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Every person has every human gene. Nevertheless, genes play a very decisive role in determining the individual behavior of a single person. Behavior is strongly determined by the different functionality and activity of the genes. Through the activity and functionality of the gene variants that a person has, his behavior or his health is also influenced.
There are two types of genetic hereditary factors related to the activity of genes that contribute to the development of ADHD:
Genes whose variants are differentially 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 cause different activity levels of the gene.
There is considerable genetic overlap in the genetic causes of mental disorders. This so-called general psychopathological factor (P factor)1 accounts for 10% to 57% of the phenotypic variance.23
Strikingly, 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.4
We understand this to mean that ADHD is, in a sense, a more general 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 to cause 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 then remains virtually unchanged during life.
Radioactivity or rare diseases can mutate genes.
One known gene variant that may contribute to ADHD involves the DRD4 gene, which expresses the dopamine D4 receptor.The 7R gene variant of the DRD4 gene causes the D4 receptor to require three times as much dopamine to be targeted.
This in itself is not yet good or bad. Depending on the combination with other genes, environmental influences and life circumstances, it can be favorable or unfavorable for the living being. Since other genes also have an influence on dopamine levels, a constellation of several gene variants that alter a neurotransmitter level in a specific brain area can have very serious effects. DRD4-7R correlates with motivation problems and impulsivity in ADHD. DRD4-7R arose by 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 seem to be involved in ADHD, see below.
SNPs explain about 22% of the heritability of ADHD52 and up to 25% of individual symptoms of ADHD:6
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. From the results, the authors suggest specificity of genetic overlap between inattention and various aspects of neurocognitive efficiency.
The environmental causes known so far also explain 22% of the development of ADHD.2
Obviously, significant proportions of ADHD causation to date cannot be explained by SNP (22%) and environmental causes (another 22%) alone.
Similarly, copy number variations (CNVs) may contribute to the development of ADHD.72
1.1.4. Animal models with genetically induced ADHD¶
Animal models show that ADHD can be caused by specific genes alone, i.e. without environmental influences (whether directly or via epigenetics).
One model for ADHD-HI (with hyperactivity) is the so-called “spontaneously hypertensive rat” (SHR).8 The SHR are rats that develop hypertension at about 15 months of age due to their genes alone.
These rats show at the same time quite typical ADHD symptoms. With increasing age and parallel to increasing hypertension, an increasing sensitivity of the HPA axis to stress is observed in SHR.9
The rearing of these animals does not involve any stress.10
This shows that certain genetic constellations can cause mental disorders even without the addition of stressful environmental influences.
Interestingly, the first generations of SHR had a massive problem of cannibalism on newborns. This problem has since been solved by isolating pregnant rat mothers until the young reach a certain age. It would be interesting to know if the SHR also shows special behavior towards young animals in other ways.
There are other genetically distinct mouse models that also show ADHD symptoms, e.g., the Naples-high-excitability rat (NHE).11 These show increased DAT in the PFC but not in the striatum (report in text does not correspond to abstract) and increased glutamate receptor sensitivity in the PFC and dorsal striatum.
This is consistent with the fact that, for example, dopamine deficiency in the mPFC can be caused by different genes, alone or together.
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 heritable.
We hypothesize that ADHD (like many other mental disorders) is caused by a confluence of
a. specific genes and
b. Environmental influences that activate these genes (gene-environment interaction)
is caused.
Just as stress (for example) can alter certain neurotransmitter levels in certain brain regions, it can also do so through certain gene polymorphisms/gene variants.
Example: Working memory, which is located in the dorsolateral PFC, requires, among other things, a moderate dopamine level for optimal function. Dopamine levels that are too high or too low impair its function. Such changes can arise in quite different ways:
Toxins (e.g., nicotine or other stimulants) can increase dopamine levels in the brain, and malnutrition can decrease them.
Acute severe stress greatly increases dopamine levels in the dlPFC, and certain other forms of stress (e.g., chronic social stress in adolescence) decrease dopamine levels there.
