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Genetic and Epigenetic Causes of ADHD - Introduction

Genetic and Epigenetic Causes of ADHD - Introduction

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Author: Ulrich Brennecke
Review: Waldemar Zdero, M.A. in Psychology

Both genetic variants and epigenetic changes play a role in the hereditary development of ADHD.
Gene variants and epigenetic factors, for example, influence the amount of protein encoded by a gene.

Epigenetic changes can be caused by environmental factors (e.g., toxins, diseases) as well as by life experiences (e.g., stress, trauma).

Genes associated with ADHD can influence various functions in the brain, such as dopamine and norepinephrine metabolism. However, many ADHD-related genes also influence very basic functions of cell biology.
Genes can influence a person’s sensitivity and vulnerability to environmental factors. It has been shown that traumatic experiences affect gene expression and that these changes can even be passed on to the next generation. In addition, environmental influences such as nicotine use before 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 acting together. Genetic risk can be measured using the Polygenic Risk Score (PRS). A combination of PRS studies significantly improves predictive accuracy for ADHD, among other conditions.1 Nevertheless, the PRS is not currently useful in diagnostic practice.2
Monogenic causes of ADHD are rarely identified.

We expect that, within a few years, genetic tests will be developed that will help us better understand ADHD in each person with ADHD and treat it on a case-by-case basis.

Psychotherapy can influence epigenetic changes and thus contribute to the prevention and treatment of mental disorders such as ADHD.

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 influenced by differences in the functionality and activity of genes. A person’s behavior and health are influenced by the activity and functionality of the gene variants they possess.

There are two types of genetic factors related to gene activity that contribute to the development of ADHD:

  • Genes whose variants have different levels of activity (regardless of environmental factors) and
  • Genes whose activity is altered by environmental factors (epigenetically).

The heritability of ADHD ranges from 70 to 80% in studies that use parent and teacher ratings to assess ADHD symptoms, and is less than 50% in studies that use self-reports in adolescence and adulthood.3 Self-reports are considered less reliable.
Among children from families affected by ADHD or ASD, 50% developed normally between the ages of 6 and 12.4

1.1. Gene

A gene can have different DNA sequences due to mutations, polymorphisms, or recombinations, for example. These can result in different levels of gene activity.

Once inherited, DNA remains virtually unchanged throughout a person’s life.
Radioactivity or rare diseases can cause genes to mutate.

There is significant genetic overlap in the genetic causes of mental disorders. This so-called general psychopathological factor (P-factor)5 accounts for 10% to 57% of phenotypic variance.67 3 It is striking that the genetic overlap between ADHD and the general psychopathological factor (P-factor) appears to be significantly greater than the overlap between depression or anxiety disorder and the P-factor.8 We interpret this to mean that ADHD is, in a sense, a more general Disorder than the more specific disorder patterns of anxiety disorder or depression. This aligns with our view that ADHD symptoms would be functional stress symptoms if they resulted from chronic stress (which, as we understand it, 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.

There is evidence that the various genetic pathways (gene mutations, SNPs, CNVs) influence one another in increasing the risk of ADHD.9

1.1.1. Genetic Variants in ADHD

A very large GWAS study identified 7,300 genetic variants (not genes) that correlate with ADHD.10 Over 90% of the ADHD risk variants also influence schizophrenia and major depression, and 84% also influence ASD.10 The overlap between ADHD and the three disorders mentioned corresponds to the level of association between schizophrenia and bipolar disorder, which are among the mental disorders with the strongest genetic correlations. The extent of their shared genetic architecture appears to have been underestimated thus far.11
Almost all genetic variants that influence ADHD correlate with educational attainment. A very clear majority (79%) are associated with lower educational attainment.10

About one-third of the heritability of ADHD is attributable to a polygenic component, which involves many gene variants, each with a small effect. In addition, copy number variants play a role, accounting for part of the heritability of ADHD through rare insertions or deletions.3

A well-known genetic variant that may contribute to ADHD involves the DRD4 gene, which encodes the dopamine D4 receptor.The 7R variant of the DRD4 gene causes the D4 receptor to require three times as much dopamine to be activated.
That in itself is neither good nor bad. Depending on how it interacts with other genes, environmental factors, and life circumstances, this can be beneficial or detrimental to the organism. Since other genes also influence dopamine levels, a combination of multiple gene variants that alter neurotransmitter levels in a specific area of the brain can have very serious consequences. In ADHD, the DRD4-7R variant correlates with motivational problems and impulsivity.
DRD4-7R arose through mutation only 40,000 to 50,000 years ago and is far more common than a normal distribution would suggest. DRD4-7R thus appears to be a very successful gene variant.

Hundreds of genes appear to be involved in ADHD; see below for more on this.

1.1.2. Heritability Based on SNPs

SNPs account for approximately 22% of the heritability of ADHD126 3 and up to 25% of individual ADHD symptoms:13

  • 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 reached genome-wide significance for inattention. Based on the results, the authors interpret the genetic overlap between inattention and various aspects of neurocognitive efficiency as specific.

The environmental factors identified to date also account for 22% of ADHD cases.6
Clearly, a significant portion of the causes of ADHD cannot yet be explained by SNPs (22%) and environmental factors (another 22%) alone.

