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
- Alcoholism35: threefold higher occurrence of A1 allele gene variant in severe alcoholism, no difference from control group in mild alcoholism
-
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
Single genes in schizophrenia
Among other things, the gene DTNBP1 is called Susceptibility-Gene. It is located on chromosome 6 in region 22.3 and encodes the protein dysbindin-1. In particular, the single base polymorphisms rs3213207 with P = 0.034, mainly for the heterozygous genotype A/G and rs2619538 lead to an increased susceptibility to schizophrenia.
COMT rs4680, which is involved in schizophrenia, enhances the degradation of dopamine and norepinephrine by producing a more active and thermally stable catechol-O-methyltransferase enzyme. 42 This causes higher schizotypal symptoms.
This can be reconciled with the recent dopamine hypothesis, according to which the positive symptoms of schizophrenia are not caused by a generally increased level of dopamine in the frontal cortex (and especially in the nucleus accumbens), but by an increased activity (firing rate) of the mesolimbic system, which in turn is caused or influenced by a lack of dopamine in the ventral tegmentum.42
Similarly, the COMT-Val158Val gene variant is likely to correlate with schizophrenia due to increased dopamine degradation in the PFC (compared to COMT-Met158Met), resulting in lower dopamine levels in the PFC, and concomitant higher dopamine levels in the striatum.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
To date, only the glutamate transporter gene variant SLC1A1 has been found to be dispositional.44
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
Coolidge, Thede, Jang (2001): Heritability of personality disorders in childhood: a preliminary investigation. J Pers Disord. 2001 Feb;15(1):33-40. ↥ ↥
Skodol, Gunderson, Shea, McGlashan, Morey, Sanislow, Bender, Grilo, Zanarini, Yen, Pagano, Stout (2005): THE COLLABORATIVE LONGITUDINAL PERSONALITY DISORDERS STUDY (CLPS): OVERVIEW AND IMPLICATIONS, J Pers Disord. 2005 Oct; 19(5): 487–504. doi: 10.1521/pedi.2005.19.5.487; PMCID: PMC3289284; NIHMSID: NIHMS349849, Kapitel: ANTECEDENTS ↥
Klengel, Max Plank Institut für Psychiatrie, München, n = 2000 ↥ ↥ ↥
Yehuda, Teicher, Seckl, Grossman, Morris, Bierer (2007): Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring of holocaust survivors. Arch Gen Psychiatry. 2007 Sep;64(9):1040-8. ↥
Yehuda, Teicher, Trestman, Levengood, Siever (1996): Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996 Jul 15;40(2):79-88. N = 15, 14 und 15 ↥
Pervanidou (2008): Biology of post-traumatic stress disorder in childhood and adolescence. J Neuroendocrinol. 2008 May;20(5):632-8. doi: 10.1111/j.1365-2826.2008.01701.x. Epub 2008 Mar 15. ↥
Siever, Torgersen, Gunderson, Livesley, Kendler (2002): The borderline diagnosis III: identifying endophenotypes for genetic studies; Biological Psychiatry; Volume 51, Issue 12, 15 June 2002, Pages 964–968 ↥
Bozzatello, Bellino, Bosia, Rocca (2019): Early Detection and Outcome in Borderline Personality Disorder. Front Psychiatry. 2019 Oct 9;10:710. doi: 10.3389/fpsyt.2019.00710. eCollection 2019. ↥ ↥
http://www.neurologen-und-psychiater-im-netz.org/psychiatrie-psychosomatik-psychotherapie/stoerungen-erkrankungen/borderline-stoerung/ursachen/ ↥
Klossika, Schmahl, Bohus (2007): Wenn der Schmerz nicht mehr weh tut. Was ereignet sich im Körper, wenn Menschen selbst schwerste Verletzungen nicht spüren? Uni Heidelberg ↥
