The Genetics of ADHD

Almost 2000 studies into the genetics of Attention Deficit Hyperactivity Disorder have been published to date. These include family studies, twin studies, genome-wide genetic screening, and studies of specific genes. A 2005 review(1) found that genetics account for roughly 76% of the risk of developing ADHD.

No one gene causes ADHD, but many genes influence attention, response inhibition, memory, planning and organisation, motivation, processing speed, self-control and impulsivity.

Single nucleotide polymorphisms (SNPs), duplications, deletions, and variable number tandem repeats (VNTRs) of sequences can all influence genetic susceptibility to different conditions. In the case of ADHD, the genes which have been best studied and have the strongest associations with ADHD include:

Dopaminergic NeurotransmissionNoradrenergic NeurotransmissionSerotonergic NeurotransmissionOther Neurotransmission
DRD4NET1/SLC6A25-HTT/SLC6A4SNAP25
DRD5ADRA2AHTR1BCHRNA4
DAT1/SLC6A3ADRA2CHTR2ANMDA
DBHTPH2MAO
DDCCOMT
MTHFR

DRD4

Dopamine receptor D4 variants are linked to many neurological and psychiatric conditions including schizophrenia, Parkinson’s disease, bipolar disorder, addictive behaviours, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating. The ‘DRD4 long’ variant, in particular the 7 repeat (7R), has been linked to a susceptibility for developing ADHD in several meta-analyses.(2)(3)

DRD5

Also a dopamine receptor, whilst less conclusive than DRD4, there is evidence that variations in the DRD5 gene have similar, possibly weaker, associations with ADHD.<sup>(2)</sup>

DAT1/SLC6A3

DAT is a dopamine transporter gene, shuttling dopamine in and out of brain cells, with a VNTR in this gene causing the dopamine transporter to run in the opposite direction, resulting in significant changes in the distribution of dopamine in the brain. DAT is thought to act as a dopamine modulator, and some VNTRs of this gene are more strongly associated with persistent ADHD than others.(4)

DBH

DBH is the dopamine beta-hydroxylase (also known as dopamine beta-monoxygenase) gene. With the aide of cofactors copper and ascorbic acid (vitamin C), DBH converts dopamine into norepinephrine. DBH is associated with decision making and addictive behaviours such as alcohol consumption and smoking, along with susceptibility to migraine headaches, schizophrenia, Alzheimer’s, and ADHD.(5) It is a matter of debate as to the exact mechanism at work with this gene, as some studies have connected low levels of DBH to ADHD,(6) whilst other studies have connected high levels of DBH to ADHD.(7)

DDC

DDC is the dopa decarboxylase (also known as the aromatic L-amino acid decarboxylase) gene. It catalyses several different decarboxylation reactions, including L-DOPA to dopamine and 5-HTP to serotonin, using B6 (pyridoxal phosphate) as a cofactor. It may be associated with bipolar disorder and autism along with ADHD. A 4-bp insertion/deletion may have a marginal effect on ADHD.(8)

NET1/SLC6A2

The norepinephrine transporter (NET), also known as solute carrier family 6 member 2 (SLC6A2), is a protein that in humans is encoded by the SLC6A2 gene. An overabundance of NET is associated with ADHD.(9)(10)

ADRA2A and ADRA2C

Alpha-2A adrenergic receptor and the alpha-2C adrenergic receptor play critical roles in the central nervous system regulating neurotransmitter release from sympathetic nerves. SNPs for these genes are associated with response time variations between individuals and may play a role in the inattentive (ADD) rather than the hyperactive/impulsive (ADHD) subtype of ADD.(11)

5-HTT/SLC6A4

5-HTT is the serotonin transporter, the gene for this being SLC6A4. There may be an association between a 44-base-pair insertion/deletion (5-HTTLPR) in the promoter region of the serotonin transporter gene. This insertion/deletion causes long or short alleles with the long variant coding a more active transporter associated with ADHD. It is possible that this effect is only present when combined with another polymorphism in intron-2 (STin2).(1)

HTR1B and HTR2A

The 5-hydroxytryptamine receptors 1B and 2A, also known as the 5-HT1B and 5-HT2A receptors are proteins that in humans are respectively encoded by the HTR1B and HTR2A genes and variants have been associated with ADHD.(1)(11) These proteins have different roles in the brain depending on the area being studied, for example 5-HT1B inhibits the release of dopamine in the frontal cortex, or induces the release of serotonin in the basal ganglia and striatum. Variations in both genes have been associated with alcohol and sugar preference, increased violence, and mood disorders, along with ADHD and violence in children, but not in adults.(12)(13)

TPH2

With the aide of cofactors tetrahydrobiopterin (BH4) and iron, the tryptophan hydroxylase 2 gene (TPH2) mediates the transformation of tryptophan to 5-hydroxytryptophan. An association between TPH2 variants and ADHD has been found. It may be involved in modulating response control(11) and overt aggressive impulsivity in children.(14)

