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Most mental disorders share the basic pattern that interactions between genes and environmental influences contribute to their development. This article shows a few examples of gene candidates for other mental disorders and the locations where they can be found, which explain how the respective disorder arises from a combination of genetic predisposition and early childhood stress.
The parallelism of the causes (genetic disposition plus activation through early childhood stress experience) of ADHD, trauma, depression, borderline and many other mental disorders proves that the question of what kind of psychological injury a person suffers from a massive early childhood exposure to stress depends very much on what genetic disposition(s) they carry. Some suffer trauma as a result, others depression and others ADHD - or more than one at the same time (comorbidities).1
With regard to environmental influences / the experience of stress, in addition to the intensity and the coincidence with certain gene variants, the time of their occurrence is also important, as confirmed by extensive and long-term monitoring of 733 affected persons with various personality disorders.2
A special variant of the FKBP5 gene (which models the sensitivity of the glucocorticoid receptor) makes its carriers more susceptible to trauma.3 The study shows that people with a certain polymorphism of this gene develop post-traumatic stress disorder even in the case of minor (but still massive) stress. People without this gene variant therefore require a higher level of stress to develop trauma (relative resilience).
In the case of childhood trauma, the stress regulation system of genetically predisposed sufferers is permanently damaged by epigenetic changes:
“Extreme stress and therefore high concentrations of stress hormone(s) cause what is known as an epigenetic change: a methyl group is cleaved from the DNA at this point, which significantly increases the activity of FKBP5. This permanent change in DNA is primarily caused by trauma in childhood. For example, no disease-associated demethylation in the FKBP5 gene can be detected in study participants who were traumatized exclusively in adulthood.”3
“The result is a lifelong disability in dealing with stressful situations for the person affected, which often leads to depression or anxiety disorders in adulthood.”3
Holocaust survivors who developed PTSD/PTSD pass on permanently lower cortisol levels to their offspring.4
While the cortisol level in post-traumatic stress disorder is evenly lower throughout the day than in healthy people, the cortisol level in (severely) depressed people is distributed rather chaotically throughout the day.5
While children initially show permanently elevated cortisol levels after a trauma, adults with post-traumatic stress disorder have permanently low cortisol levels (which are accompanied by elevated dopamine and noradrenaline levels).6 We assume that prolonged elevated cortisol levels in childhood cause an overload of stress regulation (HPA axis), which manifests itself in the chronic state after downregulation through hypocortisolism (lowered cortisol levels).
2. Borderline PS (emotionally unstable personality disorder of the borderline type)¶
The same pattern exists with borderline. The causes of borderline are multifactorial and are made up of a genetic disposition and stressful environmental experiences that activate it.78
Excessive stress exposure in childhood leads to chronic overactivity of the stress response system in people with a certain genetic disposition through epigenetic changes.910
The genes and neurotransmitters involved are less well researched.
Candidate genes for Borderline are
DAT1 9R
The 9-repeat variant of the DAT1 gene probably causes an excess of dopamine in the synaptic cleft because DAT1 9 does not allow the dopamine transporters to reabsorb the dopamine sufficiently presynaptically. DAT 9R is associated with affective disorders and borderline personality disorder.1112
DAT1 9R is associated with increased dopamine levels in PFC and striatum and therefore does not correlate with ADHD, which is associated with decreased dopamine levels and accordingly the DAT1 10/10 variant.
5 HTTPLR short13
Impulsive aggressiveness is attributed to a reduced serotonin level, which is caused by a variant of the serotonin (reuptake) transporter gene that is activated in early childhood.1415
The MAO-A gene is also suspected in cases of aggression problems.13 There is an association with BPD.12
COMT rs4680 (BPD, impulse control, self-injurious behavior)16
Catechol-O-methyltransferase (COMT) is involved in the breakdown of dopamine and noradrenaline.
COMT rs4680 enhances the degradation of dopamine and noradrenaline by forming a more active and thermally stable catechol-O-methyltransferase enzyme.12
The COMT Val158Met polymorphism (rs4680) is associated with increased reactivity to negative stimuli.17
COMT rs4680 also interacts with MAO-A in that high MAO-A activity causes low COMT rs4680 activity and vice versa.12
The main cause is said to be a serotonin deficiency.
The emotional dysregulation in borderline patients is attributed to an increased sensitivity of the anticholinergic system.15
Noradrenergic and GABAergic imbalances are also thought to be responsible for this.18
There is probably still an excess of dopamine and/or noradrenaline in the PFC and striatum.
Due to the increase in aggressiveness caused by dopamine-increasing stimulants such as methylphenidate or amphetamine drugs in borderline patients and the positive experiences with typical and atypical antipsychotics, which antagonistically block the dopamine D2 receptors, an impairment of the dopamine balance is suspected.18Dopamine is also named by Guillot.16
In addition, borderline sufferers
With high impulsive-aggressive values have a reduced prolactin response,
With high levels of anxiety and depression, on the other hand, have an increased prolactin response,
which could indicate an influence of the serotonin system.
No deviations were found in this study with regard to cortisol, noradrenaline and acetylcholine.19
Interestingly, the atypical antipsychotic quetiapine, for example, reduces the effect of dopamine by blocking the D2 receptor, but at the same time increases the release of dopamine by blocking the 5-HT-2 receptor.20
D2 antagonists are also sometimes used for ADHD.
