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Both genetic variants and epigenetic genetic changes play a role in the development of ADHD through inheritance.
Gene variants such as epigenetic factors influence, for example, the quantity of proteins encoded by a gene.
Epigenetic changes can be caused by environmental influences (e.g. toxins, diseases) as well as by life experiences (e.g. stress, trauma).
Genes associated with ADHD can affect various functions in the brain, such as dopamine and noradrenaline metabolism. However, many ADHD genes also influence very basic functions of cell biology.
Genes can influence a person’s sensitivity and vulnerability to environmental factors. Traumatic experiences have been shown to affect gene expression and these changes can even be passed on to the next generation. Additionally, environmental factors such as nicotine use prior to conception can cause epigenetic changes and increase the risk of ADHD. It is important to note that ADHD is usually caused jointly by many different genes. The genetic risk can be measured using the Polygenic Risc Score (PRS). A combination of PRS studies significantly improves the prediction accuracy for ADHD, among other things1
Only very rarely can monogenetic causes of ADHD be identified.
We expect that in a few years, genetic analyses will be developed that will help to better understand and individually treat the ADHD of each person with ADHD.
Psychotherapy can influence epigenetic changes and thus contribute to the prevention and treatment of mental disorders such as ADHD.
Every person has every human gene. Nevertheless, genes play a decisive role in determining an individual’s behavior. Behavior is strongly determined by the different functional capacity and activity of the genes. A person’s behavior or health is influenced by the activity and functionality of the gene variants they have.
There are two types of genetic heritable factors related to the activity of genes that contribute to the development of ADHD:
Genes whose variants are differently active (independent of environmental influences) and
Genes whose activity is altered by environmental influences (epigenetic).
A gene can have different DNA sequences due to mutations, polymorphisms or recombinations, for example. These can result in different activity levels of the gene.
There is a considerable genetic overlap between the genetic causes of mental disorders. This so-called general psychopathological factor (P-factor)2 accounts for 10% to 57% of the phenotypic variance.34
It is striking that the genetic overlap between ADHD and the general psychopathological factor (P-factor) appears to be much stronger than the overlap between depression or anxiety disorder and the P-factor.5
We understand this to mean that ADHD is, in a sense, a more generalized disorder than the more specific disorders of anxiety disorder or depression. This is consistent with our perception that ADHD symptoms would be functional stress symptoms if they resulted from chronic stress (which we understand causes the same symptoms as ADHD through the same neurotransmitter shifts), whereas the symptoms typical of anxiety or depression are individual symptoms that have become dysfunctional.
Once inherited, the DNA remains virtually unchanged throughout life.
Radioactivity or rare diseases can cause genes to mutate.
There is evidence that the different genetic causative pathways (gene mutations, SNP, CNV) interact in increasing the risk of ADHD.6
A known gene variant that can contribute to ADHD concerns the DRD4 gene, which expresses the dopamine D4 receptor.gene variant 7R of the DRD4 gene causes the D4 receptor to require 3 times as much dopamine to be addressed.
This in itself is not yet good or bad. Depending on the combination with other genes, environmental influences and living conditions, this can be favorable or unfavorable for the living being. As other genes also have an influence on dopamine levels, a constellation of several gene variants that alter neurotransmitter levels in a certain area of the brain can have very serious effects. DRD4-7R correlates with motivational problems and impulsivity in ADHD. DRD4-7R was created by mutation only 40,000 to 50,000 years ago and is far more common than would be expected from a normal distribution. DRD4-7R therefore appears to be a very successful gene variant.
Hundreds of genes appear to be involved in ADHD, see below.
SNPs explain around 22% of the heritability of ADHD73 and up to 25% of individual symptoms of ADHD:8
Executive function (25 %, SE = 0.08)
Complex cognition (24 %, SE = 0.08)
Inattention (20 %, SE = 0.08)
Memory (17 %, SE = 0.08)
Social cognition (13 %, SE = 0.08)
Overall, a positive genetic correlation of 0.67 (SE = 0.37) and a negative residual covariance of -0.23 (SE = 0.06) were found between inattention and social cognition.
No SNPs achieved genome-wide significance for inattention. The authors suggest from the results a specificity of genetic overlap between inattention and various aspects of neurocognitive efficiency.
The environmental causes known to date also explain 22% of the development of ADHD.3
Obviously, a significant proportion of the causation of ADHD cannot yet be explained by SNP (22%) and environmental causes (another 22%) alone.