SNAP25

SNAP25 regulates calcium ion signalling in neurons. Mice with one of their SNAP25 genes deleted exhibit hyperactive behaviour similar to that seen in ADHD. SNAP25 regulates neurotransmitter secretion, particularly glutamate secretion, synaptic transmission, and insulin secretion. The deletion of both copies of the SNAP25 gene is lethal. SNAP25 polymorphisms in humans have been associated with neuroticism, and with ADHD.(15)

CHRNA4

CHRNA4 encodes nicotinic acetylcholine receptors which mediate fast signal transmission at the synapses. Mutations in CHRNA4 have been associated with frontal lobe epilepsy, internet addiction, nicotine addiction, and ADHD.(16)

NMDA

The N-methyl-D-aspartate receptor is a glutamate receptor, and the predominant controller of synaptic plasticity and memory function. Glutamate is an excitatory neurotransmitter that can act as a neurotoxin at high doses. Several mental conditions including bipolar disorder have been associated with high glutamate levels in the brain. ADHD is believed to be a condition of high glutamate as well as low dopamine, and polymorphisms in the NMDA gene have been associated with ADHD.(17)(18)

MAO

Monoamine oxidase is an enzyme vital for the inactivation of monoamines such as serotonin, melatonin, norepinephrine, adrenaline, dopamine, tyramine and tryptamine. MAO works with the aide of FAD, a riboflavin derived cofactor. There are two types of MAO, MAO-A and MAO-B, which play slightly different roles in the body, with MAO-A being particularly important in the breakdown of monoamines from food. Though the association with MAO-B is less clear, short VNTR variants of MAO-A have been associated with ADHD, and in particular conduct disorder and oppositional defiance disorder.(19)(20)

COMT

Catechol-o-methyltransferase is one of several enzymes that degrade catecholamines such as dopamine, norepinephrine, and adrenaline. COMT requires magnesium as a cofactor, along with SAMe, making it part of the methylation cycle. The high activity val allele that increases dopamine clearance has been associated with ADHD.(21)

MTHFR

Methylenetetrahydrofolate reductase is the rate-limiting enzyme in the methylation cycle, a vital cycle with many metabolic functions, including the recycling and use of folate and B12 and the manufacture and destruction of neurotransmitters. The C677T variant SNP has been associated with a low activity version of the enzyme, meaning individuals with this SNP recycle folate poorly. Opinion is mixed as to the relationship between this SNP and ADHD, however, a different genetic variation, the A1298C SNP has been associated with ADHD.(22)