Joyce, McHugh, Light, Rowe, Miller, Kennedy (2009): Relationships between angry-impulsive personality traits and genetic polymorphisms of the dopamine transporter; Biol Psychiatry. 2009 Oct 15;66(8):717-21. doi: 10.1016/j.biopsych.2009.03.005. Epub 2009 Apr 15. ↥
Grant et al (2013); Januar 2013, Seite 140, in: Smillie, Wacker (Hrsg): Dopaminergic Foundations of Personality and Individual Differences ↥ ↥ ↥ ↥ ↥
Maier, Hawellek, Genetik, S. 74, in: Dulz, Herpertz, Kernberg, Sachsse (2000/2011): Handbuch der Borderline-Störungen, Schattauer, 2. Auflage ↥ ↥ ↥
Siever, Torgersen, Gunderson, Livesley, Kendler (2002): The borderline diagnosis III: identifying endophenotypes for genetic studies; Biological Psychiatry; Volume 51, Issue 12, 15 June 2002, Pages 964–968, Seite 9 ↥ ↥
Skodol, Sievera, Livesleya, Gundersona, Pfohla, Widigera (2002): The borderline diagnosis II: biology, genetics, and clinical course; Biological Psychiatry; Volume 51, Issue 12, 15 June 2002, Pages 951–963 ↥ ↥
Guillot (2012): Genetic associations with borderline personality disorder and related traits and behaviors; Dissertation, UNIVERSITY OF SOUTHERN MISSISSIPPI ↥ ↥ ↥ ↥
Gschwendtner (2013): Von den Genen zum Verhalten: Der Einfluss des COMT Val158Met Polymorphismus auf visuell-räumliche Aufmerksamkeitslenkung bei emotionalen Verarbeitungsprozessen; Dissertation, Universität Würzburg ↥
Friedel (2004): Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis; Neuropsychopharmacology (2004) 29, 1029–1039, mwNw. ↥ ↥
Parisa, Zweig-Frank, Ying Kin, Schwartz, Steiger, Nair (2004): Neurobiological correlates of diagnosis and underlying traits in patients with borderline personality disorder compared with normal controls; Psychiatry Research; Volume 121, Issue 3, 1 January 2004, Pages 239–252; n = 55 ↥
Berndt (2013): Resilienz, S. 135 ↥ ↥
Berndt (2013): Resilienz, S. 136 ↥ ↥ ↥ ↥
Liu, Guan, Chen, Ji, Li, Li, Qian, Yang, Glatt, Faraone, Wang (2011): Association analyses of MAOA in Chinese Han subjects with attention-deficit/hyperactivity disorder: family-based association test, case-control study, and quantitative traits of impulsivity. Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156B(6):737-48. doi: 10.1002/ajmg.b.31217. Epub 2011 Jul 14. ↥
Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper, Moleküle. Seite 287 ↥
Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper, Moleküle. Seiten293 ↥
Dow-Edwards, MacMaster, Peterson, Niesink, Andersen, Braams (2019): Experience during adolescence shapes brain development: From synapses and networks to normal and pathological behavior. Neurotoxicol Teratol. 2019 Sep 7;76:106834. doi: 10.1016/j.ntt.2019.106834. ↥
Caspi, Sugden, Moffitt, Taylor, Craig, Harrington, McClay, Mill, Martin, Braithwaite, Poulton: Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene; Vol. 301, Issue 5631, pp. 386-389; DOI: 10.1126/science.1083968, zitiert von Flügge (2012), Neurotransmitterhypothesen, Seite 116 in: Gründer, Benkert (Hrsg.) Handbuch der Psychopharmakotherapie ↥
Berndt (2013): Resilienz, S. 133 ↥
Ising (2012) Stresshormonregulation und Depressionsrisiko – Perspektiven für die antidepressive Behandlung; Forschungsbericht 2012 – Max-Planck-Institut für Psychiatrie ↥ ↥
Rampp (2014): Einfluss eines Polymorphismus im FKBP5-Gen (rs1360780) auf Antidepressivatherapie sowie auf den Effekt einer algorithmusgestützten Behandlung: eine Studie aus dem German Algorithm Project (Dissertation), Seite 72 ↥