Copy number variations (CNV) can also contribute to the development of ADHD.93
1.1.4. Animal models with genetically caused ADHD¶
Animal models show that ADHD can be caused by certain genes alone, i.e. without environmental influences (either directly or via epigenetics).
One model for ADHD-HI (with hyperactivity) is the so-called “Spontaneously hypertensive rat” (SHR).10 SHRs are rats that develop high blood pressure at around 15 months of age solely due to their genes.
These rats also show typical ADHD symptoms. With increasing age and parallel to increasing high blood pressure, an increasing sensitivity of the HPA axis to stress is observed in SHR.11
The rearing of these animals does not involve any stress.12
This shows that certain genetic constellations can cause mental disorders even without additional stressful environmental influences.
Interestingly, the first generations of SHR had a massive problem with cannibalism of newborns. This problem is now solved by keeping the pregnant rat mothers in isolation until the young reach a certain age. It would be interesting to find out whether the SHR also exhibits special behavior towards young animals in other ways.
Due to their genetic predisposition, SHR have a disturbed HPA axis, which is otherwise only caused by early childhood stress. SHR were originally bred as a model for high blood pressure. Only later was it discovered that they were also a model for ADHD-HI. If the animals are treated with dexamethasone (a corticoid), the high blood pressure that would otherwise occur in all animals at the age of 15 months disappears - and the ADHD symptoms also disappear. ⇒ ADHD in animal models
There are other genetically distinct mouse models that also show ADHD symptoms, e.g. the Naples-high-excitability rat (NHE).13 These show increased DAT in the PFC, but not in the striatum (report in the text does not correspond to the abstract) and increased glutamate receptor sensitivity in the PFC and dorsal striatum.
This corresponds to the fact that, for example, a dopamine deficiency in the mPFC can be caused by different genes, alone or together.
For comprehensive information see ADHD in animal models In the chapter Neurological aspects.
1.2. Epigenetic information that influences the activity of a gene¶
Epigenetic information can be changed by experiences during life. These epigenetic changes are also hereditary.
We assume that ADHD (like many other mental disorders) is caused by a combination of
a. specific genes
or
b. specific genes and environmental influences that activate these genes (gene-environment interaction)
is caused.
Just as stress (for example) can change certain neurotransmitter levels in certain regions of the brain, this can also be caused by certain gene polymorphisms / gene variants.
Example: Working memory, which is located in the dorsolateral PFC, requires a moderate level of dopamine, among other things, in order to function optimally. Dopamine levels that are too high or too low impair its function. Such changes can occur in very different ways:
Toxins (e.g. nicotine or other stimulants) can increase the dopamine level in the brain, malnutrition can reduce it.
Acute severe stress strongly increases the dopamine level in the dlPFC, while certain other forms of stress (e.g. chronic social stress in adolescence) reduce the dopamine level there.
Severe (especially early childhood) stress can epigenetically alter genes, which permanently increases or decreases their activity, e.g. for the production of an enzyme or messenger substance. In our example, this can lead to the dopamine level in the PFC being permanently increased or decreased. Such epigenetic changes are hereditary, meaning that changes triggered by (stress) experiences can be passed on over several generations.
In addition, various gene variants (polymorphisms) have an influence on the dopamine and noradrenaline effect. These are not caused by environmental influences, but represent gene variants that are likely to have arisen through mutation.
1.2.1. (Epi) genes change - experience can be inherited¶
Epigenetics means that the expression (activity) of genes changes as a result of (intensive) experiences. Experiences that a living being has itself are also reflected in the expression of its own genes and thus in their activity. The epigenetic information that codes the activity of the genes can be passed on to the offspring. In this way, adaptations to experiences can be passed on to future generations.
Identical twins have an identical genome and a very similar epigenome at the beginning of their lives. While the genes do not change, the epigenomes of the twins develop further apart with increasing age, the more different their life circumstances were.14 The genome, i.e. the DNA sequence itself, remains unchanged.15
Such epigenetic changes can occur in different ways.16
DNA methylation is a heritable epigenetic mark in which methyl groups are added to the DNA molecule and form 5-methyl-cytosine (5mC) by DNA methyltransferases (DNMTs). In the genomes of mammals, 5mC accounts for 2-5 % of all cytosines.
