Molecular Genetics of Attention Deficit–Hyperactivity Disorder (ADHD)

David R Coghill, University of Dundee, Dundee, Scotland, UK
Kirsty M Hogg, University of Dundee, Dundee, Scotland, UK

Published online: September 2012

DOI: 10.1002/9780470015902.a0006012.pub2

Attention deficit–hyperactivity disorder (ADHD) comprises a common and highly heritable group of syndromes with childhood onset that are characterised by impairments in attention span, impulse control and/or activity level. Neurobehavioral, imaging, treatment and genetic studies are consistent with the clinical symptoms of ADHD being caused by abnormalities of the ventral projections of catecholamine pathways in the brain. Twin and adoption studies suggest that there is a strong genetic influence on ADHD with a heritability of approximately 0.76. Linkage studies have identified chromosome areas 5p13, 11q22–25, 17p11 and bin16.4 as being associated with ADHD. Candidate gene studies have focused on the genes influencing catecholaminergic and serotoninergic pathways. Whilst no one gene has yet been unequivocally demonstrated to be causally associated with ADHD, systematic review and meta-analysis supports the involvement of several genes (DRD4 and DRD5, DAT1, SNAP25 and the 5-HTT gene). Genome wide association scans have not yet found any genome-wide significant associations. Preliminary findings suggest increased numbers of copy number variants (CNVs) in ADHD.

Key Concepts:

  • ADHD is characterised by pervasive and impairing inattention, impulsivity and hyperactivity.
  • ADHD is a neurodevelopmental disorder with a prevalence of approximately 5% worldwide.
  • ADHD is thought to be associated with abnormalities in dopaminergic and noradrenergic functioning.
  • Twin and adoption studies have established that ADHD is highly heritable with a heritability of approximately 0.76.
  • Linkage studies have identified chromosome areas 5p13, 11q22–25, 17p11 and bin16.4 as being associated with ADHD.
  • Candidate gene studies have thus far tended to focus on genes located within the dopaminergic, noradrenergic and serotonergic pathways.
  • Converging lines of evidence and meta analyses of candidate gene studies have identified that polymorphisms within the dopamine receptor genes 4 and 5 (DRD4 and DRD5), the dopamine transporter gene (DAT1), the synaptosome-associated protein gene (SNAP25) and the serotonin receptor gene (5-HTT) are associated with an increased the risk of ADHD.
  • None of these genes have yet be unequivocally associated with ADHD as p values do not yet meet the strict criteria required to demonstrate causality (p<10–8).
  • Whilst signals of interest have been identified using GWAS, none have yet reached the required levels of statistical significance.
  • Recent studies have suggested that those with ADHD have increased numbers of CNVs. However, further study is required to investigate the specificity of these findings to ADHD.

Keywords: dopamine DRD4 receptor; dopamine transporter DAT1; dopamine DRD5 receptor; SNAP25; catecholamines; attention; hyperactivity