As the MAO-A gene is located on the X chromosome, it primarily affects boys and men.22 This is confirmed by a study that found a link between impulsivity and MAO-A only in males.23
The enzyme monoaminooxidase-A is responsible for the breakdown of certain neurotransmitters, including serotonin.22
A certain variant of the MAO-A gene, which is responsible for the enzyme monoaminooxidase-A, doubles the risk of aggression and antisocial behavior if those affected were exposed to violence (or let’s say more generally: intense stress) in their childhood. Boys who experienced massive stress at home developed
40% had violent reactions (behavioral disorder requiring treatment or conviction for violence before the age of 26) if they had the harmless MAO-A gene variant.
80% of those with the risky MAO-A gene variant had violence-related disorders.22
Only 20% of children with violent behavior if they came from loving homes.
Measurements of the brain activity of the boys with the more vulnerable MAO-A as well as the more vulnerable 5-HTTPR gene variant showed that they generally reacted more intensively to stress, with the hippocampus and amygdala being put on alert more quickly.22
According to this view, this is also a key to understanding high sensitivity.
A similar pattern can be seen in depression. A combination of genetic causes and early childhood stress experiences is also assumed for depression.24 The two-hit model assumes damage in early childhood, which leads to a manifestation of depression in adulthood as a result of further traumatizing (stress) experiences in adolescence.2526
Highly stressful experiences such as the loss of close relatives or ongoing problems at work or other strokes of fate lead to depression more frequently in carriers of the serotonin (reuptake) transporter gene 5HTTPR in the short allele variant than in carriers of the long allele variant.27
The same gene variant of FKBP5 that makes people more susceptible to trauma is also involved in depression.29
“*Excessive FKBP5 induction as a result of cortisol release in response to a stressor appears to lead to an impaired negative feedback mechanism of the HPA system in T/T carriers and thus to a prolonged increase in cortisol levels. This prolonged stress response may lead to increased vulnerability to stress-associated diseases (Binder 2009).”30* Depression can therefore be understood as a disorder of stress regulation,2931 just as we understand ADHD as a disorder of stress regulation.
While the cortisol level in post-traumatic stress disorder (PTSD) is evenly lower throughout the day than in healthy people, the cortisol level in (severely) depressed people is distributed rather chaotically throughout the day.32
The risk of alcohol addiction is also significantly influenced by genetic predispositions.33
A number of gene polymorphisms are simultaneously involved in addiction and ADHD. At the same time, they represent a disposition for the personality trait of novelty seeking (which, according to this view, co-determines the stress response phenotype). Among others, certain polymorphisms of the following genes are affected, which control the following neurological positions:
DRD2, minor TaqI A (A1) allele
Gene for the dopamine receptor DRD234
Alcoholism35: threefold higher occurrence of the A1 allele gene variant in severe alcoholism, no difference to the control group in mild alcoholism
3′(TaqI A) and 5′(TaqI B) variants of the DRD2 gene are also associated with alcoholism35
In schizophrenia, at least 50 Susceptibility-Genes (candidate genes) are known.37 A combination of genetic factors and environmental influences is also assumed to be the cause of schizophrenia.38
Emotional trauma, social stress or hallucinogenic drugs have been identified as environmental influences for schizophrenia.3940
Early stress, in conjunction with corresponding genes, is thought to be responsible for sensitizing the dopamine system, making it susceptible to acute stress, which leads to progressive dysregulation.4142
Individual genes in schizophrenia
Among other things, the DTNBP1 gene is used as a Susceptibility-Gene. It is located on chromosome 6 in region 22.3 and codes for the protein dysbindin-1. In particular, the single base polymorphisms rs3213207 with P = 0.034, primarily for the heterozygous genotype A/G and rs2619538 lead to an increased susceptibility to schizophrenia.
The COMT rs4680 involved in schizophrenia increases the degradation of dopamine and noradrenaline by forming a more active and thermally stable catechol-O-methyltransferase enzyme. 43 This causes higher schizotypal symptoms.
This can be reconciled with the more recent dopamine hypothesis, according to which the positive symptoms of schizophrenia are not caused by a generally increased dopamine level in the frontal cortex (and in particular in the nucleus accumbens), but by an increased activity (firing rate) of the mesolimbic system, which in turn is caused or influenced by a dopamine deficiency in the ventral tegmentum.43
The COMT-Val158Val gene variant is also likely to correlate with schizophrenia due to the increased dopamine degradation in the PFC (compared to COMT-Met158Met) and the resulting lower dopamine level in the PFC as well as a simultaneously higher dopamine level in the striatum.41
The genetic predisposition For obsessive-compulsive disorder means that relatives of obsessive-compulsive patients have around five times the risk of also developing obsessive-compulsive disorder than unaffected people.44
So far, only the glutamate transporter gene variant SLC1A1 has been identified as a predisposing factor.45
Trauma, unfavorable educational conditions and dysfunctional cognitive styles were identified as possible stressors.46
In addition to a genetic predisposition, the causes of psychosis are considered to be a severe disturbance of the child’s brain maturation, whereby the latter can be massively influenced postnatally by environmentally induced disturbances. This is true even though the symptoms of psychosis only become apparent after puberty,47
The parallelism of the causes (genetic disposition plus its activation through early childhood stress experience) of ADHD, post-traumatic stress disorder, depression, borderline, schizophrenia and many other disorders proves that the question of what kind of psychological injury a person suffers from a massive early childhood exposure to stress depends very much on what genetic disposition they carry. Some suffer trauma as a result, others depression and others ADHD - or more than one at the same time (comorbidities).1
Extensive and long-term monitoring of 733 patients with various personality disorders showed that the different intensity and timing of early childhood stress also contributes to the differentiation of the disorders.48 All those affected were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% early childhood neglect.
We assume that above a certain level, massive stress causes psychological injury to everyone and leaves permanent damage. If there is a genetic disposition for a higher sensitivity to stress, this injury occurs more frequently / more likely, so that no stress loads of traumatic intensity are required.