During DNA methylation17, methyl groups are added to the DNA. This is usually done at the cytosine bases by DNA methyltransferases (DNMTs) forming 5-methyl-cytosine (5mC). The DNMT family comprises five members, but only three enzymes, DNMT1, DNMT3a and DNMT3b, have methyltransferase activity that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to cytosine.18 Depending on the type of methylation and the methylated gene, methylation causes transcription initiation or gene silencing.19 The repression caused by DNA methylation can occur in two ways. The direct way is when the methyl groups prevent the transcription factors from binding to the promoter region. The indirect pathway represses DNA expression using other chromatin-modifying factors that bind to methylated CpGs. Methylation of promoter cytosines in repetitive dinucleotide sequences of cytosine and guanine (CpG) allows other methyl CpG-binding proteins, such as methyl CpG-binding protein 2 (MeCP2), to bind and repress expression of the gene.20
DNA methylation is necessary for the healthy development of eukaryotic organisms. Mouse models that lack DNA methyltransferases die during embryonic development.19
DNA methyltransferases are essential for the maintenance or establishment of methylation patterns. If the activity of DNA methyltransferases is restricted, e.g. by
Treatment with DNMT inhibitors slightly increased DAT mRNA levels in human neuroblastoma cells, while administration of HDACs caused a more pronounced DAT increase, suggesting that DAT levels may be more susceptible to enhanced histone acetylation18
Histones are proteins that organize and package DNA into nucleosomes (structural units). Nucleosomes usually consist of two copies of each of the four core histones, H2A, H2B, H3 and H4, with 146 base pairs of DNA wrapped around to form an octamer. Histone modifications are changes in the properties of the histones, such as charge, shape and size. The state of chromatin is largely controlled by covalent modifications of the histone tails. The most important modifications are20
Histone acetylation involves the binding of an acetyl group of acetyl-CoA to the α-amino group of the specific lysine (K) side chains. Histone acetylation is carried out by the enzyme histone acetyltransferase (HAT).
Deacetylation catalyzed by histone deacetylases (HDAC) removes the acetyl groups
Valproate, an HDAC inhibitor, can increase DAT mRNA and protein levels in human SK-N-AS cells. Epigenetic modifications, such as histone acetylation, may play an important role in the regulation of DAT expression18
Is catalyzed by the histone methyltransferases (HMTs), which transfer a methyl group from the methyl donor S-adenosyl-L-methionine (SAM) to the residues. Depending on which residue is methylated, histone methylation can either enhance or repress transcriptional expression.
Acetylation, phosphorylation and methylation of histones contribute to the
Activation and inactivation of genes over a larger range and can occur over several cell divisions
be maintained.22
Micro-RNAs (miRNAs) are involved in the post-transcriptional regulation of genes. miRNAs are small, single-stranded RNAs with a length of around 21-23 nucleotides. They bind to their specific target genes and reduce their expression.18
One study found in relation to 51 genes associated with ADHD alone in the 3’UTR of miRNA23
81 MRE-forming SNP
101 MRE-breaking SNP
61 MRE-enhancing SNP
41 MRE-reducing SNP
MRE: miRNA recognition element / microRNA binding element SNP: Single nucleotide polymorphisms / single nucleotide polymorphisms
These candidate SNPs within the miRNA binding sites of these 51 genes may alter miRNA binding and thus mRNA gene regulation, playing an important role in ADHD. Single nucleotide polymorphisms (SNPs) present within 3’UTRs of mRNAs may influence miRNA-mediated gene regulation and thereby susceptibility to a variety of human diseases.
Various environmental influences alter dopaminergic transmission through epigenetic changes,20 including PAR-4 and DRD-2 expression in the striatum.24 In around 30 % of people with depression, serotonin or noradrenaline reuptake inhibitors do not work. However, these people with ADHD show characteristics of dopaminergic dysfunction.
(Traumatic) experiences are capable of changing the expression of a creature’s genes in such a lasting way that they even pass the experience on to their children. Humans and other mammals that have developed an increased susceptibility to stress due to intense stress experiences pass this increased susceptibility to stress on to their children (e.g. through hypocortisolism).25 Holocaust survivors who developed PTSD pass on a permanently lower cortisol level to their offspring.25
A genetic disposition can therefore be inherited after parents have first acquired it themselves through stressful experiences.26
Example of genetically determined stress sensitivity in mice
Dysfunctional stress processing causes typical symptoms such as impulsivity, delay aversion or difficulties in decision-making. Massive unavoidable stress permanently alters dopaminergic functional processes in brain areas essential for decision-making and impairs the PFC in terms of inhibition and working memory. Glial derived neurotrophic factor (GDNF) plays a key role in the regulation of dopamine in the basal ganglia and in the survival of dopaminergic neurons.27
GDNF in the striatum causes stress resilience.
