Genetics of posttraumatic stress disorder

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The potential Genetic influences of post-traumatic stress disorder are ill understood due to the limitations of any genetic study of mental illness; in that it cannot be ethically induced in selected groups. So all studies must use naturally occurring groups with genetic similarities and difference, thus the amount of data is limited. However, Genetics play some role in the development of PTSD. Approximately 30% of the variance in PTSD is caused from genetics alone. For twin pairs exposed to combat in Vietnam, having a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin's having PTSD compared to twins that were dizygotic (non-identical twins).

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Research and potential influences

Genetics play some role in the development of PTSD. Approximately 30% of the variance in PTSD is caused from genetics alone. For twin pairs exposed to combat in Vietnam, having a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin's having PTSD compared to twins that were dizygotic (non-identical twins). [1] There is also evidence that those with a genetically smaller hippocampus are more likely to develop PTSD following a traumatic event. Research has also found that PTSD shares many genetic influences common to other psychiatric disorders. Panic and generalized anxiety disorders and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and drug dependence share greater than 40% genetic similarities. [2]

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. A recent study reported significant interactions between three polymorphisms in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults. A study found those with a specific genotype for G-protein signaling 2 (RGS2), a protein that decreases G protein-coupled receptor signaling, and high environmental stress exposure as adults and a diagnosis of lifetime PTSD. This was particularly prevalent in adults with prior trauma exposure and low social support. [2]

Recently, it has been found that several single-nucleotide polymorphisms (SNPs) in FK506 binding protein 5 (FKBP5) interact with childhood trauma to predict severity of adult PTSD. [3] [4] These findings suggest that individuals with these SNPs who are abused as children are more susceptible to PTSD as adults.

This is particularly interesting given that FKBP5 SNPs have previously been associated with peritraumatic dissociation in medically injured children (that is, dissociation at the time of the birth trauma), [5] which has itself been shown to be predictive of PTSD. [6] [7] Furthermore, FKBP5 may be less expressed in those with current PTSD. [8] Another recent study found a single SNP in a putative estrogen response element on ADCYAP1R1 (encodes pituitary adenylate cyclase-activating polypeptide type I receptor or PAC1) to predict PTSD diagnosis and symptoms in females. [9] Incidentally, this SNP is also associated with fear discrimination. The study suggests that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD.

PTSD is a psychiatric disorder that requires an environmental event that individuals may have varied responses to so gene-environment studies tend to be the most indicative of their effect on the probability of PTSD then studies of the main effect of the gene. Recent studies have demonstrated the interaction between PFBP5 and childhood environment to predict the severity of PTSD. Polymorphisms in FKBP5 have been associated with peritraumatic dissociation in mentally ill children. A study of highly traumatized African-American subjects from inner city primary-care clinics indicated 4 polymorphisms of the FKBP5 gene, each of these functional. The interaction between the polymorphisms and the severity of childhood abuse predicts the severity of the adult PTSD symptoms. A more recent study of the African-American population indicated that the TT genotype of the FKBP5 gene is associated with the highest risk of PTSD among those having experienced childhood adversity, however those with this genotype that experienced no childhood adversity had the lowest risk of PTSD. In addition alcohol dependence interacts with the FKBP5 polymorphisms and childhood adversity to increase the risk of PTSD in these populations. Emergency room expression of the FKPB5 mRNA following trauma was shown to indicate a later development of PTSD. [2]

Catechol-O-methyl transferase (COMT) is an enzyme that catalyzes the extraneuronal breakdown of catecholamines. The gene that codes for COMT has a functional polymorphism in which a valine has been replaced with a methionine at codon 158. This polymorphism has lower enzyme activity and has been tied to slower breakdown of the catecholamines. A study, of Rwandan Genocide survivors, indicated that carriers of the Val allel demonstrated the expected response relationship between the higher number of lifetime traumatic events and a lifetime diagnosis of PTSD. However, those with homozygotes for the Met/Met genotype demonstrated a high risk of lifetime PTSD independent of the number of traumatic experiences. Those with Met/Met genotype also demonstrated a reduced extinction of conditioned fear responses with may account for the high risk for PTSD experienced by this genotype. [2]