1.1.3. Heritability Due to CNV

Similarly, copy number variations (CNVs) may contribute to the development of ADHD.146

1.1.4. Animal models of genetically caused ADHD

Animal models show that ADHD can be caused solely by certain genes, that is, without environmental influences (whether direct or via epigenetics).

One model for ADHD-HI (with hyperactivity) is the so-called “spontaneously hypertensive rat” (SHR).15 SHRs are rats that develop high blood pressure at around 15 months of age solely due to their genes.
These rats also exhibit very typical ADHD symptoms. As they age, and in parallel with rising blood pressure, SHR rats show an increasing sensitivity of the HPA axis to stress.16

Raising these animals does not involve any stress.17
This shows that certain genetic combinations can cause mental disorders even in the absence of additional adverse environmental factors.

Interestingly, the first generations of SHR rats had a serious problem with cannibalism of newborns. This problem has since been resolved by keeping pregnant female rats in isolation until the young reach a certain age. It would be interesting to find out whether SHRs also exhibit any other specific behaviors toward their young.

Due to their genetic predisposition, SHRs have a disrupted HPA axis, a condition that otherwise arises only as a result of early childhood stress.
SHR mice were originally bred as a model for high blood pressure. It was only later that researchers discovered they also serve as a model for ADHD-HI. When the animals are treated with dexamethasone (a corticosteroid), the high blood pressure that would otherwise develop in all animals at 15 months of age does not occur—and the ADHD symptoms also disappear.
⇒ ADHD in Animal Models

There are other genetically distinct mouse models that also exhibit ADHD symptoms, such as the Naples high-excitability rat (NHE).18 These models show elevated DAT levels in the PFC, but not in the striatum (the description in the text does not match the abstract), as well as increased glutamate receptor sensitivity in the PFC and the dorsal striatum.
This is consistent with the fact that, for example, a dopamine deficiency in the mPFC can be caused by various genes, either alone or in combination.

For a comprehensive overview of this topic, see ADHD in Animal Models In the chapter on Neurological Aspects.

1.2. Epigenetic information that influences a gene’s activity

Epigenetic information can be altered by life experiences. These epigenetic changes are also heritable.

We assume that ADHD (like many other mental disorders) is caused by a combination of

a. specific genes
or
b. specific genes and environmental factors that activate these genes (gene-environment interaction)

is caused by.

Just as stress (for example) can alter certain neurotransmitter levels in specific regions of the brain, so too can certain gene polymorphisms or gene variants.
Example: Working memory, which is located in the dorsolateral PFC, requires, among other things, moderate dopamine levels to function optimally. Dopamine levels that are too high or too low impair its function. Such changes can arise in a variety of ways:

  • Toxins (such as nicotine or other stimulants) can increase dopamine levels in the brain, while malnutrition can decrease them.
  • Acute severe stress significantly increases dopamine levels in the dlPFC, while certain other forms of stress (e.g., chronic social stress during adolescence) decrease dopamine levels there.
  • Severe stress (especially during early childhood) can epigenetically alter genes, which permanently increases or decreases their activity (e.g., the production of an enzyme or neurotransmitter). In our example, this can lead to a permanent increase or decrease in dopamine levels in the PFC. Such epigenetic changes are heritable, meaning that changes triggered by (stressful) experiences can be passed down through several generations.
  • In addition, various genetic variants (polymorphisms) influence the effects of dopamine and norepinephrine. These are not caused by environmental factors, but rather represent genetic 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 can change as a result of (intense) experiences. Experiences that an organism has itself are also reflected in the expression of its own genes and thus in their activity. The epigenetic information that encodes gene activity can be passed on to 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 remain unchanged, the twins’ epigenomes diverge more and more as they age, the greater the differences in their living conditions.19 The genome—that is, the DNA sequence itself—remains unchanged.20

Epigenetic information is not the same at every age. Genetic studies on epigenetic methylation showed different correlations at birth and in later years.21

Such epigenetic changes can occur in various ways.22

1.2.1.1. Types of Epigenetic Modification
1.2.1.1.1. DNA de- and methylation

DNA methylation is an heritable epigenetic mark in which methyl groups are attached to the DNA molecule and, through the action of DNA methyltransferases (DNMTs), form 5-methylcytosine (5mC). In mammalian genomes, 5mC accounts for 2 to 5% of all cytosines.

In DNA methylation23, methyl groups are added to DNA. This usually occurs at cytosine bases, where DNA methyltransferases (DNMTs) form 5-methylcytosine (5mC). The DNMT family comprises five members, but only three enzymes—DNMT1, DNMT3a, and DNMT3b, possess methyltransferase activity that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to cytosine.24 Depending on the type of methylation and the methylated gene, methylation either initiates transcription or silences genes.25 The repression caused by DNA methylation can occur in two ways. The direct pathway occurs when methyl groups prevent transcription factors from binding to the promoter region. The indirect pathway suppresses gene expression by utilizing other chromatin-modifying factors that bind to methylated CpGs. The 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 to and suppress gene expression.26
DNA methylation is essential for the healthy development of eukaryotic organisms. Mouse models lacking DNA methyltransferases die during embryonic development.25
DNA methyltransferases are essential for maintaining or establishing methylation patterns. If the activity of DNA methyltransferases is restricted, for example by