Severe (especially early childhood) stress can alter genes epigenetically, permanently increasing or decreasing their activity, e.g. to produce an enzyme or messenger substance). In our example, this may result in permanently increasing or decreasing dopamine levels in the PFC. Such epigenetic changes are heritable, so that changes triggered by (stress) experiences can be passed on over several generations.
In addition, various gene variants (polymorphisms) influence dopamine and norepinephrine action. These are not caused by environmental influences, but adjust 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 is variable due to (intense) 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 encodes the activity of genes 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 do not change, the epigenomes of the twins develop further apart with increasing age, the more different their living conditions were.12 The genome, i.e. the DNA sequence itself, remains unchanged.13
Such epigenetic changes can occur in a variety of ways.14
In DNA methylation15, methyl groups are added to the DNA. This usually occurs at the cytosine bases. Depending on the type of methylation and the gene methylated, methylation causes transcription initiation or gene silencing.16 Repression caused by DNA methylation can occur in two ways. The direct pathway is when the methyl groups prevent 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 gene expression.17
DNA methylation is necessary for healthy development of eukaryotic organisms. Mouse models lacking DNA methyltransferases die during embryonic development.16
DNA methyltransferases are essential for the maintenance or establishment of methylation patterns. If the activity of DNA methyltransferases is restricted, e.g. by
Histones are proteins that organize and package DNA into nucleosomes (structural units). Nucleosomes idR 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 histones, such as charge, shape, and size. The state of chromatin is controlled, by and large, by covalent modifications of histone tails. The most important modifications are17
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
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 repress transcriptional expression.
Acetylation, phosphorylation, and methylation of histones contribute to the
Activation and inactivation of genes over a wider range, and can be expressed over several cell divisions
be maintained.19
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’UTR of mRNAs may influence miRNA-mediated gene regulation and thereby susceptibility to a variety of human diseases.
These modifications affect the net charge, shape, or other properties of histones.
Various environmental influences alter dopaminergic transmission through epigenetic changes,17 including PAR-4 and DRD-2 expression in the striatum.21 Serotonin or norepinephrine reuptake inhibitors do not work in about 30% of depression sufferers. However, these affected individuals show features of dopaminergic dysfunction.
1.2.1.2. Environmental influences alter epigenetics¶
(Traumatic) experiences are able to change the expression of genes of a living being so permanently that they even pass the experience on to their children. Humans and other mammals who have developed an increased susceptibility to stress as a result of intense stress experience pass on this increased susceptibility to stress to their children (by means of hypocortisolism, among other things).22 Holocaust survivors who developed PTSD inherit permanently lower cortisol levels to their offspring.22
A genetic disposition can therefore be inherited after parents have acquired it themselves for the first time through stress experience.23
Example of genetic stress sensitivity in mice
Dysfunctional stress processing causes typical symptoms such as impulsivity, delay aversion, or difficulty in decision making. Massive unavoidable stress permanently alters dopaminergic functioning in brain areas essential for decision making and impairs the PFC in terms of inhibition and working memory. Glial derived neurotrophic factor (GDNF) has a major role in the regulation of dopamine in the basal ganglia and in the survival of dopaminergic neurons.24
GDNF in the striatum causes stress resilience.
Mice unable to form GDNF had as little problem with delay aversion before stress exposure as mice able to form GDNF. After stress exposure, mice that had partially reduced GDNF levels showed more impulsive decision-making responses, as evidenced by a reduced number of decisions for a subsequent larger reward in terms of delay aversion. In addition, the mice with decreased GDNF showed decreased neuronal activation in the oPFC and nucleus accumbens after stress exposure, suggesting dysfunctional stress processing.25
Genes are thus permanently altered in their activity by environmental influences.2627
Thesis: Trauma has a purpose
A cross-generational effect of trauma makes evolutionary sense. If an individual has an extremely (i.e. survival-relevant) negative experience, its offspring have a higher chance of survival if they keep away from this source of danger without having to go through the experience themselves first.
We suggest that this model explains why many northern Europeans also have a deep-seated, instinctive fear of snakes and spiders, although hardly 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 might 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 understandable that these traumas grew deeper into the genes of Homo sapiens, because they were not isolated incidents, but were refreshed again and again over many generations.