Mice that could not form GDNF had as few problems with delay aversion before stress exposure as mice that could form GDNF. After stress exposure, mice with a partially reduced GDNF level showed more impulsive decision responses, which was reflected in a reduced number of decisions for a later larger reward in terms of delay aversion. In addition, the mice with reduced GDNF showed reduced neuronal activation in the oPFC and nucleus accumbens after stress exposure, suggesting dysfunctional stress processing.28
The activity of genes is therefore permanently altered by environmental influences.2930
Thesis: Traumas have a purpose
The cross-generational effect of trauma makes sense in terms of evolutionary biology. If an individual has an extremely (i.e. survival-relevant) negative experience, their offspring have a better chance of survival if they stay away from this source of danger without having to experience it themselves first.
We suspect that this model explains why many northern Europeans also have a deep-seated, instinctive fear of snakes and spiders, even though barely any life-threatening specimens of these species ever lived in northern European latitudes and this fear can therefore neither be useful nor learned through personal experience. People with an instinctive fear of spiders and snakes could be considered the (more successful) descendants of those who survived a traumatic experience with such a creature long before their descendants migrated to northern Europe. It would be plausible that these traumas became deeply ingrained in the genes of Homo sapiens because they were not isolated incidents, but were repeatedly refreshed over many generations.
Proven: Epigenetics - it doesn’t always have to be trauma
A significant and not just short-term stress load on the person with ADHD can activate predisposed genes just as much as a short-term but very serious stress load (trauma). Such stress can take various forms. Depending on a person’s sensitivity, different levels of stress are required to generate the stress level that causes permanent damage.
In particular, altered epigenetics (e.g. due to an early childhood stress experience) can be passed on over several generations. In rats, third-generation offspring of rats stressed in early childhood still showed an increased vulnerability to developing mental disorders due to a second hit in adolescence. In other words, rats that were exposed to stress in the first days of life epigenetically passed on an increased vulnerability to their offspring, offspring and offspring’s offspring (although all 3 subsequent generations grew up stress-free) to develop mental disorders throughout adulthood in case of stress exposure in adolescence.31 This fully explains the second hit model known from stress medicine for the development of mental disorders in humans. Mechanisms have also been found in humans that explain such epigenetic inheritance of experiences.32 There are also indications of the effect of the second hit with regard to the severity of symptoms of ASD.33
Stress levels during puberty can lead to an increase in early childhood stress levels.34 Another study shows that adults who reported more than five ADHD symptoms from their childhood were more likely than average to develop mental disorders or addiction.35
Interestingly, middle adolescence does not only appear to be a particularly sensitive period in negative terms. Studies on the effects of enriched environments in rats showed positive effects already in childhood. However, the greatest benefit was observed in middle adolescence. Enriched environments resulted in improved selective and auditory sustained attention performance, increased exploratory and food-gathering behavior, and a significant decrease in corticosterone levels and reduced anxiety levels.36
Individual genes involved in ADHD (in particular DRD4-7R, a gene variant of the DRD4 gene that was created around 50,000 years ago by mutation (i.e. not epigenetically)) cause a higher sensitivity and thus also higher vulnerability (vulnerability) in people with ADHD. Since these genes also cause a higher sensitivity to stimulation, i.e. they also cause a greater external influence of external influences even if there is no ADHD, these genes can generally represent the basis of high sensitivity. More on opportunity/risk genes at⇒Parents’ attachment style to the child is particularly important for chance/risk genes in the article⇒ Secure attachment beats genetic disposition in ADHD in the chapter ⇒ Prevention.
Attempts have been made to mathematically calculate the influence of epigenetic influences (here: through methylation) on the one hand and environmental influences on the other on the development of ADHD.37
Environmental and life experiences influence biological age. This can be determined using DNA methylation values as markers.
One study investigated the relationship between a. ADHD-C-PRS (Polygenic Risc Score), b. shortened life expectancy in ADHD and c. epigenome-wide DNA methylation levels as an indication of biological aging and an earlier age of death (here: GrimAge).
The ADHD-PRS adjusted for covariates was significantly and directly associated with GrimAge. The effect of ADHD-PRS on GrimAge was most strongly mediated by education, then by smoking, depressive symptoms, BMI and income.