  • Mutations
  • Polymorphisms
  • Lifestyle factors
  • Foods, e.g.:
    • Alcohol
    • Cigarettes
    • Flavonoids
    • Methionine deficiency
    • Choline Deficiency
    • Folic Acid Deficiency
    • Vitamin B12 Deficiency

This significantly reduces methylation.25

Treatment with DNMT inhibitors slightly increased DAT mRNA levels in human neuroblastoma cells, whereas administration of HDACs caused a more pronounced increase in DAT, suggesting that DAT levels may be more susceptible to enhanced histone acetylation24

Telomere length, which is influenced by methylation, among other factors, showed no correlation with ADHD in children aged 6 to 12; however, shorter telomeres showed a slight correlation with hyperactivity.27

1.2.1.1.2. Modification of histones

Histones are proteins that organize and package DNA into nucleosomes (structural units). Nucleosomes typically consist of two copies of each of the four core histones—H2A, H2B, H3, and H4—with 146 base pairs of DNA wrapped around them to form an octamer. Histone modifications are changes in the properties of 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 are26

  • Acetylation28
    • Histone acetylation involves the attachment of an acetyl group from acetyl-CoA to the α-amino group of specific lysine (K) side chains. Histone acetylation is catalyzed by the enzyme histone acetyltransferase (HAT).
    • Deacetylation catalyzed by histone deacetylases (HDACs) 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 regulating DAT expression.24
        *29 phosphorylation
    • Influences processes such as transcription, DNA repair, apoptosis, and chromatin condensation
      *28 Methylation
    • Is catalyzed by 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 suppress transcriptional expression.
    • Methylation can be single, double, or triple29

Acetylation, phosphorylation, and methylation of histones contribute to—through varying degrees of compaction—
Gene activation and inactivation over a larger range can occur and persist through several cell divisions
be maintained.29

1.2.1.1.3. Other epigenetic mechanisms
  • ADP-ribosylation29
  • Ubiquitination29
  • X-Chromosome Inactivation
    • In female cells, one of the X chromosomes is largely silenced, for example, by
      • DNA methylation
      • Histone modification
      • NcRNA (e.g., Xist RNA)
  • Changes in the Thickness of Myelin Sheaths
  • Chromatin Remodeling28
  • Changes Caused by Non-Coding RNA

    • Non-coding RNAs can regulate gene expression. ⇒ Building Blocks of Heredity and Behavior: Genes, DNA, RNA, Proteins, and More

      • MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of genes. miRNAs are small, single-stranded RNAs approximately 21–23 nucleotides in length. They bind to their specific target genes and reduce their expression.24
      • One study found, with regard to 51 genes associated with ADHD alone, in the 3’UTR of miRNA30
        • 81 MRE-forming SNPs
        • 101 MRE-breaking SNPs
        • 61 MRE-enhancing SNPs
        • 41 SNPs that reduce MRE

      MRE: miRNA recognition element / microRNA binding element
      SNP: Single-Nucleotide Polymorphisms
      These candidate SNPs within the miRNA binding sites of these 51 genes may alter miRNA binding and, consequently, mRNA-mediated gene regulation, thereby playing an important role in ADHD. Single-nucleotide polymorphisms (SNPs) located within the 3’UTR of mRNAs can influence miRNA-mediated gene regulation and, consequently, susceptibility to a wide range of human diseases.

These epigenetic changes influence how actively the gene is expressed—that is, how intensely it is active. For an introduction, see also Gene Expression on Wikipedia; Epigenetics on Wikipedia.

Various environmental factors alter dopaminergic transmission through epigenetic changes,26 including, among others, PAR-4 and DRD-2 expression in the striatum.31 In approximately 30% of people with ADHD, serotonin or norepinephrine reuptake inhibitors are ineffective. However, these individuals exhibit signs of dopaminergic dysfunction.

1.2.1.2. Environmental factors alter epigenetics

(Traumatic) experiences can alter the expression of a living being’s genes so profoundly that they even pass this experience on to their offspring. Humans and other mammals that have developed increased susceptibility to stress due to intense stressful experiences pass this increased susceptibility (including through hypocortisolism) on to their children.32 Holocaust survivors who developed PTSD pass on permanently lower cortisol levels to their offspring.32
A genetic predisposition can therefore be passed down after parents have acquired it themselves for the first time through a stressful experience.33

Dysfunctional stress processing causes typical symptoms such as impulsivity, delay aversion, or difficulties with decision-making. Severe, unavoidable stress permanently alters dopaminergic processes in brain regions essential for decision-making and impairs the prefrontal cortex (PFC) in terms of inhibition and working memory. Glial-derived neurotrophic factor (GDNF) plays a key role in regulating dopamine in the basal ganglia and in the survival of dopaminergic neurons.34
GDNF in the striatum promotes stress resilience.
Mice that cannot produce GDNF showed just as little aversion to delay before stress exposure as mice that can produce GDNF. After stress exposure, mice with partially reduced GDNF levels exhibited more impulsive decision-making, as evidenced by a reduced number of decisions to delay for a larger reward, consistent with delay aversion. Furthermore, after stress exposure, the mice with reduced GDNF levels showed reduced neuronal activation in the oPFC and the nucleus accumbens, suggesting dysfunctional stress processing.35

