Genetic and epigenetic causes of ADHD - Introduction

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

Both gene variants and epigenetic gene 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 by many different genes together. The genetic risk can be measured by the Polygenic Risc Score (PRS). A combination of PRS studies significantly improves the predictive accuracy for ADHD, among other things¹
Only very rarely can monogenetic causes be identified for ADHD.

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.

• 1. Genes and epigenetic factors
  • 1.1. Genes
    • 1.1.1. Gene variants in ADHD
    • 1.1.2. Heritability through SNP
    • 1.1.3. Heritability through CNV
    • 1.1.4. Animal models with genetically caused ADHD
  • 1.2. Epigenetic information that influences the activity of a gene
    • 1.2.1. (Epi) genes change - experience can be inherited
      • 1.2.1.1. Types of epigenetic modification
        • 1.2.1.1.1. De-/methylation of the DNA
        • 1.2.1.1.2. Modification of histones
        • 1.2.1.1.3. Further epigenetic mechanisms
      • 1.2.1.2. Environmental influences change epigenetics
      • 1.2.1.3. Examples of epigenetic inheritance in relation to ADHD
        • 1.2.1.3.1. Nicotine consumption by the father before conception
        • 1.2.1.3.2. Abuse or neglect of the mother in her childhood
• 2. Heritability of ADHD
  • 2.1. Heritability of gene variants: unlimited in time
  • 2.2. Heritability of epigenetic information: limited in time
• 3. Multigenetic cause - hundreds of candidate genes for ADHD
  • 3.1. Polygenic risk score (PRS) for ADHD
  • 3.2. Transcriptomic risk score (TRS) for ADHD
  • 3.3. Model of synergistic summation of several gene effects
• 4. Epigenetic effect of psychotherapy
• 5. Candidate genes and their activation by early childhood stress in other mental disorders
• 6. The phenomenon of resilience
• 7. Gene-specific treatment of ADHD
• 8. Human endogenous retroviruses (HERV) and ADHD
  • 8.1. Introduction to HERV
  • 8.2. HERV and ADHD
  • 8.2. HERV and other mental disorders

1. Genes and epigenetic factors¶

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).

The heritability of ADHD is 70-80% in studies that use parent and teacher assessments to determine ADHD symptoms and less than 50% in studies that use self-assessments in adolescence and adulthood.² Self-assessments are considered less reliable.

1.1. Genes¶

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)³ accounts for 10% to 57% of the phenotypic variance ^{4 52}

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.⁶
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 causal pathways (gene mutations, SNP, CNV) influence each other in increasing the risk of ADHD.⁷

1.1.1. Gene variants in ADHD¶

Around a third of the heritability of ADHD is due to a polygenic component, which comprises many gene variants, each with minor effects. In addition, copy number variants play a role, which are responsible for part of the heritability of ADHD via rare insertions or deletions.²

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.

1.1.2. Heritability through SNP¶

SNPs explain around 22% of the heritability of ADHD^{84 2} and up to 25% of individual symptoms of ADHD:⁹

• 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.⁴
Obviously, a significant proportion of the causation of ADHD cannot yet be explained by SNP (22%) and environmental causes (another 22%) alone.

1.1.3. Heritability through CNV¶

Copy number variations (CNV) can also contribute to the development of ADHD.¹⁰⁴

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).¹¹ 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.¹²

The rearing of these animals does not involve any stress.¹³
This shows that certain genetic constellations can cause mental disorders even without additional stressful environmental influences.

