multimorbidity scores (ages 7-9 years) were measured by total impairments in 4 domains known to share genetic liability with ADHD: IQ, social communication, pragmatic language, and conduct. Data analysis was conducted from March 1 to September 8, 2016. Main Outcomes and Measures:Attention-deficit/hyperactivity disorder symptom trajectories from ages 4 to 17 years (7 time points). Results:Among 9757 children with data on symptoms of ADHD at multiple time points (age range, 4-17 years; 4968 boys and 4789 girls), 4 ADHD symptom trajectories were identified: low (82.6%), intermediate (7.7%), childhood-limited (5.8%), and persistent (3.9%). Mean (SE) PRS for ADHD were higher in children in the persistent trajectory (0.254 [0.069]) compared with each of the other 3 trajectories (low, -0.018 [0.014], ?21?=?14.67, P?

SUBMITTER: Riglin L

PROVIDER: S-EPMC6485350 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population.

Riglin Lucy L Collishaw Stephan S Thapar Ajay K AK Dalsgaard Søren S Langley Kate K Smith George Davey GD Stergiakouli Evie E Maughan Barbara B O'Donovan Michael C MC Thapar Anita A

JAMA psychiatry 20161201 12

<h4>Importance</h4>Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder that shows clinical and genetic overlap with other childhood neurodevelopmental disorders. Levels of ADHD symptoms typically decline across childhood and adolescence, although they remain elevated for some individuals. The determinants of symptom persistence and decline are not yet fully understood.<h4>Objectives</h4>To test the hypothesis that genetic risk variant load for ADHD (indexed ...[more]

PMID: 27806167

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Project description:BackgroundThe genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population.MethodsChildren (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure.ResultsThe results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (β = -.05, p < .001) and working memory performance (β = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05).ConclusionsThese findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level.

Project description:Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10-10 ≤ p ≤ 1.2 × 10-4 ; α = 2.5 × 10-3 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10-7 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.

Dataset Information

Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population.

Publications

Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population.

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