Genes and stress as the cause of other mental disorders

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

Most mental disorders share the basic pattern that interactions between genes and environmental influences contribute to their development. This article shows some examples of candidate genes and sites for other mental disorders, which explain how the respective disorder arises from the interaction 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 people with ADHD with various personality disorders.²

• 1. Post-traumatic stress disorder
• 2. Borderline PS (emotionally unstable personality disorder of the borderline type)
• 3. Aggression disorders
• 4. Depression
• 5. Addiction
• 6. Schizophrenia
• 7. Obsessive-compulsive disorders
• 8. Psychosis
• 9. Summary

1. Post-traumatic stress disorder¶

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 people with ADHD 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
“Consequences are a lifelong disability in dealing with stressful situations for the person with ADHD, 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
• 5-HT2c¹³
• 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
• GABRA2 rs279871 (BPD, impulse control, self-injurious behavior)¹⁶
• SNCA rs356195 (BPD, impulse control)¹⁶
• DRD2¹²
• Oxytocin transporter AA/GA variant⁸

Neurotransmitters involved in borderline:

• 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
• In addition, noradrenergic and GABAergic imbalances are 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.¹⁸ Dopamine is also named by Guillot.¹⁶

In addition, people with ADHD also have the following problems

• 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.

3. Aggression disorders¶

Aggression disorders are primarily associated with specific genetic variants that

• Lower the serotonin level¹⁴ and
• Influence the enzyme monoamine oxidase-A.

MAO-A is involved in the following disorders:

• (oppositional) behavioral disorder
• Borderline (suspected, see above)
• Antisocial behavior disorder²¹
• Depression²¹

As the MAO-A gene is located on the X chromosome, it is primarily boys and men who are affected.²² This is confirmed by a study that found a link between impulsivity and MAO-A only in male people with ADHD.²³

The enzyme monoamine oxidase-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 the people with ADHD were themselves 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 who had the high-risk 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.

4. Depression¶

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

MAO-A is also involved in depression.²⁸

The same gene variant of FKBP5 that makes people more susceptible to trauma is also involved in depression.²⁹
“*Excessive FKBP5 induction as a consequence 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

5. Addiction¶

The risk of alcohol addiction is also significantly influenced by genetic predispositions.³³

Several 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, people with ADHD are affected by certain polymorphisms of the following genes, 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
  • Nicotine abuse³⁵
  • Substance abuse
    • Cocaine abuse³⁵
  • ADHD
  • Novelty Seeking

• Dopamine receptor DRD4 [³⁶

  • Alcoholism
  • Substance abuse
  • ADHD
  • Novelty Seeking

• Dopamine transporter DAT [³⁶

  • Alcoholism
  • ADHD
  • Novelty Seeking

• COMT (dopamine degrading enzyme) [³⁶

  • Substance abuse
  • ADHD
  • Novelty Seeking

6. Schizophrenia¶

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

7. Obsessive-compulsive disorders¶

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

Trauma, unfavorable educational conditions and dysfunctional cognitive styles were identified as possible stressors.⁴⁶

8. Psychosis¶

In addition to genetic predisposition, a severe disorder of the child’s brain maturation is seen as a cause of psychosis, 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

9. Summary¶

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 persons with ADHD 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 of the people with ADHD 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. Nevertheless, individual protective factors can protect against damage caused by stress.

See also ⇒ Chronic stress regulation problems with other disorders