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Examining the Genetic Link of ADHD
Connor A. Hufford
Charleston Southern University
BIOL 161: Foundations of Biology 1 Lab
Professor Joequise Wright
November 20, 2024
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Attention Deficit Hyperactive Disorder otherwise know as ADHD has gone
through several iterations since being recognized in 1968 as a disorder. It was first
called Hyperkinetic reaction of childhood by the APA (American Psychological
Association) in 1968. In 1980 the APA changed the name to Attention Deficit Disorder
(ADD) At the time they created two subtypes of ADD because researchers at the time
didn’t believe hyperactivity was a common symptom of the disorder, the two subtypes
were ADD with Hyperactivity and ADD without Hyperactivity. It wasn’t till 1987 that the
APA labeled it as ADHD. In 2000 the APA established three subtypes of ADHD that
healthcare professionals still use to diagnose ADHD. Those subtypes are combined
type ADHD, predominantly inattentive type ADHD, and predominantly hyperactiveimpulsive type ADHD. Since first being considered a disorder in 1968 the diagnoses
have only been on the rise increasing every year. According to the CDC in 2022 children
between the ages of 3 and 17 that have received a diagnoses of ADHD has increased
by a million children compared to a study conducted in 2016. (CDC, Data and statistics
on ADHD 2024) This continued increase of diagnoses has established that ADHD is a
disorder that is only going to keep increasing. Since then more and more children have
been diagnosed with this disorder.
Research has pointed towards a genetic link between parent and child in
response to data indicating that children whose biological parents are diagnosed with
ADHD are also highly likely to be diagnosed with ADHD. Its also believed that the
reason that the number of diagnoses keeps rising is not only because the methods for
diagnosing ADHD have gotten better but that parents are also recognizing the
symptoms present with ADHD and getting their children checked for the disorder.
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(Healthline Media. 2024) Even though we recognized that there is a genetic link present
between parents and children with ADHD, what exactly is that that genetic link. This
analysis aims to discuss what exactly ADHD is in terms of the current physiological
understanding of this disorder.
What Is ADHD?
Since being recognized researchers have been trying to figure out what causes
ADHD and it has been shown that ADHD has something to do with dopamine receptors.
The question that now comes to place is which dopamine receptors are responsible for
ADHD. There are 5 major dopamine receptors in the human body each with their own
function, those being D1, D2, D3, D4, and D5. Studies have been conducted on each of
those receptors to see which one is most commonly seen in those diagnosed with ADHD.
According to most studies that have been conducted on this topic, the D4 receptor is most
commonly associated with ADHD.
Dopamine Receptor D1
DRD1 is the most abundant dopamine receptor subtype of seen in the brain and
its role is to regulate adenylyl cyclase and phosphoinositide hydrolysis by coupling with
Gs and Gq heterotrimeric G proteins. The D1 dopamine receptor is mainly expressed in
regions like the striatum, cerebral cortex, and olfactory bulb, along with being moderately
expressed hippocampus and amygdala. When viewed at the cellular level D1 receptors
can be seen in axon terminals and dendrites, particularly it is seen at increased levels on
the dendritic spines. With this receptor being seen all around the central nervous system
it can be suggested that it plays a role in many physiological functions of the central
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nervous system. Those functions being influencing some behavioral responses,
regulating neuronal growth and development, and modulating D2- receptor mediated
processes. Studies have been performed where mice who are lacking D1 dopamine
receptor have shown reduced striatal volume, increased locomotor activity, hyperactivity,
resistance to psychostimulant effects of drugs, such as cocaine and amphetamine,
decreased levels of substance P, and impaired performance and slower learning
demonstrated in the Morris water maze. [3] Because DRD1 is primarily expressed in the
prefrontal cortex, numerous studies have shown that a dysfunction with the prefrontal
cortex can perform similar behaviors seen in those diagnosed with ADHD, DRD1 can also
be seen in GABAergic interneurons which is responsible for regulating working memory,
which in turn is associated with attention and severely impaired in patients diagnosed with
ADHD. Several studies have been conducted on genetic variations of the D1 dopamine
receptor, most of those studies came back with negative results, but for a more accurate
conclusion, more studies need to be done with a higher number of participants.