Many genes impact the limbic-frontal neurocircuitry as a result of its complexity. The main effect of the D2A1 allele of the dopamine receptor D2 (DRD2) has a strong association with the diagnosis of PTSD. The D2A1 allele has also shown a significant association to PTSD in those having engaged in harmful drinking. In addition a polymorphism in the dopamine transporter SLC6A3 gene has a significant association with chronic PTSD. A polymorphism of the serotonin receptor 2A gene has been associated with PTSD in Korean women. The short allele of the promoter region of the serotonin transporter (5-HTTLPR) has been shown to be less efficient then the long allele and is associated with the amygdala response for extinction of fear conditioning. However, the short allele is associated with a decreased risk of PTSD in a low risk environment but a high risk of PTSD in a high risk environment. The s/s genotype demonstrated a high risk for development of PTSD even in response to a small number of traumatic events, but those with the l allele demonstrate increasing rates of PTSD with increasing traumatic experiences. [2]

Genome-wide association study (GWAS) offer an opportunity to identify novel risk variants for PTSD that will in turn inform our understanding of the etiology of the disorder. Early results indicate the feasibility and potential power of GWAS to identify biomarkers for anxiety-related behaviors that suggest a future of PTSD. These studies will lead to the discovery of novel loci for the susceptibility and symptomatology of anxiety disorders including PTSD.[ dubious – discuss ] [2]

Epigenetics

Gene and environment studies alone fail to explain the importance the developmental stressor timing exposure to the phenotypic changes associated with PTSD. Epigenetic modification is the environmentally induced change in DNA that alters the function rather than the structure of the gene. The biological mechanism of epigenetic modification typically involves the methylation of cytosine within a gene that produces decreased transcription of that segment of DNA. The neuroendocrine alteration seen in animal models parallel those of PTSD in which low basal cortisol and enhanced suppression of cortisol in response to synthetic glucocorticoid becomes hereditary. Lower levels of glucocorticoid receptor (GR) mRNA have been demonstrated in the hippocampus of suicide victims with histories of childhood abuse. It has not been possible to monitor the state of methylation over time, however the interpretation is early developmental methylation changes are long-lasting and enduring. It is hypothesized that epigenetic-mediated changes in the HPA axis could be associated with an increased vulnerability to PTSD following traumatic events. These findings support the mechanism in which early life trauma strongly validates as a risk factor for PTSD development in adulthood by recalibrating the set point and stress-responsivity of the HPA axis. Studies have reported an increased risk for PTSD and low cortisol levels in the offspring of female holocaust survivors with PTSD. Epigenetic mechanisms may also be relevant to the intrauterine environment. Mothers with PTSD produced infants with lower salivary cortisol levels only if the traumatic exposure occurred during the third trimester of gestation. These changes occur via transmission of hormonal responses to the fetus leading to a reprogramming of the glucocorticoid responsivity in the offspring. [2]

Evolutionary psychology

Evolutionary psychology views different types of fears and reactions caused by fears as adaptations that may have been useful in the ancestral environment in order to avoid or cope with various threats. In general, mammals display several defensive behaviors roughly dependent on how close the threat is: avoidance, vigilant immobility, withdrawal, aggressive defense, appeasement, and finally complete frozen immobility (the last possibly to confuse a predator's attack reflex or to simulate a dead and contaminated body). PTSD may correspond to and be caused by overactivation of such fear circuits. Thus, PTSD avoidance behaviors may correspond to mammal avoidance of and withdrawal from threats. Heightened memory of past threats may increase avoidance of similar situations in the future as well as be a prerequisite for analyzing the past threat and develop better defensive behaviors if the threat should recur. PTSD hyperarousal may correspond to vigilant immobility and aggressive defense. Complex posttraumatic stress disorder (and phenomena such as the Stockholm syndrome) may in part correspond to the appeasement stage and possibly the frozen immobility stage. [10] [11]

There may be evolutionary explanations for differences in resilience to traumatic events. Thus, PTSD is rare following traumatic fire that may be explained by events such as forest fires' long being part of the evolutionary history of mammals. On the other hand, PTSD is much more common following modern warfare, which may be explained by modern warfare's being a new development and very unlike the quick inter-group raids that are argued to have characterized the paleolithic. [12]

Related Research Articles

Posttraumatic stress disorder An anxiety disorder that can develop after experiencing or witnessing a terrifying or life-threatening event

Posttraumatic stress disorder (PTSD) is a mental disorder that can develop after a person is exposed to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, or other threats on a person's life. Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in how a person thinks and feels, and an increase in the fight-or-flight response. These symptoms last for more than a month after the event. Young children are less likely to show distress, but instead may express their memories through play. A person with PTSD is at a higher risk for suicide and intentional self-harm.