Education appears to play a central role in mitigating negative effects on epigenetic aging from behavioral and sociodemographic risk factors associated with ADHD.38
1.2.1.3. Examples of epigenetic inheritance in relation to ADHD¶
1.2.1.3.1. Nicotine consumption by the father before conception¶
Mice whose fathers were chronically exposed to nicotine, while the mothers were not exposed to any drug, showed hyperactivity, nicotine-induced impaired motor sensitization and reduced dopamine and noradrenaline levels in the striatum and PFC.39 This hyperactivity was mediated by reduced dopamine transporters. Nicotine exposure epigenetically increased the DNA methylation level of DAT in the sperm of the mouse sires and the brains of the mouse offspring. This resulted in reduced expression of DAT in the brains of the offspring, leading to increased extracellular dopamine levels. This resulted in activation of D2 receptors, which led to dephosphorylation of AKT, which in turn increased the activation of GSK3α/β, which ultimately caused hyperactivity in the offspring.40
Nicotine consumption by the father caused epigenetic changes in the dopamine D2 receptor. The children of the first and second generation showed impairments typical of ADHD:41
1. Generation:
Significantly increased spontaneous locomotor activity (hyperactivity) (males and females)
Significant deficits in reversal learning (males and females)
Significant attention deficits (males)
Significantly reduced monoamine content in the brain (males)
Reduced dopamine receptor mRNA expression (males)
2. Generation:
Significant deficits in reversal learning (males)
We suspect that nicotine consumption by the mother before conception is also passed on epigenetically to the children.
1.2.1.3.2. Abuse or neglect of the mother in her childhood¶
The children of mothers who were abused in their childhood were more likely to have42
internalizing problems on a clinical scale (odds ratio 2.70)
ADHD (OR 2.09)
Autism spectrum disorder (OR 1.70)
Obesity (in girls) (OR 1.69)
Asthma (OR 1.54)
Multimorbidities
The mothers who were exposed to multiple forms of childhood maltreatment had the children with the highest risk increases, suggesting a dose-response relationship.
There is a strong genetic influence (genetic prevalence: 76 %);43 others cite 70 - 80 %, 50 - 98 %44 or 88 %45 An extremely large study of 4.4 million twins found a heritability of 80 %.46 Among ADHD cases with clinical intensity, it is even said to be up to 90 %.47
It is discussed whether the heritability of ADHD is lower in adults than in children, i.e. whether the proportion of environmental influences on the development of ADHD is higher in adults.48
A study of 15,198 Swedish twins aged 20 to 46 years found a heritability of 37% for inattention and 38% for hyperactivity-impulsivity. 52% of the phenotypic correlation between inattention and hyperactivity-impulsivity could be explained by genetic influences, while the remaining part of the covariance was explained by nonshared environmental influences. These results were replicated across age strata.49
What does heritability mean?
Heritability is the extent to which ancestral traits are also found in children.
The % figures indicate how often children share the characteristics of their parents, not the probability of their occurrence.
The heritability of a trait in a population always depends on the number and intensity of different environmental conditions.
Thought experiment: If all members of a population lived under 100 % identical environmental conditions (which is impossible in practice, as the members would still have individual experiences, which we will ignore in our thought experiment), the heritability of all traits would be 100 % - and this only because the environmental influence would always be identical, i.e. cause 0 % differences. Conversely, this means that two populations with differently variable environmental conditions have different heritabilities with regard to the same trait. Or, to put it another way: The more extreme the environmental conditions differ, the lower the heritability becomes, even though the genes exert the same influence.
Genes that trigger characteristics also cause these in the parents. These characteristics (behaviors) of the parents also have an effect on their children through their upbringing. Mothers with ADHD treat their children more inattentively than mothers without ADHD.50 This treatment has its own influence on the behavior of the children. Heritability cannot distinguish here between genes and parenting effects.
The heritability for major depression was 30%. The estimates based on the measured genotypes were lower and ranged from 10% for alcohol dependence to 28% for OCD. Other sources put the genetic contribution to the development of depression at around 40%.51 The heritability for anxiety disorders is 30 to 40 %, for intelligence 55 % and for personality traits 40 %. The heritability for SCT is said to be 55 to 60 %.47
18% of parents of people with ADHD have ADHD themselves.52 It should be noted that the prevalence of ADHD in adults is only half as high as in children.
The risk of siblings of people with ADHD also having ADHD is 35%.52
Identical twins of a person with ADHD have a 65% risk of ADHD,5253](http://www.devcogneuro.com/Publications/ADD.pdf) fraternal twins (as well as siblings from separate pregnancies) of “only” 28 %53](http://www.devcogneuro.com/Publications/ADD.pdf) to 35 %52
The biological parents of people with ADHD are three times more likely to also have ADHD than non-biological parents (adoptive parents).52
2.1. Heritability of gene variants: unlimited in time¶
Gene variants / gene mutations are independent of environmental influences and can be passed on permanently.