Proven: Epigenetics - it doesn’t always have to be trauma
A significant and not only short-term stress load on the affected person can activate predisposed gene systems just as much as a short-term but very severe stress load (trauma). Such a stress can have different forms. Depending on the sensitivity of people, different levels of stress are required to produce the stress level that causes permanent damage.
In particular, altered epigenetics (e.g., due to an early childhood stress experience) can be inherited over several generations. In rats, third-generation offspring of rats stressed in early childhood still showed increased vulnerability to developing mental disorders from a second hit at adolescent age. In other words, rats exposed to stress in the first days of life epigenetically passed on to their children, children’s children, and children’s children’s children an increased vulnerability (even though all 3 subsequent generations grew up stress-free) to developing mental disorders throughout adulthood in the event of stress exposure in adolescence.28 This fully explains the second hit model for the development of mental disorders in humans, known from stress medicine. In humans, mechanisms have also been found to explain such epigenetic inheritance of experience.29
Stressful events during adolescence can potentiate early childhood stressful events.30 Another study shows that adults who reported more than five ADHD symptoms from childhood were more likely than average to develop mental disorders or addiction.31
Interestingly, middle adolescence seems to be a particularly sensitive time not only in a negative direction. 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 Environment caused improved selective and auditory sustained attention, increased exploratory and food-gathering behavior, and a significant decrease in corticosterone levels as well as reduced anxiety levels.32
Individual genes involved in ADHD (in particular DRD4-7R, a gene variant of the DRD4 gene that was created by mutation (i.e. not epigenetically) about 50,000 years ago) cause a higher sensitivity and thus also higher vulnerability of those affected. Since these genes also cause a higher sensitivity to stimulation, i.e. also establish a greater external influence of external influence, 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 particularly important for chance/risk genes in the article⇒ Secure attachment beats genetic disposition in ADHD in the chapter ⇒ Prevention.
That ADHD symptoms are generally thought to have appeared before age 12 (DSM 5; earlier age 7, DSM IV) confirms the component of stress exposure in early childhood in the development of ADHD.
There are attempts of a mathematical calculation, which influence epigenetic influences (here: by methylation) on the one hand and environmental influences on the other hand have on the development of ADHD.33
1.2.1.3. Examples of epigenetic inheritance in relation to ADHD¶
1.2.1.3.1. Nicotine consumption of the father before conception¶
Mice whose fathers were chronically exposed to nicotine while their mothers were not exposed to drugs showed hyperactivity, nicotine-induced impaired motor sensitization, and decreased dopamine and norepinephrine levels in the striatum and PFC.34 This hyperactivity was mediated by decreased dopamine transporters. Nicotine exposure epigenetically increased the DNA methylation level of DAT in the spermatozoa of mouse fathers and the brains of mouse offspring. This caused decreased 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 activation of GSK3α/β, which eventually caused hyperactivity in the offspring.35
Nicotine use by the father caused epigenetic changes in the dopamine D2 receptor. The children of the first and second generation showed ADHD-typical impairments:36
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.
There is a strong genetic influence (genetic prevalence: 76%;37 others cite 70-80% or 50-98%38 or 88%39 An extremely large study of 4.4 million twins found heritability of 80%.40 Among ADHD cases with clinical intensity, it is said to be as high as 90%.41
It is discussed whether the heritability of ADHD is lower in adults than in children, i.e. whether the proportion of environmental influences on ADHD development is higher in adults.42
A study of 15,198 Swedish twins aged 20 to 46 years found a heritability of 37% for inattention and of 38% for hyperactivity-impulsivity. 52% of the phenotypic correlation between inattention and hyperactivity-impulsivity could be explained by genetic influences, whereas the remaining part of the covariance was explained by environmental influences that were not shared. These results were replicated across age strata.43
What does heritability mean?
Heritability is the degree to which characteristics of ancestors are also found in children.
The % figures here give the measure of how often children share their parents’ characteristics, 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, since the members still have individual experiences, which we 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. This means the other way round: two populations with differently variable environmental conditions have a different heritability with respect to the same trait. Or, formulated differently: the more extreme the environmental conditions differ, the lower the heritability becomes, although the genes exert the same influence.