Environmental factors therefore permanently alter gene activity.3637

The intergenerational impact of trauma makes sense from an evolutionary perspective. If an individual undergoes an extremely (i.e., survival-relevant) negative experience, their descendants have a better chance of survival if they stay away from that source of danger without having to go through the experience 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 life-threatening specimens of these species have barely ever lived in Northern European latitudes, and this fear can therefore be neither useful nor learned through personal experience. People with an instinctive fear of spiders and snakes can likely be regarded as the (more successful) descendants of those who survived a traumatic encounter with such a creature—long before their descendants migrated to Northern Europe. It would be understandable that these traumas have become more deeply ingrained in the genes of Homo sapiens, because they were not isolated incidents but were repeatedly reinforced over many generations.

Significant, long-term stress experienced by a person with ADHD can activate predisposing genetic factors just as much as a short-term but very severe stressor (trauma). Such stress can take various forms. Depending on a person’s sensitivity, different levels of stress are required to reach the threshold that causes lasting damage.

In particular, epigenetic changes (e.g., resulting from an early-life stressful experience) can be passed down across several generations. In rats, third-generation offspring of rats exposed to early-life stress still exhibited increased vulnerability to the development of mental disorders following a “second hit” during adolescence. In other words: Rats exposed to stress in the first days of life epigenetically passed on an increased vulnerability to their children, grandchildren, and great-grandchildren (even though all three subsequent generations grew up stress-free), specifically to develop mental disorders throughout adulthood in the event of stress exposure during adolescence.38 This fully explains the “second hit” model, well-known in stress medicine, for the development of mental disorders in humans. Mechanisms have also been identified in humans that explain such epigenetic inheritance of experiences.39 There is evidence that the “second hit” also influences the severity of symptoms in ASD.40
Stress during adolescence can amplify the effects of stress experienced in early childhood.41 Another study shows that adults who reported more than five ADHD symptoms from their childhood were more likely than average to develop mental health disorders or substance use disorders.42
Interestingly, middle adolescence does not appear to be a particularly sensitive period only in negative terms. Studies on the effects of enriched environments in rats have already shown positive effects during childhood. However, the greatest benefit was observed during middle adolescence. An enriched environment led to improved selective and auditory sustained attention, increased exploration and foraging behavior, as well as a significant decrease in corticosterone levels and reduced anxiety scores.43

Specific genes involved in ADHD (particularly DRD4-7R, a gene variant of the DRD4 gene that arose approximately 50,000 years ago through mutation—that is, not epigenetically—result in greater sensitivity and, consequently, greater vulnerability in people with ADHD. Since these genes also result in greater sensitivity to positive influences—meaning they lead to a greater impact from external factors even in the absence of ADHD—they can generally serve as the basis for high sensitivity. Learn more about opportunity/risk genes at*⇒* Parental attachment style is particularly important in the context of opportunity/risk genes in the article*⇒ Secure attachment trumps genetic predisposition in ADHD* in the chapter at ⇒ Prevention.

There have been attempts to mathematically calculate the impact of epigenetic factors (in this case, methylation) on the one hand, and environmental factors on the other, on the development of ADHD.44

Environmental and life experiences influence biological age. This can be determined using DNA methylation levels as a marker.
A study examined the relationship between a. ADHD-PRS (Polygenic Risk Score), b. the reduced life expectancy associated with ADHD, and c. genome-wide DNA methylation levels as an indicator of biological aging and an earlier age at death (here: GrimAge).
The ADHD-PRS, adjusted for covariates, was significantly and directly associated with GrimAge. The effect of the ADHD-PRS on GrimAge was most strongly mediated by education, followed by smoking, depressive symptoms, BMI, and income.
Education appears to play a key role in mitigating the negative effects on epigenetic aging caused by behavioral and sociodemographic risk factors associated with ADHD.45

1.2.1.3. Examples of epigenetic inheritance in relation to ADHD
1.2.1.3.1. The father’s nicotine use before conception

Mice whose fathers were chronically exposed to nicotine, while their mothers were not exposed to the drug, exhibited hyperactivity, nicotine-induced impaired motor sensitization, and reduced dopamine and norepinephrine levels in the striatum and PFC.46 This hyperactivity was mediated by reduced dopamine transporters. Nicotine exposure epigenetically increased the level of DAT DNA methylation in the sperm of the mouse fathers and the brains of the mouse offspring. This resulted in reduced DAT expression in the offspring’s brains and, consequently, increased extracellular dopamine levels. This resulted in the activation of D2 receptors, which led to the dephosphorylation of AKT, which in turn enhanced the activation of GSK3α/β, ultimately causing hyperactivity in the offspring.47
The father’s nicotine use caused epigenetic changes in the dopamine D2 receptor. The first- and second-generation children exhibited impairments typical of ADHD:48

1st generation:

  • Significantly increased spontaneous motor activity (hyperactivity) (males and females)
  • Significant deficits in reversal learning (males and females)
  • Significant attention deficits (boys)
  • Significantly reduced monoamine levels in the brain (males)
  • Reduced dopamine receptor mRNA expression (males)

2nd generation:

  • Significant deficits in reversal learning (male mice)

We suspect that a mother’s nicotine consumption prior to conception is also passed on to her children through epigenetic mechanisms.

