Genes and stress as a cause of other mental disorders

The basic pattern that interactions of genes and environmental influences contribute to the development is shared by most mental disorders. This article shows for other mental disorders exemplarily some gene candidates and references, which explain for the respective disorder the presented mode of development from an interaction of gene disposition and early childhood stress.

The parallelism of the causes (genetic disposition plus activation by early childhood stress experience) of ADHD, trauma, depression, borderline and many other mental disorders proves that the question of what kind of mental injury a person suffers from an early childhood massive stress exposure depends very much on which genetic disposition(s) he carries. Some suffer from trauma, others from depression, and others from ADHD - or even more at the same time (comorbidities).¹

Regarding the environmental influences / the stress experience, besides the intensity and the coincidence with certain gene variants, it further depends on the time of their occurrence, as confirmed by an extensive and long-term follow-up of 733 affected persons with different personality disorders.² All affected persons were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% early childhood neglect.

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

1. Post-traumatic stress disorder¶

A specific variant of the FKBP5 gene (which models glucocorticoid receptor sensitivity) makes its carriers more vulnerable to trauma.³ The study demonstrates that people with a specific polymorphism of this gene develop post-traumatic stress disorder even at lower (but still massive) levels of stress. People without this gene variant thus need a higher stress level to develop trauma (relative resilience).

In childhood trauma, the stress regulatory system of genetically predisposed individuals is permanently damaged by epigenetic changes:
“Extreme stress and thus high concentrations of stress hormone(s) cause a so-called epigenetic change: A methyl group is split off from the DNA at this point, which significantly increases the activity of FKBP5. This permanent change in the DNA is mainly produced by trauma in childhood. Thus, 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 sufferer, which often leads to depression or anxiety disorders in adulthood.”³

Holocaust survivors who developed PTSD/PTSD inherit permanently lower cortisol levels in their offspring.⁴

While in post-traumatic stress disorder cortisol levels are uniformly lower throughout the day than in healthy individuals, in (severely) depressed individuals cortisol levels are distributed rather chaotically throughout the day.⁵

While children initially have permanently elevated cortisol levels after trauma, adults with post-traumatic stress disorder have permanently depressed cortisol levels (which are accompanied by elevated dopamine and norepinephrine levels).⁶ We hypothesize that prolonged elevated cortisol levels in childhood cause an overload of stress regulation (HPA axis), which is manifested in the chronicized state after downregulation by hypocortisolism (lowered cortisol levels).

2. Borderline (emotionally unstable personality disorder of the borderline type)¶

The same pattern exists in Borderline. The causes of Borderline are multifactorial and consist of genetic disposition and these activating stressful environmental experiences.⁷⁸
Excessive stress exposure in childhood leads to chronic overactivity of the stress response system in people with a particular gene disposition by means of epigenetic changes.⁹¹⁰

The genes and neurotransmitters involved are less well understood.

Candidate genes in 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 then allows the dopamine transporters to insufficiently reuptake dopamine presynaptically. DAT 9R is associated with affective disorders and borderline.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 aggression is attributed to a decreased serotonin level, which results from a variant of the serotonin (reuptake) transporter gene activated in early childhood.¹⁴¹⁵
• 5-HT2c¹³
• In aggression problems, the MAO-A gene is further suspected.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 norepinephrine.
  COMT rs4680 enhances the degradation of dopamine and norepinephrine 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:

• Primarily, there is said to be a serotonin deficiency.
• The emotional dysregulation in borderline is attributed to increased sensitivity of the anticholinergic system.¹⁵
• In addition, noradrenergic and gabaergic imbalances are thought to be responsible for this.¹⁸
• There is likely to be further dopamine and or norepinephrine excess in the PFC and striatum.
  • Due to the increase of aggressiveness by dopamine increasing stimulants like methylphenidate or amphetamine drugs in borderline 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 also names Guillot.¹⁶

In addition, borderline patients have the following problems

• With high impulsive-aggressive levels a decreased prolactin response,
• With high anxiety and depression levels, on the other hand, have an increased prolactin response,

which could indicate an influence of the serotonin system.
With respect to cortisol, norepinephrine, and acetylcholine, no abnormalities were observed in this study.¹⁹

Interestingly, the atypical antipsychotic quetiapine, for example, on the one hand decreases the effect of dopamine by means of a D2 receptor blockade, but at the same time increases dopamine release by blocking the 5-HT-2 receptor.²⁰
D2 antagonists are also sometimes used in ADHD.