Dopamine Receptor D2
D2 receptors are highly distributed across dopamine-rich brain areas, including the
neostriatum, olfactory tubercle, substantia nigra, ventral tegmental area, and nucleus
accumbens. At the subcellular level D2 receptors can be seen distributed among
presynaptic and postsynaptic compartments, it can also be seen in dendrites and
dendritic spines, including the axon terminal in both excitatory and inhibitory synapses. In
NG108-15 cells, the D2S isoform is mainly located at the plasma membrane, while the
D2L isoform localizes around the Golgi apparatus. Among dopamine receptor subtypes,
D2 is pivotal for regulating presynaptic dopamine synthesis, release, and firing rates. It
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can be noted that D2 receptors can be split into two different variants depending on which
synaptic compartment it resides in, variant D2L can be found in the postsynaptic
compartment, while D2S in the presynaptic compartment. Taking those two variants into
account it can be concluded that each variant plays its own role in processes that are
attributed to the D2 receptor. Researchers conducted studies on mice that lack the D2
dopamine receptor, those mice demonstrated a lack of locomotor activity, delayed
movement initiation, and axonal degeneration with Lewy Body-like inclusions in
dopaminergic neurons. [20] In an study conducted by Maldonado R A, he and his
colleagues used an experimental mice model of ADHD, the deletion of the DRD2
polymorphism was associated with heightened locomotor hyperactivity and a marked
increase in reward-seeking behavior. [21] Using positron emission tomography (PET)
imaging using F-deoxyglucose revealed that DRD2 A1 allele carriers exhibit significantly
reduced glucose metabolism in various brain regions, including the putamen, temporal,
frontal, central, prefrontal, orbital, and occipitotemporal cortices. [22] A meta-analysis
conducted by Jing Wu (2012) supported that the conclusion that the D2 dopamine
receptor is associated with impulsive, addictive and compulsive behavior. Notably it was
a specific polymorphism that demonstrated that association, the TaqIA (rs1800497)
polymorphism. After several studies were conducted on the connection of the TaqIA
polymorphism and its association with ADHD, it was determined that there was to much
of a variability between all the studies and that the reason for those differences in results
should be explored to understand what factors were leading to those results.
Dopamine Receptor D3
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The dopamine receptor D3 functions by inhibiting adenylyl cyclase through
coupling to Gi/Go proteins in suitable expression systems. When viewed subcellularly
some D3 receptors are located presynaptically as autoreceptors, regulating neuronal
firing, and regulating dopamine synthesis and release. They play crucial roles in
phosphoinositide hydrolysis, modulating potassium and P/Q calcium channels, and
activating MAPK, which induces c-Fos expression. Additionally, D3 receptors can initiate
phosphorylation independent of G protein activity through PKC activation. D3 dopamine
receptors are mainly expressed in mesolimbic brain areas, particularly their seen in the
nucleus accumbens, where they are crucial for reward processing related to addiction
and incentive learning. D3 dopamine receptors can also be found in the pre frontal cortex,
where they influence dopamine-linked cognitive functions, and their association with
impulsive and reward-seeking traits connects them to behaviors found in conditions like
ADHD and obesity. D3 receptors are also involved in motor inhibition, with their presence
in the ventral striatum suggesting they may influence motivation and motor behavior more
than attentional processes. Their role in the limbic system, especially in areas like the
nucleus accumbens, further links them to motivation and emotional regulation. Research,
including a study on the Chinese Han population by Guan et al., has found a specific
association between DRD3 and ADHD, particularly with hyperactive/impulsive symptoms.
[23] When it comes to the association with ADHD and dopamine receptor D3, research
has focused on a specific genetic variation called rs6280 SNP (Ser9Gly) in exon 1.
Although most studies have reported negative results, which leads to the assumption that
DRD3 has no association with ADHD. [25,24]
Dopamine Receptor D4
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The D4 dopamine receptor is widely expressed throughout the brain. The D4
dopamine receptor is highly expressed in areas such as the hippocampus, (including
CA1, CA2, CA3, and the dentate gyrus), frontal and entorhinal cortices, olfactory tubercle,
the cerebellum, caudate putamen, nucleus accumbens, supraoptic nucleus, and
substantia nigra pars compacta. When viewed at the subcellular level, D4 receptors are
primarily seen on the edge of cell bodies, with a prominent presence in dendritic shafts
and spines in the striatum, where it extends to the substancia nigra. The D4 receptor
plays critical roles in the central nervous system where it regulates corticostriatal
neurotransmission
by
modulating
glutamate
receptors,
facilitates
phospholipid
methylation, and influences ion channel dynamics which are vital for the regulation of
synaptic strength and the modulation of neuronal firing activity, that is seen to be impaired
in ADHD. In the study conducted by Jing Wu (2012), he and his other colleagues
examined the exon 3 region of the DRD4. This polymorphism varies in length between
2916 to 11916 amino acids, where a 48-bp sequence exists as two to 11-fold variable
number of tandem repeats (VNTR), which is denoted as D4.2 and D4.11. Their study
focused on the VNTR of DRD4 from two- to eight- repeated allele’s to determine which
one is most associated with ADHD. Their results showed that allele two-, three-, four-,
five-, six-, and eight- had no correlation with ADHD, but allele seven- which demonstrated
a significant risk factor for ADHD. That conclusion can also be drawn from M.C. Gornik’s
study (2006), where his study showed that those who were diagnosed with ADHD
presented with a higher frequency of the seven- repeated allele, whereas their control
group demonstrated a higher frequency of the four- repeated allele. Similarly, a study
conducted by Eva Kereszturi (2006) demonstrated that the one- repeated allele is
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considered a prominent risk factor as compared to the other repeated alleles. To continue
further several studies [11,12,13] put the repeated alleles into two different categories.
Short repeat (which are alleles two to four) and long repeat (which are alleles five to eight).