1.2.1.3.2. Traumas the mother experienced during her childhood

Children of mothers who were abused during their childhood were more likely to:49

  • clinical-level internalizing problems (odds ratio 2.70)
  • ADHD (OR 2.09)
  • Autism spectrum disorder (OR 1.70)
  • Obesity (in girls) (OR 1.69)
  • Asthma (OR 1.54)
  • Multimorbidity
  • Mothers who had been exposed to multiple forms of childhood maltreatment had children with the highest increases in risk, suggesting a dose-response relationship.

The more adverse childhood experiences (ACEs, childhood traumas) mothers reported from their own lives,50

  • the younger they were when they had their children
  • the less likely they were to be married
  • the lower their level of education
  • the more symptoms their offspring exhibited
    • internalizing symptoms
      • 1 ACE: 1.81 more points
      • 2 ACE: 2.07 more points
      • 3 ACE: 2.68 points more
    • externalizing symptoms
      • 1 ACE: 1.78 more points
      • 2 ACE: 3.08 points more
      • 3 ACE: 3.30 more points
1.2.1.3.3. Epigenetic Aging in ADHD Remains Unchanged

A study found no evidence of altered epigenetic aging in the tissue of the ACC, the caudate, or peripheral tissue.51

1.2.2. Epigenetics varies within an individual

While inherited genes are the same in all cells, epigenetic changes within an individual vary significantly among different cell types.525354
It cannot therefore be assumed that epigenetic changes are identical in peripheral and central tissues.

2. Heritability of ADHD

There is a strong genetic influence (genetic prevalence: 76%);55 Others cite 70–80%, 50–98%56, or 88%57. An extremely large study of 4.4 million twins found a heritability of 80%.58 Among cases of ADHD with clinical severity, the figure is said to be as high as 90%.59

The discussion focuses on whether ADHD is less heritable in adults than in children—that is, whether environmental factors play a greater role in the development of ADHD in adults.60
A study of 15,198 Swedish twins aged 20 to 46 found a heritability of 37% for inattention and 38% for hyperactivity-impulsivity. Genetic influences accounted for 52% of the phenotypic correlation between inattention and hyperactivity-impulsivity, while the remaining portion of the covariance was explained by non-shared environmental influences. These results were replicated across age groups.61

Heritability is the extent to which traits found in ancestors are also found in their offspring.
The percentages indicate how often children share their parents’ traits, not the probability of those traits occurring.
The heritability of a trait in a population always depends on the number and intensity of the various environmental conditions.
Thought experiment: If all members of a population lived under 100% identical environmental conditions (which is impossible in practice, since members still have individual experiences even in a shared environment—a fact we will set aside for the purposes of this thought experiment), the heritability of all traits would be 100% —and this would be solely because the environmental influence would always be identical, thus causing 0% variation. Conversely, this means that two populations with differently variable environmental conditions would have different heritabilities for the same trait. Or, to put it another way: The more extreme the differences in environmental conditions, the lower the heritability becomes, even though the genes exert the same influence.
Genes that trigger certain traits also cause these traits to manifest in the parents. These traits (behaviors) of the parents also influence their children through their upbringing. Mothers with ADHD treat their children with less attention than mothers without ADHD.62 This treatment has its own influence on the children’s behavior. Heritability cannot distinguish here between the effects of genes and those of upbringing.

The heritability of major depression was 30% in this study. Estimates based on the measured genotypes were lower, ranging from 10% for alcohol dependence to 28% for OCD. Other sources cite the genetic contribution to the development of depression as approximately 40%.63 The heritability of anxiety disorders is 30 to 40%, that of intelligence is 55%, and that of personality traits is 40%. The heritability of SCT is reported to be 55 to 60%.59

18% of parents of people with ADHD have ADHD themselves.64 It should be noted that the prevalence of ADHD among adults is only half that of children.
The risk that siblings of people with ADHD will also have ADHD is 35%.64
Identical twins of a person with ADHD have a 65% risk of having ADHD,6465 while fraternal twins (as well as siblings from separate pregnancies) have a risk of “only” 28%65 to 35%64

Biological parents of people with ADHD are three times more likely to have ADHD themselves than non-biological parents (adoptive parents).64

2.1. Heritability of gene variants: unlimited in time

Gene variants and gene mutations are independent of environmental factors and can be permanently passed down through generations.

2.2. Heritability of epigenetic information: time-limited

Epigenetic changes have three main characteristics:66

  • They are caused by environmental factors67
  • They are hereditary, at least over about three generations68
  • They are dynamic throughout life and potentially reversible69

Hamza et al. authored a review article on the epigenetic causes of ADHD70 Epigenetics is thus the key to understanding the significance of environmental influences in ADHD, which account for a higher proportion than the non-hereditary component of ADHD (20 to 25%), while 75 to 80% of the risk for ADHD is hereditary.