3. Aggression disorders¶

Aggression disorders are primarily associated with specific genetic variants that are

• Lower the serotonin level¹⁴ and
• Affect the enzyme monoaminooxydase-A.

MAO-A is involved in the following disorders:

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

Since the MAO-A gene is located on the X chromosome, boys and men are primarily affected.²² This is confirmed by a study that found a correlation between impulsivity and MAO-A only in males.²³

The enzyme monoaminooxydase-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 monoaminooxydase-A, doubles the risk of aggression and antisocial behavior if those affected were themselves exposed to violence (or let’s say more generally: intense stress) in their childhood. Boys with massive stress experience in the parental home developed

• To 40% violent reactions (behavioral disorder requiring treatment or conviction for violent offense before 26th birthday) if they possessed the harmless MAO-A gene variant.
• 80% of them had violence-related disorders if they had the high-risk MAO-A gene variant.²²
• Only 20% had violent tendencies if they came from loving homes.

Measurements of the brain activity of the boys with the more vulnerable MAO-A as well as with the more vulnerable 5-HTTPR gene variant showed that they responded more intensely to stress in general, with the hippocampus and amygdala being put on alert more quickly.²²
According to this view, this is at the same time a key to understanding high sensitivity.

4. Depression¶

A comparable pattern is discernible in depression. In depression, too, an interaction of genetic causes with early childhood stress experience is assumed.²⁴ The two-hit model assumes damage in early childhood, which leads to the 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 persistent problems at work or other strokes of fate, lead to depression more frequently in carriers of the serotonin (reuptake) transproter 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 vulnerable to trauma is also implicated 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 subjects, resulting in a prolonged elevation of cortisol levels. This prolonged stress response possibly leads to increased vulnerability to stress-associated diseases (Binder 2009).”³⁰* Depression can thus be understood as a disorder of stress regulation,²⁹³¹ just as we understand ADHD as a disorder of stress regulation.

While in post-traumatic stress disorder (PTSD/PTSD) cortisol levels are uniformly lower throughout the day than in healthy individuals, in (severely) depressed individuals cortisol levels are distributed rather chaotically throughout the day.³²

5. Addiction¶

The risk of alcohol addiction is also significantly co-determined by genetic dispositions.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, 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 A1 allele gene variant in severe alcoholism, no difference from 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 Also in schizophrenia, an interaction of genetic factors and environmental influences is assumed to be the cause.³⁸
Environmental influences for schizophrenia have been found to be emotional trauma, social stress, or hallucinogenic drugs.³⁹⁴⁰
Early stress, in conjunction with appropriate genes, is thought to sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation.⁴¹

7. Obsessive Compulsive Disorder¶

The genetic disposition For obsessive-compulsive disorder means that relatives of obsessive-compulsive patients have about five times the risk of also developing obsessive-compulsive disorder as unaffected individuals.⁴³

Trauma, adverse parenting, dysfunctional cognitive styles were identified as possible stressors.⁴⁵

8. Psychosis¶

In addition to 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 disturbance variables. This is true even though the symptoms of psychosis do not become apparent until after the completion of puberty,⁴⁶

9. Summary¶

The parallelism of the causes (genetic disposition plus its activation by 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 an early childhood massive stress exposure depends very much on which genetic disposition he carries. Some suffer from trauma, others from depression, and still others from ADHD - or even more at the same time (comorbidities).¹
An extensive and long-term follow-up of 733 affected persons with different personality disorders showed that the different intensity and timing of early childhood stress also contributes to the differentiation of the disorder patterns.⁴⁷ All affected individuals were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% early childhood neglect.

We assume that massive stress above a certain level injures everyone psychologically and leaves permanent damage. If there is a genetic disposition for a higher sensitivity to stress, this injury occurs more often / more likely, so that no stress loads of the extent of a traumatic intensity are needed.

See also ⇒ Chronic stress regulation problems in other disorders