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Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5-BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR?=?2.43, P?=?1.6?×?10^-21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

SUBMITTER: Gudmundsson OO

PROVIDER: S-EPMC6797719 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

Gudmundsson Olafur O OO Walters G Bragi GB Ingason Andres A Johansson Stefan S Zayats Tetyana T Athanasiu Lavinia L Sonderby Ida Elken IE Gustafsson Omar O Nawaz Muhammad S MS Jonsson Gudbjorn F GF Jonsson Lina L Knappskog Per-Morten PM Ingvarsdottir Ester E Davidsdottir Katrin K Djurovic Srdjan S Knudsen Gun Peggy Strømstad GPS Askeland Ragna Bugge RB Haraldsdottir Gyda S GS Baldursson Gisli G Magnusson Pall P Sigurdsson Engilbert E Gudbjartsson Daniel F DF Stefansson Hreinn H Andreassen Ole A OA Haavik Jan J Reichborn-Kjennerud Ted T Stefansson Kari K

Translational psychiatry 20191017 1

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association ...[more]

PMID: 31624239

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Project description:Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) are two of the most represented neurodevelopmental conditions in childhood. The diagnostic shift introduced by the DSM-5, allowing a combined diagnosis of ADHD and ASD, poses different clinical challenges related to diagnostic overshadowing, accuracy of clinical judgment and potential delay in an ASD diagnosis in children presenting with ADHD. Here we tried to disentangle the clinical phenotype and specificity of the two co-occurring conditions in relation to autism traits and empathy, by comparing children with ASD with and without comorbid ADHD with children presenting ADHD only and children with typical development. The child versions of the Autism Quotient (C-AQ) and Empathy Quotient (C-EQ) were administered to a total sample of 198 male children between 6 and 14 years old with age appropriate language skills and normal intelligence. Univariate analysis demonstrated no significant differences in the C-AQ total and subscale scores as well as the C-EQ between children with ASD and children with ASD + ADHD, while children with ADHD alone presented an intermediate phenotype between ASD and TD. Furthermore, a receiver operating characteristic (ROC) analysis was applied to discriminate among the different phenotypes. We found that the C-AQ and C-EQ were accurate at distinguishing with satisfactory reliability between: (a) ASD vs. non- ASD (N-ASD) groups comprising both ADHD and TD children (Area Under the Curve AUC 88% for C-AQ and 81% for C-EQ); (b) ASD and TD (AUC 92% for C-AQ and 95% for C-EQ); (c) ASD and ADHD (AUC 80% for C-AQ and 68% for C-EQ). Our data confirm the reliability of the C-AQ and C-EQ as behavioral markers to differentiate ASD (regardless of comorbid ADHD) from an ADHD condition and TD. Interestingly, in our sample an ADHD condition does not increase the severity of the clinical phenotype in terms of autism traits distribution and empathy, suggesting that the psychological measures detected by the two quantitative instruments are independent of ADHD traits. This evidence will contribute to the translational efforts in developing better tailored treatments and preventive strategies.

Project description:ImportanceClinical overlap between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date.ObjectiveTo examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches.Design, setting, and participantsThis investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015.Main outcomes and measuresThe primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA).ResultsThis cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software.Conclusions and relevanceDimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms.

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Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

Publications

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

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