3. Multigenic cause – hundreds of candidate genes for ADHD

ADHD is not caused or predisposed by a single gene. Based on current knowledge, hundreds of candidate genes are known, and thousands of genes are likely involved. (For more information, see ⇒ Candidate Genes for ADHD)

Nevertheless, the known genes account for only 5% of heritability so far, suggesting that many more genes are involved. One study found that among participants in the lowest 20% of the ADHD PGS (polygenic (risk) score)71

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

3.1. Polygenic Risk Score (PRS) for ADHD

The risk resulting from the combination of existing genes can be described as a polygenic risk score.
ADHD-PRS scores (the individual estimate of the total effect of SNPs) correlate significantly, depending on the score, with ADHD diagnosis and ADHD symptom severity according to6

  • clinical samples
  • Population samples
  • Parent Reports
  • Self-reports
  • Teacher evaluations
  • Twin studies

A study found that, based on psychological symptoms at ages 7 and 13, children had an elevated PRS for ADHD and schizophrenia, but not for depression or ASD.72
A large-scale study (n = 5,808) concluded that the multiple genetic risks associated with ADHD have a significant impact on educational attainment and cognitive performance.73 Genetic risk is a good predictor of the onset and severity of ADHD.74 Other studies have also begun to derive polygenic risk scores from the analysis of identified genetic variants, which can predict ADHD symptoms.75 The PRS should now be able to support the diagnosis of ADHD.76

3.2. Transcriptomic Risk Score (TRS) for ADHD

The transcriptome is the totality of genes transcribed from DNA to RNA in a cell at a given time—that is, the sum of all RNA molecules produced in a cell. It reflects the status of all active genes in the cell.
A transcriptome-based association study generated transcriptomic risk scores (TRS) in peripheral blood mononuclear cells from people with ADHD. The TRS is elevated in people with ADHD. The TRS did not correlate with the PRS (polygenic risk score). A combination of PRS and TRS significantly improved the proportion of explained variance compared to the PRS-only model.77

3.3. Model of the synergistic summation of multiple gene effects

Our current understanding of the interaction of multiple genes in relation to the development of ADHD and other disorders with multifactorial causes is as follows.

If we stick with the (highly simplified) model that ADHD symptoms are mediated by reduced effects of dopamine and norepinephrine, each of the involved (activated) genes would, in its own way, exert a (small and, on its own, completely insignificant) influence that reduces the effectiveness of the neurotransmitters involved.

Factors that influence dopamine levels in the striatum include:

  • DAT1-10R 40 bp78 causes the dopamine that has been released in sufficient quantities in the striatum to be reabsorbed by the sending synapse (reuptake) before it can be taken up by receptors at the receiving synapse, where it would exert its necessary effect.
  • DRD4-7R 48 bp7879 80 81 reduces the sensitivity of D4 receptors in the receiving synapse in the striatum, so that they only respond to higher levels of dopamine. Since D4 receptors have an inhibitory effect, DRD4-7R results in reduced inhibition and thus greater reactivity of the neurons (in this case, in the striatum).
  • Other genes contribute to reduced dopamine activity in the striatum in different ways.
  • Each of these genes (in the variant considered “harmful” in ADHD) contributes only a small part to ADHD (e.g., to the dopamine deficit in the striatum). These effects add up when multiple ADHD candidate gene variants (e.g., DAT1-10 R 40 bp, DRD4-7R 48 bp, and other genes) are present simultaneously.82

If there were additional genes with variants or epigenetic modifications that reduced dopamine levels or the utilization of dopamine in the striatum by inhibitory receptors (e.g., D2, D3), this would synergistically lead to even greater reactivity in the striatum.
The striatum mediates motivation and motor control. Reduced activity in the striatum due to decreased dopamine levels in the synaptic cleft—resulting from increased dopamine reuptake via the DAT—could explain anhedonia. The reduced dopamine levels, on the one hand, and the concurrent reduction in dopamine sensitivity at the D4 receptor, on the other, could inactivate the receptor’s inhibitory function, which—alongside existing anhedonia and lack of drive—could trigger poor impulse control and increased hyperactivity. This could explain why these symptoms frequently occur together.
Studies found evidence that DRD4-7R and DAT1-10R correlated with externalizing behaviors.83

If other genes were to act in a way that enhances dopamine activity at the same time, they could partially or completely offset the problem; however, in combination with other genes that enhance dopamine activity, they could cause a dysfunction of the striatum due to excessive dopamine activity.

The distribution of genes varies among human ethnic groups.84

This model is likely applicable to all mental disorders that have multifactorial causes.
It may also explain why some people develop XY symptoms (e.g., ADHD, borderline personality disorder, anxiety disorder …) only when, in addition to their weak genetic predisposition, they are exposed to chronic stress, which then provides the necessary additional factor to throw neurotransmitter levels so far out of balance that symptoms appear.

According to this conceptual model, in these (mildly) affected people with ADHD, while a number of genes are activated in a way that contributes to the respective neurotransmitter imbalance, there are not enough of them to trigger the symptoms of the Disorder on their own. It is only the addition of chronic stress that disrupts the neurotransmitter balance to such an extent that the neurotransmitter imbalance required for symptoms to develop (in the case of ADHD: a deficiency of dopamine and norepinephrine) now occurs. This model could plausibly explain why, in a long-term study, a number of people with ADHD who have a confirmed borderline personality disorder diagnosis could no longer be diagnosed as such after six months:85 It is conceivable that the stressful situation (separation from a partner, death of a family member)—which had compensated for the genes “missing” for a full-blown diagnosis of ADHD—may have occurred. In other words: The genetic predisposition did not include enough genes for the neurotransmitter imbalance to exist even in the absence of acute stress. In contrast, for people with ADHD who experience symptoms even in the absence of significant stress, enough disorder-specific genes are jointly activated to cause the symptoms to manifest even without stress.