References

  1. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P. Molecular genetics of attention-deficit/hyperactivity disorder. Biol
    Psychiatry. 2005 Jun 1;57(11):1313-23. Epub 2005 Jan 21. Review. [PubMed] PMID: 15950004.
  2. Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol. 2012 Jun;45(3):605-20. doi: 10.1007/s12035-012-8278-5. Epub 2012 May 19. Review. [PubMed] PMID: 22610946.
  3. Faraone SV, Doyle AE, Mick E, Biederman J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry. 2001 Jul;158(7):1052-7. [PubMed] PMID: 11431226.
  4. Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hümmer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribasés M, Bosch R, Sánchez-Mora C, Gómez-Barros N, Fernàndez-Castillo N, Bayés M, Halmøy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology. 2010 Feb;35(3):656-64. doi: 10.1038/npp.2009.170. Epub 2009 Nov 4. [PubMed] PMID: 19890261; PubMed Central PMCID: PMC3055604.
  5. Bhaduri N, Sinha S, Chattopadhyay A, Gangopadhyay PK, Singh M, Mukhopadhyay KK. Analysis of polymorphisms in the dopamine beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children. Indian Pediatr. 2005 Feb;42(2):123-9. [PubMed] PMID: 15767706.
  6. Kopecková M, Paclt I, Goetz P. Polymorphisms and low plasma activity of dopamine-beta-hydroxylase in ADHD children. Neuro Endocrinol Lett. 2006 Dec;27(6):748-54. Review. [PubMed] PMID: 17187001.
  7. Smith KM, Daly M, Fischer M, Yiannoutsos CT, Bauer L, Barkley R, Navia BA. Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: genetic analysis of the Milwaukee longitudinal study. Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119B(1):77-85. [PubMed] PMID: 12707943.
  8. Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M. Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacology. 2002 Oct;27(4):607-19. [PubMed] PMID: 12377397.
  9. Schroeter S, Apparsundaram S, Wiley RG, Miner LH, Sesack SR, Blakely RD. Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter. J Comp Neurol. 2000 May 1;420(2):211-32. [PubMed] PMID: 10753308.
  10. Tellioglu T, Robertson D. Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications. Expert Rev Mol Med. 2001 Nov 19;2001:1-10. [PubMed] PMID: 14987367.
  11. Banaschewski T, Becker K, Scherag S, Franke B, Coghill D. Molecular genetics of attention-deficit/hyperactivity disorder: an overview. Eur Child Adolesc Psychiatry. 2010 Mar;19(3):237-57. doi: 10.1007/s00787-010-0090-z. Epub 2010 Feb 10. Review. [PubMed] PMID: 20145962; PubMed Central PMCID: PMC2839490.
  12. Hakulinen C, Jokela M, Hintsanen M, Merjonen P, Pulkki-Råback L, Seppälä I, Lyytikäinen LP, Lehtimäki T, Kähönen M, Viikari J, Raitakari OT, Keltikangas-Järvinen L. Serotonin receptor 1B genotype and hostility, anger and aggressive behavior through the lifespan: the Young Finns study. J Behav Med. 2013 Dec;36(6):583-90. doi: 10.1007/s10865-012-9452-y. Epub 2012 Sep 4. [PubMed] PMID: 22945537.
  13. Guimarães AP, Zeni C, Polanczyk GV, Genro JP, Roman T, Rohde LA, Hutz MH. Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys. Am J Med Genet B Neuropsychiatr Genet. 2007 Jan 5;144B(1):69-73. [PubMed] PMID: 16958038.
  14. Oades RD, Lasky-Su J, Christiansen H, Faraone SV, Sonuga-Barke EJ, Banaschewski T, Chen W, Anney RJ, Buitelaar JK, Ebstein RP, Franke B, Gill M, Miranda A, Roeyers H, Rothenberger A, Sergeant JA, Steinhausen HC, Taylor EA, Thompson M, Asherson P. The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav Brain Funct. 2008 Oct 20;4:48. doi: 10.1186/1744-9081-4-48. [PubMed] PMID: 18937842
  15. Faraone SV, Khan SA. Candidate gene studies of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006;67 Suppl 8:13-20. Review. [PubMed] PMID: 16961425.
  16. Wallis D, Arcos-Burgos M, Jain M, Castellanos FX, Palacio JD, Pineda D, Lopera F, Stanescu H, Pineda D, Berg K, Palacio LG, Bailey-Wilson JE, Muenke M. Polymorphisms in the neural nicotinic acetylcholine receptor α4 subunit (CHRNA4) are associated with ADHD in a genetic isolate. Atten Defic Hyperact Disord. 2009 May;1(1):19-24. doi: 10.1007/s12402-009-0003-5. Epub 2009 Apr 25. [PubMed] PMID: 21432576.
  17. Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Anney R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink M, Arnold R, Boer F, Buschgens C, Butler L, Christiansen H, Feldman L, Fleischman K, Fliers E, Howe-Forbes R, Goldfarb A, Heise A, Gabriëls I, Korn-Lubetzki I, Johansson L, Marco R, Medad S, Minderaa R, Mulas F, Müller U, Mulligan A, Rabin K, Rommelse N, Sethna V, Sorohan J, Uebel H, Psychogiou L, Weeks A, Barrett R, Craig I, Banaschewski T, Sonuga-Barke E, Eisenberg J, Kuntsi J, Manor I, McGuffin P, Miranda A, Oades RD, Plomin R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Taylor E, Thompson M, Faraone SV, Asherson P. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry. 2006 Oct;11(10):934-53. Epub 2006 Aug 8. Erratum in: Mol Psychiatry. 2006 Dec;11(12):1139. Aneey, R [corrected to Anney, R]. [PubMed] PMID: 16894395.
  18. Lasky-Su J, Neale BM, Franke B, Anney RJ, Zhou K, Maller JB, Vasquez AA, Chen W, Asherson P, Buitelaar J, Banaschewski T, Ebstein R, Gill M, Miranda A, Mulas F, Oades RD, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen HC, Taylor E, Daly M, Laird N, Lange C, Faraone SV. Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1345-54. doi: 10.1002/ajmg.b.30867. [PubMed] PMID: 18821565.
  19. Malmberg K, Wargelius HL, Lichtenstein P, Oreland L, Larsson JO. ADHD and Disruptive Behavior scores – associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents. BMC Psychiatry. 2008 Apr 23;8:28. doi: 10.1186/1471-244X-8-28. [PubMed] PMID: 18430257; PubMed Central PMCID: PMC2383890.
  20. Wargelius HL, Malmberg K, Larsson JO, Oreland L. Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity. Psychiatr Genet. 2012 Feb;22(1):42-5. doi: 10.1097/YPG.0b013e328347c1ab. [PubMed] PMID: 21610556.
  21. Eisenberg J, Mei-Tal G, Steinberg A, Tartakovsky E, Zohar A, Gritsenko I, Nemanov L, Ebstein RP. Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD
    impulsive-hyperactive phenotype. Am J Med Genet. 1999 Oct 15;88(5):497-502. [PubMed] PMID: 10490706.
  22. Gokcen C, Kocak N, Pekgor A. Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder. Int J Med Sci. 2011;8(7):523-8. Epub 2011 Aug 30. [PubMed] PMID: 21897766; PubMed Central PMCID: PMC3167178.