Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2010 Oct 23;376(9750):1401-8.
doi: 10.1016/S0140-6736(10)61109-9. Epub 2010 Sep 29.

Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

Nigel M Williams  1 , Irina Zaharieva, Andrew Martin, Kate Langley, Kiran Mantripragada, Ragnheidur Fossdal, Hreinn Stefansson, Kari Stefansson, Pall Magnusson, Olafur O Gudmundsson, Omar Gustafsson, Peter Holmans, Michael J Owen, Michael O'Donovan, Anita Thapar
Affiliations
Multicenter Study

Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

Nigel M Williams et al. Lancet. .

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.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
CNVs identified at chromosome 16p13.11 Log R ratio and B allele frequency plots of the six copy number variants (CNVs; all duplications) larger than 500 kb identified at the chromosome 16p13.11 region in participants with attention-deficit hyperactivity disorder.
Figure 2
Figure 2
Positions of CNVs identified at chromosome 16p13.11 The positions of rare copy number variants (CNVs) larger than 500 kb identified at the chromosome 16p13.11 region. Green lines show the six duplications identified in patients with attention-deficit hyperactivity disorder and the red line shows the deletion identified in a single control. The consensus region that is spanned by all CNVs is shown by the arrow. Orange bars show known segmental duplications and therefore the most likely location of the breakpoints for the CNVs identified. The relative locations of genes are based on National Center for Biotechnology Information reference build 36.1 in the University of California Santa Cruz (UCSC) Genome Browser.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

  • Genetic architectures of psychiatric disorders: the emerging picture and its implications.
    Sullivan PF, Daly MJ, O'Donovan M. Sullivan PF, et al. Nat Rev Genet. 2012 Jul 10;13(8):537-51. doi: 10.1038/nrg3240. Nat Rev Genet. 2012. PMID: 22777127 Free PMC article. Review.
  • Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.
    Gudmundsson OO, Walters GB, Ingason A, Johansson S, Zayats T, Athanasiu L, Sonderby IE, Gustafsson O, Nawaz MS, Jonsson GF, Jonsson L, Knappskog PM, Ingvarsdottir E, Davidsdottir K, Djurovic S, Knudsen GPS, Askeland RB, Haraldsdottir GS, Baldursson G, Magnusson P, Sigurdsson E, Gudbjartsson DF, Stefansson H, Andreassen OA, Haavik J, Reichborn-Kjennerud T, Stefansson K. Gudmundsson OO, et al. Transl Psychiatry. 2019 Oct 17;9(1):258. doi: 10.1038/s41398-019-0599-y. Transl Psychiatry. 2019. PMID: 31624239 Free PMC article.
  • The role of genetics and genomics in clinical psychiatry.
    Hoehe MR, Morris-Rosendahl DJ. Hoehe MR, et al. Dialogues Clin Neurosci. 2018 Sep;20(3):169-177. doi: 10.31887/DCNS.2018.20.3/mhoehe. Dialogues Clin Neurosci. 2018. PMID: 30581286 Free PMC article. Review.
  • Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.
    St Clair D, Johnstone M. St Clair D, et al. Philos Trans R Soc Lond B Biol Sci. 2018 Mar 19;373(1742):20170037. doi: 10.1098/rstb.2017.0037. Philos Trans R Soc Lond B Biol Sci. 2018. PMID: 29352035 Free PMC article. Review.
  • Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.
    McGrath LM, Yu D, Marshall C, Davis LK, Thiruvahindrapuram B, Li B, Cappi C, Gerber G, Wolf A, Schroeder FA, Osiecki L, O'Dushlaine C, Kirby A, Illmann C, Haddad S, Gallagher P, Fagerness JA, Barr CL, Bellodi L, Benarroch F, Bienvenu OJ, Black DW, Bloch MH, Bruun RD, Budman CL, Camarena B, Cath DC, Cavallini MC, Chouinard S, Coric V, Cullen B, Delorme R, Denys D, Derks EM, Dion Y, Rosário MC, Eapen V, Evans P, Falkai P, Fernandez TV, Garrido H, Geller D, Grabe HJ, Grados MA, Greenberg BD, Gross-Tsur V, Grünblatt E, Heiman GA, Hemmings SM, Herrera LD, Hounie AG, Jankovic J, Kennedy JL, King RA, Kurlan R, Lanzagorta N, Leboyer M, Leckman JF, Lennertz L, Lochner C, Lowe TL, Lyon GJ, Macciardi F, Maier W, McCracken JT, McMahon W, Murphy DL, Naarden AL, Neale BM, Nurmi E, Pakstis AJ, Pato MT, Pato CN, Piacentini J, Pittenger C, Pollak Y, Reus VI, Richter MA, Riddle M, Robertson MM, Rosenberg D, Rouleau GA, Ruhrmann S, Sampaio AS, Samuels J, Sandor P, Sheppard B, Singer HS, Smit JH, Stein DJ, Tischfield JA, Vallada H, Veenstra-VanderWeele J, Walitza S, Wang Y, Wendland JR, Shugart YY, Miguel EC, Nicolini H, Oostra BA, Moessner R, Wagner M, Ruiz-Linares A, Heutink P, Nestadt G, Freimer N… See abstract for full author list ➔ McGrath LM, et al. J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):910-9. doi: 10.1016/j.jaac.2014.04.022. Epub 2014 Jun 24. J Am Acad Child Adolesc Psychiatry. 2014. PMID: 25062598 Free PMC article.
See all "Cited by" articles

References

    1. Franke B, Neale BM, Faraone SV. Genome-wide association studies in ADHD. Hum Genet. 2009;126:13–50. - PMC - PubMed
    1. Thapar A, Langley K, Owen MJ, O’Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med. 2007;37:1681–1692. - PubMed
    1. Timimi S, Taylor E. ADHD is best understood as a cultural construct. Br J Psychiatry. 2004;184:8–9. - PubMed
    1. Amaral OB. Psychiatric disorders as social constructs: ADHD as a case in point. Am J Psychiatry. 2007;164:1612. - PubMed
    1. Wain LV, Armour JAL, Tobin MD. Genomic copy number variation, human health, and disease. Lancet. 2009;374:340–350. - PubMed

Publication types