According to this concept , the number of genes that are affected simultaneously and that collectively influence, for example, the level of a specific neurotransmitter at a particular site in the brain Determines the extent of the Disorder.
In our view, a categorical disorder would be plausible only in cases where the disorder can be causally attributed to a single gene or a very small number of genes.

4. Epigenetic Effects of Psychotherapy

Psychotherapy can help reduce stress. Examples:

  • Depth psychology therapy can uncover potential causes that lead to inappropriate behavior resulting from dysfunctional interpretations of others’ behavior; 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 manage symptoms and thus promote a more functional approach to dealing with problematic situations
  • Mindfulness-based therapies can reduce stress levels and increase serotonin levels over the long term.
  • Humanistic psychotherapies such as person-centered therapy, Gestalt therapy, etc.

To date, there have been only a few studies on the effect of psychotherapy on the epigenetic expression of genes. However, it has been suggested that “positive” epigenetic changes resulting from psychotherapy could be passed down through generations just as “negative” epigenetic changes resulting from stressful experiences are, and could thus contribute to the prevention of mental disorders.6686
Fundamentals of the Effects of Psychotherapy from a Neurobiological Perspective: Grave (2005): Neuropsychotherapy.

  • A study of people with ADHD found that 4 weeks of intensive dialectical behavior therapy (DBT) resulted in a reduction in CpG methylation of exons I and IV of the BDNF gene in blood leukocytes among therapy responders, whereas it continued to increase among therapy nonresponders—that is, those who did not respond to the therapy. Pre-treatment methylation correlated with the number of childhood traumas. The BDNF methylation status correlated significantly with the degree of depression, hopelessness, and impulsivity. However, no association was found between plasma BDNF levels and methylation status.87 The effect size of DBT in responders was up to 0.77 and correlated with the degree of methylation.66
  • A study of veterans with post-traumatic stress disorder (PTSD) found that higher methylation of cytosine in blood lymphocytes in the promoter region of the GR gene NR3C1 was a statistically highly significant predictor of response to a 12-week course of psychotherapy. The level of NR3C1 methylation did not change significantly as a result of the therapy. In contrast, methylation of the FK506-binding protein 5 (FKBP5) gene (which encodes a co-chaperone protein of the glucocorticoid receptor) had no predictive value for treatment response but tended to decrease as a result of therapy.88
  • Successful treatment of PTSD alters the methylation of the genes involved.89
  • A study of people with ADHD found reduced methylation in the MAO-A gene. MAO-A breaks down amines such as dopamine, norepinephrine, and serotonin. After 6 weeks of cognitive behavioral therapy (CBT), an increase in MAO-A methylation correlated with a reduction in agoraphobia symptoms.90 Here, too, the effect size appears to be very high.66
  • A study of children with anxiety disorders found that a 12-week course of cognitive behavioral therapy resulted in a statistically significant reduction in methylation of CpG IV of FKBP5 among people with ADHD who experienced the greatest reduction in anxiety. Patients who did not respond to therapy experienced an increase in methylation, which was particularly true for children with FKBP5 risk genotypes. The treatment response was not associated with FKBP5 polymorphisms or the level of DNA methylation prior to treatment. No correlation was found with glucocorticoid receptor polymorphisms or methylation.91
  • A study of people with depression found increased methylation of GLUT 1, which encodes the insulin-independent glucose transporter 1 involved in brain metabolism. Treatment responders (those whose symptoms improved) showed significantly lower GLUT 1 methylation after 6 weeks of inpatient treatment with cognitive behavioral therapy and antidepressants compared to people with ADHD whose symptoms did not improve.92 However, the effect size appears to be rather small.66
  • A pilot study observed epigenetic changes within 24 hours in response to a mind-body therapeutic protocol (MBT-T).93
  • A study reports epigenetic changes resulting from meditation.94
  • Male mice in which early-life 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—exhibit psychological behavioral changes that they—along with the epigenetic changes—also pass on to their offspring. One study showed that an enriched environment during the male mice’s adulthood prevented the behavioral changes from being passed on to their offspring. The offspring exhibited a reversal of the changes in GR gene expression and DNA methylation in the hippocampus.95
  • A 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 nonresponders.96
  • The effect of exposure therapy was measured in children with an anxiety disorder. A reduction in symptom severity correlated with a decrease in the percentage of DNA methylation of FKBP5 at a CpG site in intron 7 and a better response to therapy. Changes in DNA methylation did not affect FKBP5 expression.97

5. Candidate genes and their activation by early childhood stress in other mental disorders

The underlying mechanism—in which certain genes make people susceptible to developing a mental disorder when exposed to excessive stress during childhood—is not unique to ADHD. Depending on a person’s genetic predisposition, early childhood stress can lead to the development of various mental disorders.
This also explains the phenomenon of comorbidities. Stress experienced in early childhood activates existing genetic predispositions. If a person has genetic predispositions for multiple mental disorders, these are (at least significantly more likely to be) activated simultaneously by corresponding environmental influences.
A comprehensive overview of the effects of early childhood or prolonged stress can be found at ⇒ Genes + Early Childhood Stress as a Cause of Other Mental Disorders

6. The Phenomenon of Resilience

Some people weather life’s setbacks with relative ease, while others develop severe symptoms of stress and/or mental disorders.
Resilience is the consequence of countless protective factors, particularly personality traits, socioeconomic factors, family, religion, and others.
A genetic makeup that includes only those variants of the relevant genes that do not confer a vulnerability to stress protects against extreme behaviors—both for the better (less risk) and for the worse (fewer opportunities).