Genes that trigger traits also cause them in the parents. These characteristics (behaviors) of the parents also affect their children through education. Mothers with ADHD treat their children more inattentively than mothers without ADHD.44 This treatment has its own influence on the children’s behavior. Heritability cannot distinguish between genes and parenting effects here.
Heritability for major depression was 30% here. Estimates based on measured genotypes were lower, ranging from 10% for alcohol dependence to 28% for OCD. Other sources name the genetic contribution to the development of depression at about 40%.45 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 %.41
18% of parents of ADHD sufferers have ADHD themselves.46 It should be noted that the prevalence of ADHD in adults is only half that of children.
The risk for siblings of affected individuals to also have ADHD is 35%.46
Identical twins of an ADHD sufferer have a 65% risk of ADHD,4647](http://www.devcogneuro.com/Publications/ADD.pdf) fraternal twins (as well as siblings from separate pregnancies) of “only” 28%47](http://www.devcogneuro.com/Publications/ADD.pdf) to 35%46
Birth parents of affected individuals are three times more likely to also have AD(H)s than non-birth parents (adoptive parents).46
2.1. Heritability of gene variants: unlimited in time¶
Gene variants / gene mutations are independent of environmental influences and can be inherited permanently.
2.2. Heritability of epigenetic information: limited in time¶
Epigenetic changes have three main characteristics:48
They are hereditary, at least over about 3 generations50
They are dynamic throughout life and potentially reversible51
A review paper on the epigenetic causation of ADHD was prepared by Hamza et al.52Epigenetics is thus the key to understanding the importance of environmental influences in ADHD, which are just 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. Multigenic 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. (See ⇒ for more details Candidate genes in ADHD)
Nevertheless, the known genes so far carry only 5% of the heritability, suggesting that many more genes are involved. One study found in subjects with the lowest 20 % of ADHD PGS (polygenic (risk) score)53
An approximately 18% reduction in the likelihood of developing ADHD
The risk resulting from the sum of the genes present can be described as the polygenic risk score. ADHD PRS scores (the individual estimate of SNP total effect) correlate significantly in a value-dependent manner with ADHD diagnosis and ADHD symptom severity after2
clinical samples
Population Samples
Parent reports
Self-report
Teacher Evaluations
Twin studies
One study found increased PRS in children based on mental health symptoms at ages 7 and 13 years in relation to ADHD and schizophrenia, but not in relation to depression and ASD.54
A large-scale study (n = 5,808) concluded that the multiple gene risks of ADHD have significant effects on achieved education and cognitive performance.55 Genetic risk is a good predictor of ADHD onset and severity.56 Other studies are also now forming polygenic risk scores from analysis of the gene variants found that can predict ADHD symptoms.57 The PRS should now be able to support the diagnosis of ADHD58
3.2. Model of synergistic summation of multiple gene effects¶
We currently have the following understanding of the interaction of multiple genes in relation to the development of ADHD or disorders that are multigenic.
If we stay with the (highly simplified) picture that ADHD mediates its symptoms through a reduced effect of dopamine and norepinephrine, each of the involved (activated) genes would have, in its own way, a (small and, by itself, completely insignificant) influence that reduces the effectiveness of the involved neurotransmitters.
Among other things, the dopamine (effect) level in the striatum is influenced by:
DAT1-10R 40 bp59 leads in the striatum to the fact that the sufficiently released dopamine is already 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 bp59606162 reduces the sensitivity of D4 receptors of the receiving synapse in the striatum, so that they only react to higher amounts of dopamine. Since D4 receptors are inhibitory, DRD4-7R causes less inhibition, thus greater reactivity of neurons (here: in the striatum).
Other genes contribute in other ways to reduced dopamine action in the striatum.
Each of these genes (in the variant “harmful” in ADHD) contributes only a small part to ADHD (e.g., to the dopamine deficit in the striatum). This effect adds up when multiple ADHD candidate gene variants (e.g., DAT1-10 R 40 bp and DRD4-7R 48 bp and other genes) are present simultaneously.63
If additional genes were now present in a variant or epigenetic expression that decreased 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 of the striatum.