There are other genetically distinct mouse models that also show ADHD symptoms, e.g. the Naples-high-excitability rat (NHE).¹⁴ 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.¹⁵ The genome, i.e. the DNA sequence itself, remains unchanged.¹⁶

Such epigenetic changes can occur in different ways.¹⁷

1.2.1.1. Types of epigenetic modification¶

1.2.1.1.1. De-/methylation of the DNA¶

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 methylation¹⁸, 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.¹⁹ Depending on the type of methylation and the methylated gene, methylation causes transcription initiation or gene silencing.²⁰ 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.²¹
DNA methylation is necessary for the healthy development of eukaryotic organisms. Mouse models that lack DNA methyltransferases die during embryonic development.²⁰
DNA methyltransferases are essential for the maintenance or establishment of methylation patterns. If the activity of DNA methyltransferases is restricted, e.g. by

• Mutations
• Polymorphisms
• Lifestyle factors
• Food, e.g:
  • Alcohol
  • Cigarettes
  • Flavonoids
  • Methionine deficiency
  • Choline deficiency
  • Folic acid deficiency
  • Vitamin B12 deficiency

this significantly reduces methylation.²⁰

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 acetylation¹⁹

1.2.1.1.2. Modification of histones¶

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 are²¹

• Acetylation²²
  • 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 expression¹⁹
• Phosphorylation²³
  • Influences processes such as transcription, DNA repair, apoptosis and chromatin condensation
• Methylation²²
  • 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.
  • Methylation can be single, double or triple²³

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.²³

1.2.1.1.3. Further epigenetic mechanisms¶

• ADP-ribosylation²³
• Ubiquitylation²³
• Change in the thickness of the myelination
• Chromatin remodeling²²
• Changes due to non-coding RNA

  • Non-coding RNA can regulate the expression of genes. ⇒ Building blocks of heredity and behavior: Genes, DNA, RNA, proteins and co

    • 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.¹⁹
    • One study found in relation to 51 genes associated with ADHD alone in the 3’UTR of miRNA²⁴
    • 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.

These epigenetic changes have an influence on how actively the gene is expressed, i.e. how intensively it is active. For an introduction, see also Gene expression at Wikipedia; Epigenetics at Wikipedia.

Various environmental influences alter dopaminergic transmission through epigenetic changes,²¹ including PAR-4 and DRD-2 expression in the striatum.²⁵ 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.

1.2.1.2. Environmental influences change epigenetics¶

(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).²⁶ Holocaust survivors who developed PTSD pass on a permanently lower cortisol level to their offspring.²⁶
A genetic disposition can therefore be inherited after parents have first acquired it themselves through stressful experiences.²⁷

The activity of genes is therefore permanently altered by environmental influences.³⁰³¹

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.³⁹

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.⁴⁰ 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.⁴¹
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:⁴²

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 have⁴³

• 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.

2. Heritability of ADHD¶

There is a strong genetic influence (genetic prevalence: 76 %);⁴⁴ others cite 70 - 80 %, 50 - 98 %⁴⁵ or 88 %⁴⁶ An extremely large study of 4.4 million twins found a heritability of 80 %.⁴⁷ Among ADHD cases with clinical intensity, it is even said to be up to 90 %.⁴⁸

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.⁴⁹
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.⁵⁰

18% of parents of people with ADHD have ADHD themselves.⁵³ 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%.⁵³
Identical twins of a person with ADHD have a 65% risk of ADHD,⁵³⁵⁴](http://www.devcogneuro.com/Publications/ADD.pdf) fraternal twins (as well as siblings from separate pregnancies) of “only” 28 %⁵⁴](http://www.devcogneuro.com/Publications/ADD.pdf) to 35 %⁵³

The biological parents of people with ADHD are three times more likely to also have ADHD than non-biological parents (adoptive parents).⁵³

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:⁵⁵

• They are caused by environmental influences⁵⁶
• They are hereditary, at least over approx. 3 generations⁵⁷
• They are dynamic for life and potentially reversible⁵⁸

A review on the epigenetic causation of ADHD was prepared by Hamza et al.⁵⁹ Epigenetics 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)⁶⁰

• An approximately 18% lower probability of developing ADHD
• Higher cognitive performance
• Better level of education
• Lower BMI