Anacker (2014): Adult hippocampal neurogenesis in depression: behavioral implications and regulation by the stress system. Curr Top Behav Neurosci. 2014;18:25-43. doi: 10.1007/7854_2014_275. ↥
Yehuda, Teicher, Trestman, Levengood, Siever (1996): Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996 Jul 15;40(2):79-88. n = 44 ↥
Wagner (2013): Einfluss von sozialen und familiären Faktoren auf Schweregrad und Verlauf einer Alkoholabhängigkeit, Dissertation, Seite 7 ff ↥
Edel, Vollmoeller (2006): Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen, Seite 109 mwN ↥
Noble (1998): The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes. Alcohol. 1998 Jul;16(1):33-45. ↥ ↥ ↥ ↥
Edel, Vollmoeller (2006): Attention-deficit/hyperactivity disorder in adults](https://www.springer.com/de/book/9783540254010), page 109 mwN ↥ ↥ ↥
Vogt (2015): Chromosomale und genetische Ursachen Juveniler Schizophrenie: Prävalenzuntersuchung der Mikrodeletion 22q11.2 und der CHRNA4-776ins3-Mutation, Dissertation, Seite 12 ↥
Stiehl (2015): Genetische Ursachen der Schizophrenie: die Bedeutung von Veränderungen im Dysbindin-1-Gen (DTNBP1). Dissertation ↥
Möller, Laux, Deister (2009): Psychiatrie und Psychotherapie. 4. Auflage, Thieme, Seiten 139-167, zitiert nach Vogt (2015): Chromosomale und genetische Ursachen Juveniler Schizophrenie: Prävalenzuntersuchung der Mikrodeletion 22q11.2 und der CHRNA4-776ins3-Mutation, Dissertation, Seite 8 ↥
Howes, McCutcheon, Owen, Murray (2017): The role of genes, stress and dopamine in the development of schizophrenia; Biol Psychiatry. 2017 Jan 1; 81(1): 9–20. Published online 2016 Aug 6. doi: 10.1016/j.biopsych.2016.07.014, PMCID: PMC5675052; EMSID: EMS74692 ↥
Simpson, Morud, Winiger, Biezonski, Zhu, Bach, Malleret, Polan, Ng-Evans, Phillips, Kellendonk, Kandel (2014): Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum; Learn Mem. 2014 Apr; 21(4): 205–214. Published online 2014 Apr. doi: 10.1101/lm.032094.113, PMCID: PMC3966542 ↥ ↥
Grant et al (2013); Januar 2013, Seite 141, in: Dopaminergic Foundations of Personality and Individual Differences, Smillie, Wacker (Hrsg). ↥ ↥
Endrass, Riesel (2013): Endophänotypen der Zwangsstörung; Übersichtsarbeit; Zeitschrift für Psychiatrie, Psychologie und Psychotherapie, 61 (3), 2013, 155–165; DOI 10.1024/1661-4747/a000154 ↥
Arnold, Sicard, Burroughs, Kennedy (2006): Glutamate Transporter Gene SLC1A1 Associated With Obsessive-compulsive Disorder; Article in Archives of General Psychiatry 63(7):769-76; DOI: 10.1001/archpsyc.63.7.769 ↥
Endrass, Riesel (2013): Endophänotypen der Zwangsstörung; Übersichtsarbeit; Zeitschrift für Psychiatrie, Psychologie und Psychotherapie, 61 (3), 2013, 155–165; DOI 10.1024/1661-4747/a000154, S. 156 ↥
Lesting (2005): Adaptive Reifung von Dopamin und Serotonin im Nucleus accumbens, der integrativen Schnittebene zwischen Emotion und Bewegung: Isolationsaufzucht und Methamphetamin-Intoxikation als Induktoren einer gestörten Reifung bei Meriones unguiculatus, Seite 3, unter Bezug auf Weinberger, Lipska (1995): Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground. Schizophr. Res. Vol. 16(2): 87-110. ↥
Skodol, Gunderson, Shea, McGlashan, Morey, Sanislow, Bender, Grilo, Zanarini, Yen, Pagano, Stout (2005): THE COLLABORATIVE LONGITUDINAL PERSONALITY DISORDERS STUDY (CLPS): OVERVIEW AND IMPLICATIONS, J Pers Disord. 2005 Oct; 19(5): 487–504. doi: 10.1521/pedi.2005.19.5.487; PMCID: PMC3289284; NIHMSID: NIHMS349849, im Kapitel: ANTECEDENTS ↥