The striatum mediates motivation and motor control. Decreased activity of the striatum due to decreased dopamine levels in the synaptic cleft caused by increased DAT dopamine reuptake could explain the anhedonia. The decreased dopamine level of a concomitant decreased dopamine sensitivity of the D4 receptor could turn off its inhibitory function, which could trigger deficient impulse control and increased hyperactivity concomitant with the existing anhedonia and listlessness. This could explain why these symptoms often occur together.
Research found evidence that DRD4-7R and DAT1-10R correlated with externalizing behaviors.64
If other dopamine efficacy-enhancing genes were present at the same time, they could partially or completely offset the problem, whereas, in combination with other dopamine efficacy-enhancing genes, they could cause striatal dysfunction due to excessive dopamine action.
The distribution of genes varies between human ethnic groups.65
This model is likely to be applicable to all mental disorders that are multigene factorial.
It may further explain why some people develop XY symptoms (e.g. ADHD, borderline, anxiety disorder …) only when, in addition to their weak genetic disposition, they are exposed to a chronic stress load, which then contributes the necessary further to unbalance neurotransmitter levels to such an extent that symptoms appear.
In these (mildly) affected persons, according to this concept, quite a few genes are activated in the direction of the respective neurotransmitter balance, but not so many as to trigger the symptoms of the disorder alone. Only the added chronic stress upsets the neurotransmitter balance in such a way that the neurotransmitter imbalance required for symptom formation (in the case of ADHD: dopamine and noradrenaline deficiency) occurs. This model could explain conclusively why in a long-term study quite a number of reliably diagnosed borderline patients could no longer be diagnosed after half a year:66 it would be conceivable that the stress situation (separation from the partner, death of a family member), which had replaced the genes “missing” for a full-blown disorder, could have taken place. In other words, the genetic predisposition did not include so many genes that the neurotransmitter imbalance already existed without acute stress. In contrast, according to this picture, in affected individuals who have the symptoms even in the presence of almost inexistent stress, enough disorder-specific genes are activated together to form the symptoms already without stress.
According to this idea, the number of genes that are simultaneously affected and that together influence, for example, the level of a specific neurotransmitter at a certain location in the brain, determine dimensional The degree of the disorder.
According to our understanding, a categorical disorder would only be obvious in the case of disorders that can be causally traced back to single or very few genes.
Psychotherapy is able to reduce stress levels. Examples:
Depth psychological therapy can uncover possible causes that lead to misbehavior because behavior of others is dysfunctionally interpreted; correcting the interpretation could recode supposedly stressful situations;
Cognitive behavioral therapy can facilitate symptom management to avoid more functional ways of dealing with problematic situations;
Mindfulness-based therapies can lower stress levels and increase serotonin levels in the long term.
To date, there has been little research on the effect of psychotherapy on epigenetic expression of genes. However, it is discussed that “positive” epigenetic changes could be passed on by psychotherapy as well as “negative” epigenetic changes by stress experiences and thus could contribute to prevention from mental disorders.4867
Fundamental to the effect of psychotherapy from a neurobiological perspective: Grave (2005): Neuropsychotherapy.