Psychological trauma is damage to the mind that occurs as a result of a distressing event. Trauma is often the result of an overwhelming amount of stress that exceeds one's ability to cope, or integrate the emotions involved with that experience. Trauma may result from a single distressing experience or recurring events of being overwhelmed that can be precipitated in weeks, years, or even decades as the person struggles to cope with the immediate circumstances, eventually leading to serious, long-term negative consequences.

Gene–environment interaction Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

Complex post-traumatic stress disorder is a psychological disorder that can develop in response to prolonged, repeated experience of interpersonal trauma in a context in which the individual has little or no chance of escape. C-PTSD relates to the trauma model of mental disorders and is associated with chronic sexual, psychological and narcissistic (child) abuse and physical abuse and neglect, chronic intimate partner violence, victims of prolonged workplace or school bullying, victims of kidnapping and hostage situations, indentured servants, victims of slavery and human trafficking, sweatshop workers, prisoners of war, concentration camp survivors, residential school survivors, and defectors of cults or cult-like organizations. Situations involving captivity/entrapment can lead to C-PTSD-like symptoms, which can include prolonged feelings of terror, worthlessness, helplessness, and deformation of one's identity and sense of self.

Childhood trauma is referred to in academic literature as serious adverse childhood experiences (ACEs). Children may go through a range of experiences that classify as psychological trauma, these might include neglect, abandonment, sexual abuse, and physical abuse, parent or sibling is treated violently or there is a parent with a mental illness. These events have profound psychological, physiological, and sociological impacts and can have negative, lasting effects on health and well-being. Kaiser Permanente and the Centers for Disease Control and Prevention's 1998 study on adverse childhood experiences determined that traumatic experiences during childhood are a root cause of many social, emotional, and cognitive impairments that lead to increased risk of unhealthy self-destructive behaviors, risk of violence or re-victimization, chronic health conditions, low life potential and premature mortality. As the number of adverse experiences increases, the risk of problems from childhood through adulthood also rises. Nearly 30 years of study following the initial study has confirmed this. Many states, health providers, and other groups now routinely screen parents and children for ACEs.

Gene–environment correlation is said to occur when exposure to environmental conditions depends on an individual's genotype.

rs6295, also called C(-1019)G, is a gene variation—a single nucleotide polymorphism (SNP)—in the HTR1A gene. It is one of the most investigated SNPs of its gene. The C-allele is the most prevalent with 0.675 against the G-allele with 0.325 among Caucasian.

5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, it has been extensively investigated, e.g., in connection with neuropsychiatric disorders. A 2006 scientific article stated that "over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers" had analyzed the polymorphism. While often discussed as an example of gene-environment interaction, this contention is contested.

Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for the so-called brain-derived neurotrophic factor.

Daniel S. Schechter is an American psychiatrist known for his clinical work and research on intergenerational transmission or "communication" of violent trauma and related psychopathology involving parents and very young children. His published work in this area following the terrorist attacks on the World Trade Center in New York of September 11, 2001 led to a co-edited book entitled "September 11: Trauma and Human Bonds" (2003) and additional original articles with clinical psychologist Susan Coates that were translated into multiple languages and remain among the very first accounts of 9/11 related loss and trauma described by mental health professionals who also experienced the attacks and their aftermath Schechter observed that separation anxiety among infants and young children who had either lost or feared loss of their caregivers triggered posttraumatic stress symptoms in the surviving caregivers. These observations validated his prior work on the adverse impact of family violence on the early parent-child relationship, formative social-emotional development and related attachment disturbances involving mutual dysregulation of emotion and arousal. This body of work on trauma and attachment has been cited by prominent authors in the attachment theory, psychological trauma, developmental psychobiology and neuroscience literatures

ANKK1 protein-coding gene in the species Homo sapiens

Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ANKK1 gene. The ANKK1 is a member of an extensive family of the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways.

The C957T gene polymorphism is a synonymous mutation located within the 957th base pair of the DRD2 gene. This base pair is located in exon 7. Most synonymous mutations are silent. However, the C957T mutation is an exception to this rule. While the 957C allele codes for the same polypeptide as the 957T allele, the conformation of 957T messenger RNA differs from the conformation of 957C messenger RNA. 957T messenger RNA is less stable and more prone to degradation. As a result, dopamine D2 receptor expression is decreased among individuals who carry the 957T allele compared to individuals who carry the 957C allele.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop in certain individuals after exposure to traumatic events, such as combat and sexual assault. PTSD is commonly treated with various types of psychotherapy and pharmacotherapy.

