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 Neurotransmission||Noradrenergic Neurotransmission||Serotonergic Neurotransmission||Other Neurotransmission|
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)
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>
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 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 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)
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 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)
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 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 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)
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)
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)
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)
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)
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