Figure 1. Plotted is the sample size (cases+controls) analysed in the first meta-analyses of the psychiatric genome wide association study (GWAS) Consortium on schizophrenia, bipolar disorder, major depressive disorder, autistic spectrum disorders and attention deficit/hyperactivity disorder (ADHD) against the – log of the minimal association P-value observed in the GWAS. The P-value indicating genome-wide significance of findings is indicated. The data show the strong (r=0.91) and significant (p=0.03) correlation between the two parameters. Drawing a line through the points suggests that at least 12 000 samples (cases+controls) will be needed before genome-wide significant findings for ADHD will be observed. Reproduced from Franke et al., 2011, with permission from Nature Publishing Group.
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 References
    Arcos-Burgos M, Castellanos FX, Pineda D et al. (2004) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. American Journal of Human Genetics 75: 998–1014.
    Asherson P, Zhou K, Anney RJ et al. (2008) A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. Molecular Psychiatry 13: 514–521.
    Bakker SC, van der Meulen EM and Buitelaar JK (2003) A whole genome scan in 164 Dutch sib pairs with attention deficit/hyperactivity disorder: Suggestive evidence for linkage on chromosome 7p and 15q. American Journal of Human Genetics 72(5): 1251–1260.
    book Barkley RA (1997) ADHD and the Nature of Self Control. New York, NY: Guilford Press.
    Biederman J and Spencer TJ (2000) Genetics of childhood disorders: XIX. ADHD, part 3: is ADHD a noradrenergic disorder? Journal of the American Academy of Child and Adolescent Psychiatry 39: 1330–1333.
    Carrasco X, Rothhammer P, Moraga M et al. (2006) Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention-deficit/hyperactivity disorder in Chilean families. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 141B: 51–54.
    Coghill D and Banaschewski T (2009) The genetics of attention-deficit/hyperactivity disorder. Expert Review of Neurotherapeutics 9(10): 1547–1565.
    Coghill D, Nigg J, Rothenberger A, Sonuga-Barke E and Tannock R (2005) Whither causal models in the neuroscience of ADHD? Developmental Science 8(2): 105–114. (available from: PM:15720368).
    Coghill DR and Sonuga-Barke EJ (2012) Categories versus dimensions in the classification and conceptualisation of child and adolescent mental disorders: implications of recent empirical study. Journal of Child Psychology and Psychiatry 53(5): 469–489.
    Cook EH, Stein MA, Krasowski MD et al. (1995) Association of attention-deficit disorder and the dopamine transporter gene. American Journal of Human Genetics 56: 993–998.
    Dawei L, Sham PC, Owen MJ and He L (2006) Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Human Molecular Genetics 15(14): 22276–22284.
    Ding YC, Chi HC, Grady DL et al. (2002) Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proceedings of the National Academy of Sciences of the USA 8: 309–314.
    Faraone SV and Biederman J (2005) What is the prevalence of adult ADHD? Results of a population screen of 966 adults. Journal of Attention Disorders 9(2): 384–391.
    Faraone SV, Perlis RH, Doyle AE et al. (2005) Molecular genetics of attention-deficit/hyperactivity disorder advancing the neuroscience of ADHD. Biological Psychiatry 57: 1313–1323.
    Fisher SE, Franks C, McCracken JT et al. (2002) A genome-wide scan for loci involved in attention deficit/hyperactivity disorder. American Journal of Human Genetics 70: 1183–1196.
    Franke B, Faraone SV, Asherson P et al. (2011) The genetics of attention deficit/hyperactivity disorder in adults, a review. Molecular Psychiatry (advance online publication 22 November 2011. doi:10.1038/mp.2011.138).
    Gizer I, Ficks C and Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Human Genetics 126(1): 51–90.
    Graham J and Coghill D (2008) Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 22(3): 213–237.
    Hebebrand J, Dempfle A, Saar K et al. (2006) A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Molecular Psychiatry 11: 196–205.
    La Hoste GJ, Swanson JM, Wigal SB et al. (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Molecular Psychiatry 1: 121–124.
    Lionel AC, Crosbie J, Barbosa N et al. (2011) Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Science Translational Medicine 3: 95ra75.
    Neale BM, Medland SE, Rpike S et al. (2010) Meta-analysis of genome wide association studies of attention deficit hyperactivity disorder. Journl of Americal Academy of Child and Adolscent Psychiatry 49(9): 884–897.
    Ogdie MN, Bakker SC, Fisher SE et al. (2006) Pooled genome-wide linkage data on 424 ADHD ASPs suggests genetic heterogeneity and a common risk locus at 5p13. Molecular Psychiatry 11: 5–8.
    Poelmans G, Pauls DL, Buitelaar JK and Franke B (2011) Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. American Journal Of Psychiatry 168: 365–377.
    Polanczyk G, de Lima MS, Horta BL, Biederman J and Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. American Journal of Psychiatry 164(6): 942–948.
    Romanos M, Freitag C, Jacob C et al. (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Molecular Psychiatry 13: 522–530.
    Todd RD (2000) Genetics of childhood disorders: XXI. ADHD, part 5: a behavioral genetic perspective. Journal of the American Academy of Child and Adolescent Psychiatry 39: 1571–1573.
    Todd RD and Botteron KN (2001) Is attention-deficit/hyperactivity disorder an energy deficiency syndrome? Biological Psychiatry 50: 151–158.
    Todd RD, Rasmussen ER, Neuman RJ et al. (2001) Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. American Journal of Psychiatry 158: 1891–1898.
    Williams NM, Zaharieva I, Martin A et al. (2010) Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376(9750): 1401–1408.
    Zhou K, Dempfle A, Arcos-Burgos M et al. (2008) Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. American Journal of Medical Genetics Part B 147B: 1392–1398.
 Further Reading
    Banaschewski T, Becker K, Scherag S, Franke B and Coghill D (2010) Molecular genetics of attention-deficit/hyperactivity disorder: an overview. European Child & Adolescent Psychiatry 19(3): 237–257 (available from: PM:20145962).
    Brookes K, Xu X, Chen W et al. (2006) The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry 11(10): 934–953 (available from: PM:16894395).
    Crosbie J, Perusse D, Barr CL and Schachar RJ (2008) Validating psychiatric endophenotypes: inhibitory control and attention deficit hyperactivity disorder. Neuroscience & Biobehavioral Reviews 32(1): 40–55 (available from: PM:17976721).
    Durston S (2010) Imaging genetics in ADHD. NeuroImage 53(3): 832–838 (available from: PM:20206707).
    Franke B, Neale BM and Faraone SV (2009) Genome-wide association studies in ADHD. Human Genetics 126(1): 13–50 (available from: PM:19384554).
    Hay DA, Bennett KS, Levy F, Sergeant J and Swanson J (2007) A twin study of attention-deficit/hyperactivity disorder dimensions rated by the strengths and weaknesses of ADHD-symptoms and normal-behavior (SWAN) scale. Biological Psychiatry 61(5): 700–705 (available from: PM:16962074).
    Mill J and Petronis A (2008) Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility. Journal of Child Psychology and Psychiatry 49(10): 1020–1030 (available from: PM:18492038).
    book Nigg JT (2006) What causes ADHD: Understanding what goes wrong and why. New York: Guilford Press.
    Tripp G and Wickens JR (2009) Neurobiology of ADHD. Neuropharmacology 57(7–8): 579–589 (available from: PM:19627998).
    Thapar A, Harrington R, Ross K and McGuffin P (2000) Does the definition of ADHD affect heritability? Journal of the American Academy of Child and Adolescent Psychiatry 39: 1528–1536.
 Web Links
    ePath Dopamine receptor D4 (DRD4); Locus ID: 1815. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1815
    ePath Dopamine receptor D4 (DRD4); MIM number: . OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126452
    ePath Solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC6A3); Locus ID: 6531. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=6531
    ePath Solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC6A3); MIM number: . OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126455

Related Sub-Topics:

Neurobiology of Disease | Nervous System Development | Molecular Genetics of Common and Complex Disease
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Article Title: Molecular Genetics of Attention Deficit–Hyperactivity Disorder (ADHD)
 
How to Cite close
Coghill, David R, and Hogg, Kirsty M(Sep 2012) Molecular Genetics of Attention Deficit–Hyperactivity Disorder (ADHD). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006012.pub2]