Childbirth-related posttraumatic stress disorder is a psychological disorder that can develop in women who have recently given birth. Its symptoms are not distinct from posttraumatic stress disorder (PTSD).

Anxiety buffer disruption theory (ABDT) is an application of terror management theory to explain an individual's reaction to a traumatic event, which leads to post traumatic stress disorder. Terror management theory posits that humans, unlike any other organism, are uniquely aware that death is the inevitable outcome of life. When thoughts of death are made salient, such as when a terrorist attack carries those thoughts into the level of consciousness, humans are subject to debilitating anxiety unless it can be "buffered." Humans respond to the anxiety and dread mortality salience produces by clinging to their cultural worldview, through self-esteem and also close personal relationships. Cultural worldviews, with their cultural norms, religious beliefs and moral values infuse life with meaning. They give life a feeling of normalcy and also a feeling of control. There is no way to definitely prove one's cultural worldview, there they are fragile human constructs and must be maintained. Clinging to a cultural worldview and self-esteem buffer the anxiety connected to thoughts of mortality. When thoughts of death are salient, humans are drawn to their cultural world view which "stipulates appropriate social requirements, and standards for valued conduct, while instilling one's life with meaning, order and permanence."

Elisabeth Binder is a medical doctor and neuroscientist specializing in the study of mood and anxiety disorders. She is the director of the Department of Translational Research of the Max Planck Institute of Psychiatry in Munich, Germany. In addition to research, she is a member of the Executive Committee of the European College of Neuropsychopharmacology (ECNP).

Richard Bryant (psychologist) Australian psychologist

Professor Richard Allan Bryant is an Australian medical scientist. He is Scientia Professor of Psychology at the University of New South Wales (UNSW) and Director of the UNSW Traumatic Stress Clinic, based at UNSW and Westmead Institute for Medical Research. His main areas of research are Post Traumatic Stress Disorder (PTSD) and Prolonged Grief Disorder. On 13 June 2016 he was appointed a Companion of the Order of Australia (AC), for eminent service to medical research in the field of psychotraumatology, as a psychologist and author, to the study of Indigenous mental health, as an advisor to a range of government and international organisations, and to professional societies.

Transgenerational stress inheritance is the transmission of adverse effects of stress-exposure in parents to their offspring through epigenetic mechanisms.

Epigenetics of anxiety and stress-related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more.

Posttraumatic stress disorder (PTSD) can affect about 3.6% of the U.S. population each year, and 6.8% of the U.S. population over a lifetime. 8.4% of people in the U.S. are diagnosed with substance use disorders (SUD). Of those with a diagnosis of PTSD, a co-occurring, or comorbid diagnosis of a SUD is present in 20–35% of that clinical population.

References

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  3. ↑ Newton, Phil (16 November 2008). "A gene for anxiety, depression and posttraumatic stress disorder; FKBP5". Psychology Today. Retrieved 29 November 2011.
  4. ↑ Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ (2008). "Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults". JAMA . 299 (11): 1291–305. doi:10.1001/jama.299.11.1291. PMC   2441757 . PMID   18349090.
  5. ↑ Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, Hall E, Kaplow J, Bosquet M, Moulton S, Baldwin C (2005). "Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children". Mol Psychiatry. 10 (12): 1058–9. doi:10.1038/sj.mp.4001727. PMID   16088328.
  6. ↑ Birmes P, Brunet A, Carreras D, Ducassé JL, Charlet JP, Lauque D, Sztulman H, Schmitt L (2003). "The predictive power of peritraumatic dissociation and acute stress symptoms for posttraumatic stress symptoms: a three-month prospective study". Am J Psychiatry. 160 (7): 1337–9. doi:10.1176/appi.ajp.160.7.1337. PMID   12832251.
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  10. ↑ Chris Cantor (2005). Evolution and posttraumatic stress: disorders of vigilance and defence. Routledge. ISBN   978-1-58391-771-8 . Retrieved 2014-01-29.
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  12. ↑ Bracha HS (2006). "Human brain evolution and the "Neuroevolutionary Time-depth Principle:" Implications for the Reclassification of fear-circuitry-related traits in DSM-V and for studying resilience to warzone-related posttraumatic stress disorder" (PDF). Progress in Neuro-Psychopharmacology and Biological Psychiatry. 30 (5): 827–853. doi:10.1016/j.pnpbp.2006.01.008. PMC   7130737 . PMID   16563589.
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