These studies concluded that the short alleles were concluded to be protective factors,
while the long alleles demonstrated to be risk factors. Both were seen to be highly
associated with ADHD.
Asghari et al (1995) demonstrated that dopamine (DA) is twice as effective in
blocking forskolin-stimulated cAMP increases in D4.2 and D4.4 receptors in CHO cells
compared to the D4.7 receptor. [14] This suggests that the short alleles of DRD4 are more
likely to exhibit a gain-of-function effect, while the long alleles may function as loss-offunction variants. Additionally, carriers of the DRD4 seven-repeat allele have thinner right
orbitofrontal, inferior prefrontal, and posterior parietal cortices, as well as a unique
trajectory of cortical development, with a normalization of right parietal cortical thickening
during adolescence. These patterns are closely associated with ADHD. Interestingly,
some ADHD patients who do not carry the seven-repeat allele (noncarriers) showed
longer reaction times, suggesting that the seven-repeat allele may be linked to specific
behavioral traits rather than cognitive deficits.
Other mutations in the promoter region of the DRD4 gene have also been
extensively studied, including the 120-base pair duplication (120-base pair dup), −521
C/T (rs1800955), −616 C/G (rs747302), −615 A/G, and −376 C/T (rs916455), all of which
are located in the 5′ untranslated region. Researcher Seaman et al, identified the 120
base pair duplication. [15] Seaman et al also noted that the sequence contains several
transcription factor-binding sites, such as MEP-1, CEB/P and Sp1. The most commonly
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seen alleles are the one-repeat 120-bp and the two-repeat 240-bp variants. Functional
studies on the 120-bp dup suggest that the one-repeat allele has higher promoter activity
compared to the two-repeat allele, implying that the 120-bp dup plays a role in the
transcriptional regulation of the DRD4 gene. Given the association between the 120-bp
allele and novelty-seeking behavior, the one-repeat allele may act as a risk allele for
ADHD. However after my own analysis of Jing Wu et al’s, my conclusion is similar to Jing
Wu’s stating that this allele variant has no association with ADHD. [16,17,13,18,19]
Other studies have been conducted on other alleles that are a part of dopamine
receptors D4 genes, those alleles being -521 C/T allele located 521 base pairs upstream
of DRD4 transcription site, -616 C/G, -615 A/G, and -376 C/T. All the studies that were
conducted on these alleles came back with the same conclusion of those alleles having
no relation to ADHD.
Dopamine receptor D5
The D5 receptor is final DA receptor, and it belongs to G protein-coupled receptors
and is responsible for stimulating adenyl cyclase activity. The DRD5 receptor is expressed
broadly throughout the entire central nervous system, some examples of where it can be
found are the hippocampus, frontal cortex, cerebellum, hypothalamus, striatum, basal
forebrain, amygdala, and the thalamus. The D5 receptor also binds to dopamine more
readily compared to dopamine receptor D1. When viewed at the cellular level, DRD5
receptors can be seen only binding to large aspiny cholinergic neurons of the neostriatum
region. If you look further to the subcellular level, D5 receptors can be found in the cell
bodies (perikarya) and nearby dendrites of neurons, and occasionally within the neuropil
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of regions such as the olfactory bulb, cerebral cortex, superior colliculus, and the
molecular layer of the cerebellum. The D5 receptor can also be seen interacting with the
gamma-2 subunit of the GABA-A receptor. This interaction suggests that the D5 receptor
can possibly influence GABA-A receptor activity through both the secondary messenger
pathways and the direct receptor-to-receptor interactions. Studies that have been
conducted using mice who lack the D5 receptor have shown reduced locomotor activity
compared to wild mice, but the mice demonstrated increased exploratory behavior. Those
studies indicated that the D5 dopamine receptor may have a potential inhibitory role with
controlling movement. Additionally research has been conducted using antisense
oligonucleotides, demonstrated that DRD5 plays a role in regulating hypothalamic
functions. (Rivkees SA, 1997), (Karlsson RM, 2008) Human studies have been
conducted, where researchers focused on a highly variable dinucleotide repeat sequence
in the DRD5 gene, located on the 5’ flank, for its connection to ADHD. This sequence
includes 12 different alleles that range from 134 to 156 base pairs, where the base pairs
136 and 148 being the most common. After analysis of Jing Wu’s meta-analysis along
with other research it was concluded that most of the base pairs had zero correlation with
ADHD, while the 148 base pair appeared to be a risk factor for ADHD. [6,7,8,9,10] Further
research ended up categorizing alleles into two types, short (<= 148 base pairs) and long
(<148 base pairs). The short alleles demonstrated a small association with ADHD while
the long alleles demonstrated zero association with ADHD.
Discussion
In conclusion, Research has shown that ADHD has a substantial link to dopamine
receptors. Through my findings in this paper it demonstrates that ADHD has a
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considerable association with Dopamine Receptor D4.7 and Dopamine receptor D5.
Dopamine receptor D4.7 in my opinion has the strongest association with ADHD and is
most likely the genetic link that connects ADHD to family members.
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