3.1. Polygenic risk score (PRS) for 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 to⁴

• 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.⁶¹
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.⁶² Genetic risk is a good predictor of the occurrence and severity of ADHD.⁶³ Other studies are now also forming polygenetic risk scores that can predict ADHD symptoms from analyzing the gene variants found.⁶⁴ The PRS should now be able to support the diagnosis of ADHD⁶⁵

3.2. Transcriptomic risk score (TRS) for ADHD¶

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.⁶⁶

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 bp⁶⁷ 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 bp^{6768 69 70} 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.⁷¹

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.⁷²

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.⁷³

This model should be transferable to all mental disorders that are caused by multiple factors.
It can 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 makes the further contribution necessary to bring neurotransmitter levels so far out of balance that symptoms appear.

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.

4. Epigenetic effect of psychotherapy¶

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; by correcting dysfunctional patterns of thought and behavior, stressful situations can be reinterpreted and reintegrated in a meaningful way.
• 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.
• Humanistic psychotherapies such as person-centered therapy, Gestalt therapy, etc.

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.⁵⁵⁷⁵
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 (DBT) 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 non-responders, i.e. those who did not respond to therapy. Methylation before 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.⁷⁶ Effect size of DBT in responders was up to 0.77 and correlated in degree with methylation.⁵⁵
• 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.⁷⁷
• Successful treatment of PTSD/PTSD alters the methylation of involved genes.⁷⁸
• 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.⁷⁹ Again, the Effect size seems to be very high.⁵⁵
• 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.⁸⁰
• 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.⁸¹ However, the Effect size seems to be rather small.⁵⁵
• A pilot study observed epigenetic changes within 24 hours of a mind-body therapeutic protocol (MBT-T) treatment.⁸²
• One study reports epigenetic changes through meditation.⁸³
• 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 resulted in 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.⁸⁴
• 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.⁸⁵
• 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.⁸⁶

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

6. The phenomenon of resilience¶

Some people survive blows of fate quite unimpressed, others develop very severe stress symptoms and/or mental disorders.
Resilience is a consequence of countless protective factors, in particular personality traits, socio-economic factors, family, religion and others.
A genetic make-up that includes those variants of the relevant genes that do not impart vulnerability to stress sensitivity protects 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 Berndt⁸⁷, which impressively confirms this conclusion.

7. Gene-specific treatment of ADHD¶

One study deals with the direct drug targeting of ADHD candidate genes.⁸⁸

8. Human endogenous retroviruses (HERV) and ADHD¶

8.1. Introduction to HERV¶

The endogenous retroviruses discovered in the 1960s 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.⁸⁹

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.⁹⁰
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 genes⁹¹⁹²
It is therefore conceivable that HERV also affect the expression of genes that are relevant in ADHD.⁹³

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. ⁸⁹

8.2. HERV and ADHD¶

In ADHD, the expression of some human endogenous retroviruses appears to be altered compared to unaffected individuals:

• HERV-H expression significantly increased⁹⁴
• HERV-K - Expression unchanged⁹⁴
• HERV-W - Expression unchanged⁹⁴

8.2. HERV and other mental disorders¶

Inappropriate expression of HERV genes appears to be involved in the development of neurological and psychiatric disorders.

• ASS
  Expression of
  • HERV-H significantly increased⁹⁵⁹⁶⁹⁷
  • HEMO [human endogenous MER34 (medium-reiteration-frequency-family-34) ORF - expression increased⁹⁵
  • HERV-W expression significantly reduced⁹⁷
  • HERV-K - Expression unchanged⁹⁷
• Multiple sclerosis
  • HERV-H/F - Expression increased⁹⁸
  • HERV-W - Expression increased⁹⁸
• Schizophrenia⁹⁸
  • HERV-W⁹⁹
• Bipolar disorders
  • HERV-W⁹⁹

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.¹⁰⁰ 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.¹⁰¹

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.¹⁰²