A study of borderline victims found that 4 weeks of intensive dialectical behavior therapy (DBHT) caused a reduction in CpG methylation of exons I and IV of the BDNF gene in blood leukocytes in therapy responders, whereas it continued to increase in therapy nonresponders, i.e., those who did not respond to therapy. Pretreatment methylation 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 plasma BDNF levels and methylation status.68 The effect size of DBHT in responders was up to 0.77 and correlated in measure with methylation.48
A study of veterans with post-traumatic stress disorder (PTSD/PTSD) found that higher methylation of blood lymphocyte cytosine in the promoter region of the GR gene NR3C1 was highly statistically predictive of responding to 12 weeks of psychotherapy. NR3C1 methylation levels did not change significantly with therapy. In contrast, methylation of the FK506-binding protein 5 (FKBP5) gene (encoding a co-chaperone protein of the glucocorticoid receptor) had no predictive power for treatment response but tended to decrease with therapy.69
Successful treatment of PTSD alters the methylation of involved genes.70
A study of panic disorder sufferers found reduced methylation in the MAO-A gene. MAO-A degrades amines such as dopamine, norepinephrine, or serotonin. After 6 weeks of cognitive behavioral therapy CBT, an increase in MAO-A methylation correlated with a reduction in agoraphobia symptoms.71 Again, the effect size seems to be very high.48
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 those with the greatest reduction in anxiety. Therapy nonresponders experienced an increase in methylation, which was especially true for children with FKBP5 risk genotypes. Therapy response was not associated with FKBP5 polymorphisms or pretreatment levels of DNA methylation. No correlation was found with glucocorticoid receptor polymorphisms or methylation.72
A study of depression sufferers found increased methylation of GLUT 1, which encodes the insulin-independent glucose transporter 1 involved in brain metabolism. Therapy responders (symptoms abated) showed significantly lower GLUT 1 methylation after 6 weeks of inpatient treatment with cognitive behavioral therapy and antidepressants compared with sufferers whose symptoms did not abate.73 However, the effect size seems to be rather small.48
A pilot study observed epigenetic changes within 24 hours to a mental-body treatment “mind-body therapeutic protocol (MBT-T).”74
One study reports epigenetic changes from meditation.75
Male mice in which early childhood trauma (separation from the mother) causes epigenetic changes in the hippocampus (increased glucocorticoid receptor (GR) expression and decreased DNA methylation of the GR promoter) and in sperm cells show psychological behavioral changes that they - together with the epigenetic changes - also pass on to their offspring. One study showed that Enriched Environment in adult mice males 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.76
One study found increased DNA methylation of SERT in children with an anxiety disorder who responded to cognitive behavioral therapy, whereas it continued to decrease in nonresponders.77
The effect of exposure therapy was measured in children with an anxiety disorder. A reduction in symptom severity correlated with a reduction in the percent 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.78
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 when they are exposed to excessive stress in childhood is not a specific feature of ADHD. Depending on the genetic disposition, only different mental disorders develop from early childhood stress.
This also explains the phenomenon of comorbidities. An early childhood stress load activates existing gene dispositions. If a person has gene dispositions for several mental disorders, these are activated simultaneously (at least much more likely) by corresponding environmental influences.
For a comprehensive review on the effects of early childhood or prolonged stress, see ⇒ 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 psychological disorders. A genetic makeup that includes those variants of the genes concerned that do not confer any vulnerability to stress sensitivity safeguards against extreme behavior - for better (less risk) and for worse (less chance).
When we wrote these sentences, we were still unfamiliar with the book Resilience by Christina Berndt79, which impressively confirms this conclusion.
Endogenous retroviruses, discovered in the 1960s, are retroviruses that do not undergo a complete replication cycle but are inherited in the genome of the individual as a provirus. Endogenous retroviruses probably originated many generations ago by infections of the germline cells in vertebrates. However, other viruses besides ERV can probably also become endogenous.81
Retroviruses write their RNA genome into the chromosomal DNA by means of the enzyme reverse transcriptase, thereby integrating their RNA into the DNA of the host cell. If they succeed in infecting germ cells, they thus become endogenous retroviruses and can be passed on over many generations.
In part, endogenous retroviruses remain infectious only 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, leading to gradual virus inactivation. Similarly, epigenetic changes lead to ERV deactivation.82
However, if endogenous retroviruses remain active, they can continue to produce viral particles.
To date, several thousand HERVs have been found in the human genome, accounting for about 8% of the human genome. Approximately 0.5% of the human genome consists of replication-capable proviruses.
Some human endogenous retroviruses (HERVs) 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. 81
HERV-H may affect the function of genes involved in the development of ADHD, such as the DA receptor and DAT genes.89
A first study found an influence of MPH on HERV transcription in PBMCs in a single case of an ADHD sufferer. Here, a reduction in HERV-H expression correlated with improvement in ADHD symptoms after 6 months of treatment with MPH.90 Another study confirmed a correlation between symptom reduction and HERV-H activity reduction by MPH in a very small number of subjects (7 sufferers).91
Furthermore, a correlation of the decrease of HERV-H activity and symptom improvement in ASA by methylphenidate was reported. However, the sources mentioned do not provide any information on this.89