2.2. Heritability of epigenetic information: limited in time¶
Epigenetic changes have three main characteristics:54
They are hereditary, at least over approx. 3 generations56
They are dynamic and potentially reversible throughout life57
A review on the epigenetic causation of ADHD was prepared by Hamza et al.58Epigenetics is thus the key to understanding the importance of environmental influences in ADHD, which are higher than the non-hereditary ADHD proportion of 20 to 25 %, while at the same time 75 to 80 % of the ADHD risk is hereditary.
3. Multigenetic cause - hundreds of candidate genes for ADHD¶
ADHD is not triggered or predisposed by a single gene. According to current knowledge, hundreds of candidate genes are known and probably thousands of genes are involved. (For more information, see ⇒ Candidate genes in ADHD)
Nevertheless, the known genes only account for 5% of the heritability, which suggests that many more genes are involved. One study found that subjects with the lowest 20% of the ADHD PGS (polygenic (risk) score)59
An approximately 18% lower probability of developing ADHD
The risk resulting from the sum of the genes present can be described as a polygenic risk score. ADHD PRS values (the individual estimate of SNP total effect) correlate significantly with ADHD diagnosis and ADHD symptom severity in a value-dependent manner according to3
clinical samples
Population samples
Parent reports
Self-reporting
Teacher evaluations
Twin studies
One study found increased PRS in children based on mental health symptoms at ages 7 and 13 years for ADHD and schizophrenia, but not for depression and ASD.60
A large-scale study (n = 5,808) concluded that the multiple genetic risks of ADHD have a significant impact on educational attainment and cognitive performance.61 Genetic risk is a good predictor of the occurrence and severity of ADHD.62 Other studies are now also forming polygenetic risk scores that can predict ADHD symptoms from analyzing the gene variants found.63 The PRS should now be able to support the diagnosis of ADHD64
The transcriptome is the entirety of the genes transcribed from DNA to RNA in a cell at one point in time, i.e. the sum of all RNA molecules produced in a cell. It reflects the state of all active genes in the cell.
A trancriptome association study established transcriptomic risk scores (TRS) in peripheral blood mononuclear cells of people with ADHD. The TRS in ADHD is elevated. The TRS did not correlate with the PRS (polygenic risk score). A combination of PRS and TRS significantly improved the proportion of variance explained compared to the PRS-only model.65
3.3. Model of synergistic summation of several gene effects¶
We currently have the following understanding of the interaction of several genes in relation to the development of ADHD or disorders that are caused by multiple factors.
If we stick to the (highly simplified) picture that ADHD mediates its symptoms through a reduced effect of dopamine and noradrenaline, each of the (activated) genes involved would have an influence (small and still completely insignificant on its own) that reduces the effectiveness of the neurotransmitters involved.
The dopamine (effect) level in the striatum is influenced by a number of factors:
DAT1-10R 40 bp66 in the striatum causes the dopamine that has been sufficiently released to be taken up again by the sending synapse (reuptake) before it can be accepted by receptors of the receiving synapse in order to exert its required effect there.
DRD4-7R 48 bp66676869 reduces the sensitivity of D4 receptors of the receiving synapse in the striatum so that they only react to higher dopamine levels. As D4 receptors have an inhibitory effect, DRD4-7R causes less inhibition, i.e. greater reactivity of the nerve cells (here: in the striatum).
Other genes contribute to a reduced dopamine effect in the striatum in other ways.
Each of these genes (in the variant that is “harmful” in ADHD) contributes only a small part to ADHD (e.g. to the dopamine deficit in the striatum). This effect adds up when several ADHD candidate gene variants (e.g. DAT1-10 R 40 bp and DRD4-7R 48 bp and other genes) are present at the same time.70
If other genes were present in a variant or epigenetic expression that reduced the dopamine level or the utilization of dopamine in the striatum by inhibitory receptors (e.g.: D2, D3), this would synergistically lead to an even stronger reactivity of the striatum.
The striatum mediates motivation and motor control. Reduced activity of the striatum due to reduced dopamine levels in the synaptic cleft as a result of increased DAT dopamine reuptake could explain the anhedonia. The reduced dopamine level of a simultaneously reduced dopamine sensitivity of the D4 receptor could switch off its inhibitory function, which could trigger a lack of impulse control and increased hyperactivity at the same time as the existing anhedonia and listlessness. This could explain why these symptoms often occur together.
Studies found evidence that DRD4-7R and DAT1-10R correlated with externalizing behaviors.71
If other dopamine efficacy-enhancing genes were present at the same time, they could partially or completely compensate for the problem, while in combination with other dopamine efficacy-enhancing genes they could cause dysfunction of the striatum due to excessive dopamine action.
The distribution of genes varies between human ethnic groups.72
This model should be transferable to all mental disorders that are caused by multiple factors.
It may further explain why some people only develop XY symptoms (e.g. ADHD, borderline, anxiety disorder …) when they are exposed to chronic stress in addition to their weak genetic disposition, which then contributes the further necessary to bring neurotransmitter levels so far out of balance that symptoms appear.
In these (mild) persons with ADHD, according to this concept, a number of genes are activated in the direction of the respective neurotransmitter imbalance, but not enough to trigger the symptoms of the disorder on their own. It is only when chronic stress occurs that the neurotransmitter balance is upset to such an extent that the neurotransmitter imbalance required for the development of symptoms (in the case of ADHD: dopamine and noradrenaline deficiency) occurs. This model could conclusively explain why, in a long-term study, a number of persons with ADHD who had been diagnosed with certainty could no longer be given a diagnosis after six months:73 it is conceivable that the stressful situation (separation from a partner, death of a family member) that had replaced the genes “missing” for people with ADHD to be fully affected could have occurred. In other words, the genetic predisposition did not include so many genes that the neurotransmitter imbalance would already exist without acute stress. In contrast, according to this picture, people with ADHD who have the symptoms even in the absence of stress have enough disorder-specific genes activated together to develop the symptoms even without stress.
According to this idea, the number of genes that are affected simultaneously and that together influence, for example, the level of a specific neurotransmitter at a certain location in the brain dimensional Determine the extent of the disorder.
In our understanding, a categorical disorder would only be obvious in the case of disorders that can be causally traced back to individual or very few genes.
Psychotherapy is able to reduce stress levels. Examples:
Depth psychological therapy can uncover possible causes that lead to misbehavior because the behavior of others is interpreted dysfunctionally; correcting the interpretation could recode supposedly stressful situations
Cognitive behavioral therapy can make it easier to deal with symptoms and thus promote a more functional approach to problematic situations
Mindfulness-based forms of therapy can reduce stress levels and increase serotonin levels in the long term.
To date, there have been few studies on the effect of psychotherapy on the epigenetic expression of genes. However, it is discussed that “positive” epigenetic changes due to psychotherapy could be passed on in the same way as “negative” epigenetic changes due to stress experiences and could thus contribute to the prevention of mental disorders.5474
Fundamental to the effect of psychotherapy from a neurobiological perspective: Grave (2005): Neuropsychotherapy.
A study of persons with ADHD found that 4 weeks of intensive dialectical behavioral therapy (DBHT) caused a reduction in CpG methylation of exons I and IV of the BDNF gene in blood leukocytes in therapy responders, while it continued to increase in therapy nonresponders, i.e. those who did not respond to therapy. Methylation prior to treatment correlated with the number of childhood traumas. BDNF methylation status correlated significantly with levels of depression, hopelessness and impulsivity. However, no correlation was found between BDNF plasma levels and methylation status.75 Effect size of DBHT in responders was up to 0.77 and correlated in degree with methylation.54
A study of veterans with post-traumatic stress disorder (PTSD) found that higher methylation of cytosine from blood lymphocytes in the promoter region of the GR gene NR3C1 was highly statistically significant in predicting responding to 12 weeks of psychotherapy. The NR3C1 methylation level did not change significantly as a result of the therapy. In contrast, the methylation of the FK506 binding protein 5 (FKBP5) gene (which encodes a co-chaperone protein of the glucocorticoid receptor) had no predictive power for the therapy response, but tended to decrease as a result of therapy.76
Successful treatment of PTSD/PTSD alters the methylation of involved genes.77
A study of people with ADHD found reduced methylation in the MAO-A gene. MAO-A breaks down amines such as dopamine, noradrenaline and serotonin. After 6 weeks of cognitive behavioral therapy CBT, an increase in MAO-A methylation correlated with a reduction in agoraphobia symptoms.78 Again, the Effect size seems to be very high.54
A study of children with anxiety disorders found that 12 weeks of cognitive behavioral therapy resulted in statistically significant decreased methylation of CpG IV of FKBP5 in the people with ADHD with the greatest reduction in anxiety. Therapy nonresponders experienced an increase in methylation, which was particularly true for children with FKBP5 risk genotypes. Therapy response was not associated with FKBP5 polymorphisms or the level of DNA methylation prior to treatment. There was no correlation with glucocorticoid receptor polymorphisms or methylation.79
