title: Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.
authors.affiliation: MRC Centre in Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Cardiff, UK. williamsnm@cf.ac.uk
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.forename: Irina
authors.initials: I
authors.lastname: Zaharieva
authors.forename: Andrew
authors.initials: A
authors.lastname: Martin
authors.forename: Kate
authors.initials: K
authors.lastname: Langley
authors.forename: Kiran
authors.initials: K
authors.lastname: Mantripragada
authors.forename: Ragnheidur
authors.initials: R
authors.lastname: Fossdal
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Pall
authors.initials: P
authors.lastname: Magnusson
authors.forename: Olafur O
authors.initials: OO
authors.lastname: Gudmundsson
authors.forename: Omar
authors.initials: O
authors.lastname: Gustafsson
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Anita
authors.initials: A
authors.lastname: Thapar
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics