Molecular Genetics of Attention Deficit–Hyperactivity Disorder (ADHD)

Abstract

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., , with permission from Nature Publishing Group.

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Web Links

Dopamine receptor D4 (DRD4); Locus ID: 1815. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1815

Dopamine receptor D4 (DRD4); MIM number: 126452. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?126452

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

Solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC6A3); MIM number: 126455. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?126455

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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]