A study on depression sufferers found increased methylation of GLUT 1, which encodes the insulin-independent glucose transporter 1, which is involved in brain metabolism. After 6 weeks of inpatient treatment with cognitive behavioral therapy and antidepressants, the therapy responders (symptoms subsided) showed significantly lower GLUT 1 methylation compared to people with ADHD whose symptoms did not subside.80 However, the Effect size seems to be rather small.54
A pilot study observed epigenetic changes within 24 hours of a mind-body therapeutic protocol (MBT-T) treatment.81
One study reports epigenetic changes through meditation.82
Mouse males in which early childhood trauma (separation from the mother) causes epigenetic changes in the hippocampus (increased expression of the glucocorticoid receptor (GR) and reduced DNA methylation of the GR promoter) and in sperm cells show psychological behavioral changes, which - together with the epigenetic changes - they also pass on to their offspring. One study showed that enriched environment in adult male mice led to the behavioral changes no longer being passed on to the offspring. The offspring showed a reversal of the changes in GR gene expression and DNA methylation in the hippocampus.83
One study found increased DNA methylation of SERT in children with an anxiety disorder who responded to cognitive behavioral therapy, while it continued to decrease in non-responders.84
The effect of exposure therapy was measured in children with an anxiety disorder. A reduction in symptom severity correlated with a reduction in the percentage DNA methylation of FKBP5 at a CpG site of intron 7 and a better response to therapy. Changes in DNA methylation did not affect FKBP5 expression.85
5. Candidate genes and their activation by early childhood stress in other mental disorders¶
The basic mechanism that certain genes make people susceptible to developing a mental disorder in the event of excessive stress in childhood is not specific to ADHD. Depending on the genetic disposition, only different mental disorders develop from early childhood stress.
This also explains the phenomenon of comorbidities. Early childhood stress activates existing genetic predispositions. If a person has genetic predispositions for several mental disorders, these are activated simultaneously (at least much more likely) by corresponding environmental influences.
A comprehensive description of the effects of early childhood or long-term stress can be found at ⇒ Genes + early childhood stress as a cause of other mental disorders
Some people survive strokes of fate quite unimpressed, others develop very severe stress symptoms and/or mental disorders. A genetic make-up that contains those variants of the relevant genes that do not impart vulnerability to stress ensures against extreme behavior - for better (less risk) and for worse (less chance).
When we wrote these sentences, we were still unaware of the book Resilience by Christina Berndt86, which impressively confirms this conclusion.
Discovered in the 1960s, endogenous retroviruses are retroviruses that do not undergo a complete replication cycle but are passed on in the genome of the individual as a provirus. Endogenous retroviruses probably originated many generations ago through infections of the germline cells in vertebrates. In addition to ERV, however, other viruses can also become endogenous.88
Retroviruses use the enzyme reverse transcriptase to write their RNA genome into the chromosomal DNA, thereby integrating their RNA into the DNA of the host cell. If they succeed in infecting germ cells, they become endogenous retroviruses and can be passed on over many generations.
In some cases, endogenous retroviruses only remain infectious for a short time (several hundred generations) because mutations (e.g. point mutations, deletions, insertions of other retroelements, recombinations, mini- and microsatellite expansions) accumulate during replication by the host, which lead to gradual virus inactivation. Epigenetic changes also lead to the deactivation of ERV.89
However, if endogenous retroviruses remain active, they can continue to produce virus particles.
To date, several thousand HERVs have been found in the human genome, accounting for around 8 % of the human genome. Approximately 0.5 % of the human genome consists of replication-capable proviruses.
HERVs can integrate into the human genome and thereby alter the structure and/or function of genes9091
It is therefore conceivable that HERV also affect the expression of genes that are relevant in ADHD.92
Some human endogenous retroviruses (HERV) appear to be involved in the development of certain autoimmune diseases, e.g. multiple sclerosis. Other HERVs are involved in the development and regulation of important organs, e.g. the placenta in mammals.
The potential responsiveness of HERV to environmental factors plays an important role in gene-environment interactions. 88
An initial study found an influence of MPH on HERV transcription in PBMCs in a single case of a person with ADHD. A reduction in HERV-H expression correlated with an improvement in ADHD symptoms after 6 months of treatment with MPH.99 Another study in a very small number of subjects (7 persons with ADHD) confirmed a correlation between symptom reduction and HERV-H activity reduction by MPH.100
Furthermore, a correlation was reported between the decrease in HERV-H activity and the improvement in symptoms with ASA due to methylphenidate. However, the sources cited do not provide any information on this.101
