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Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis
Open accessAbstract
Background Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia.Methods We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls.Findings Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10(-5)). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10(-6)), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010).Interpretation Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct.Funding Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.
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“The rate of large CNV carriage was even higher (42.4%) in those with both ADHD and an IQ below 70 ± 5 (which, along with poor adaptive functioning, defines intellectual disability) 42 .”
From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [42]
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“CNVs associated with ADHD also occur in s chizophrenia andautism 42 .”
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“However, in some patients, rare genetic variants 41,42 or environmental risk factors - for example, psychosocial d eprivation 54 - might have a majorinfluence.”
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“Many of the CNVs robustly implicated in schizophrenia are also implicated in neurodevelopmental disorders in which cognitive impairment is common.39, 40, 41”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [41]
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“In ADHD, increased SV burden has been reported (OR=2.1), 118,119”
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Metadata
- Authors
- Williams, N. M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O. O., Gustafsson, O., Holmans, P., Owen, M. J., O'Donovan, M., & Thapar, A.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Williams, Nigel M
- Thapar, Anita
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 376
- Issue
- 9750
- Pages
- 1401-1408
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC2965350
- OpenAlex
- W2145163559
- Cited by
- 572
- References
- 51
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 15 · 2023: 13 · 2022: 21 · 2021: 17 · 2020: 25 · 2019: 21 · 2018: 26 · 2017: 36 · 2016: 20 · 2015: 56 · 2014: 64 · 2013: 54 · 2012: 70
- FWCI
- 44.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- Wellcome Trust (076113)
- European Commission (HEALTH-F2-2009-223423, LSHM-CT-2006-037761)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- attention deficit hyperactivity disorder, copy number variation, chromosomal deletion, chromosomal duplication, hyperkinetic disorder, intellectual disability, neurodevelopmental disorders, genetic burden, children, 1958 British birth cohort, single nucleotide polymorphisms
- MeSH terms
- Adolescent, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, Child, Child, Preschool, Chromosome Aberrations, Chromosome Deletion, Female, Humans, Male, Schizophrenia, Genetic Variation, Polymorphism, Single Nucleotide, Genome-Wide Association Study, DNA Copy Number Variations
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