When we wrote these sentences, we were not yet familiar with Christina Berndt’s book Resilience (98 ), which impressively confirms this conclusion.

7. Gene-Specific Treatment of ADHD

One study is examining the direct pharmacological targeting of ADHD candidate genes.99

8. Human Endogenous Retroviruses (HERVs) and ADHD

8.1. Introduction to HERVs

Endogenous retroviruses (ERVs), discovered in the 1960s, are retroviruses that do not undergo a complete replication cycle but are passed down through the individual’s genome as proviruses. Endogenous retroviruses are thought to have originated many generations ago through infections of germline cells in vertebrates. However, in addition to ERVs, other viruses can also become endogenous.100

Retroviruses use the enzyme reverse transcriptase to transcribe their RNA genome into chromosomal DNA, thereby integrating their RNA into the host cell’s DNA. If they succeed in infecting germ cells, they become endogenous retroviruses and can be passed down through many generations.
In some cases, endogenous retroviruses remain infectious only for a short time (a few hundred generations) because mutations (e.g., point mutations, deletions, insertions of other retroelements, recombinations, mini- and microsatellite expansions) that lead to gradual viral inactivation. Similarly, epigenetic changes lead to the inactivation of ERVs.101
However, if endogenous retroviruses remain active, they can continue to produce viral particles.
To date, several thousand HERVs have been identified in the human genome, accounting for approximately 8% of the human genome.102 Approximately 0.5% of the human genome consists of replicable proviruses.

HERVs can integrate into the human genome, thereby altering the structure and/or function of genes103104

Each HERV family is named after the amino acid corresponding to its associated tRNA:105

  • HERV-K (lysine)
  • HERV-H (histidine)
  • HERV-W (tryptophan)
  • HERV-E (glutamic acid)

Some human endogenous retroviruses (HERVs) appear to be involved in the development of certain autoimmune diseases, such as multiple sclerosis, Alzheimer’s disease, and dementia.102 Other HERVs play a role in the development and regulation of important organs, such as the placenta in mammals.

The potential responsiveness of HERVs to environmental factors plays an important role in gene-environment interactions. 100

8.2. HERV and ADHD

It is therefore conceivable that HERVs also affect the expression of genes relevant to ADHD.106 In ADHD, the expression of some human endogenous retroviruses appears to be altered compared to that in unaffected individuals:102

  • HERV-H – Significantly Increased Expression107
    • HERV-H elements are highly expressed in human embryonic stem cells and are essential for maintaining pluripotency, suggesting a regulatory role in early development.108
  • HERV-K – Expression unchanged107
  • HERV-W – Expression unchanged107

MPH reduced HERV-H expression in ADHD.109
A case study of a person with ADHD describes how an improvement in ADHD symptoms after 6 months of MPH treatment correlated with a reduction in HERV-H expression.110 Another study, conducted on a very small sample size (7 people with ADHD), confirmed a correlation between symptom reduction and a decrease in HERV-H activity due to MPH.111

8.2. HERV and Other Mental Disorders

The abnormal expression of HERV genes appears to play a role in the development of neurological and psychiatric disorders.

  • ASS102
    Expression of
    • HERV-H significantly elevated112113114
    • HEMO [human endogenous MER34 (medium-reiteration-frequency-family-34) ORF – Increased expression112
    • HERV-W – Expression significantly reduced114
    • HERV-K – Expression unchanged114
  • Multiple Sclerosis
    • HERV-H/F – Increased expression115
    • HERV-W – Increased expression115
  • Schizophrenia115
  • Bipolar disorders

A mouse model expressing human HERV-1 exhibited altered behavior and gene expression.117

Furthermore, a correlation was reported between a decrease in HERV-H activity and symptom improvement in ASS following treatment with methylphenidate. However, the cited sources provide no further details on this.118

9. Human Accelerated Regions (HARs)

Human Accelerated Regions (HARs) are 17 known segments of the human genome that exhibit an unusually rapid rate of genetic change compared to the chimpanzee genome. Therefore, HARs are thought to play a role in human-specific traits. HARs are mostly found in non-coding regions of DNA and often function as gene regulatory elements—particularly as enhancers—that control when and where genes are turned on or off. HARs specifically regulate human neurodevelopment, thereby influencing brain development, morphology, and behavior.

Human Accelerated Regions (HARs), like endogenous retroviruses (ERVs), modulate gene expression and immune pathways, determine which microbes thrive in the gut, and influence brain maturation. As a result, HARs and ERVs together can have significant consequences for neurodevelopmental disorders such as ADHD, ASD, or schizophrenia.119

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