Wikipedia

Genetics of post-traumatic stress disorder

The genetic influences of post-traumatic stress disorder (PTSD) are not understood well due to the limitations of any genetic study of mental illness; in that, it cannot be ethically induced in selected groups. Because of this, all studies must use naturally occurring groups with genetic similarities and differences, thus the amount of data is limited. Still, genetics play some role in the development of PTSD.

Research and potential influences

edit

Approximately 30% of the variance in PTSD is caused by genetics alone.[1] For twins exposed to combat in the Vietnam War, a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin having PTSD, as compared to dizygotic (non-identical) twins;[2] additionally, assaultive trauma (compared to non-assaultive trauma) was more likely to exacerbate these effects.[3]

There is also evidence that those with a genetically smaller hippocampus are more likely to develop PTSD following a traumatic event.[citation needed]

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.[1] Additional disorders—such as depression, schizophrenia, and bipolar disorder—share the same fundamental genetic phenotypes as PTSD.

Nature vs. nurture

edit

An individual's potential for onset of many psychological disorders is heavily affected by genetic phenotypes, yet this is not the only contributing factor. Environment plays an important role as well, especially for trauma-based disorders such as PTSD, considering that certain life experiences can trigger the activation of an underlying genetic phenotype which might have been previously dormant.[4] This can be further understood by examining the diathesis-stress model for the onset of psychological disorders, which explains that certain individuals, due to their genetic phenotypes, are more susceptible to psychological disorders when encountering the same stressful life situations or stimuli as other individuals without these same underlying genetic phenotypes.[5]

Effects of neurotransmitters and hormones

edit

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. A 2009 study[6] reported a significant interaction between three single nucleotide polymorphisms (SNP) in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults.[1] Another study[7] found an association between a specific SNP of the RGS2 gene[note 1] and PTSD symptoms in adults who experienced high environmental stress (hurricane exposure) and low social support.[1]

Studies in 2008 found that several SNPs in the FKBP5 (FK506 binding protein 5) gene interact with childhood trauma to predict severity of adult PTSD.[8][9] These findings suggest that individuals with these SNPs who are abused as children are more susceptible to PTSD as adults. This is particularly important given that FKBP5 SNPs have previously been associated with peritraumatic dissociation in medically injured children (that is, dissociation at the time of the childhood trauma),[10][11] which has itself been shown to be predictive of PTSD.[12][13] Furthermore, FKBP5 may be less expressed in those with current PTSD.[14]

In 2011, another study found that a single SNP in a putative estrogen response element on the ADCYAP1R1 gene[note 2] predicts PTSD diagnosis and symptoms in females.[15] 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.

Environmental influences

edit

PTSD is a psychiatric disorder that requires an environmental event that individuals may variously respond to. Because of this, gene-environment studies tend to be the most indicative of their effect on the probability of PTSD than studies of the main effect of the gene. Studies have demonstrated the interaction between the FKBP5 gene and childhood environment to predict the severity of PTSD. Polymorphisms in FKBP5 have been associated with peritraumatic dissociation in mentally ill children.[1]

A 2008 study of highly traumatized, inner city African Americans demonstrated that four polymorphisms of the FKBP5 gene interacted with severity of childhood abuse to predict severity of adult PTSD symptoms. This finding was partially replicated in a 2010 study, which reported that within the African American population, the TT genotype of the FKBP5 gene is associated with the highest risk of PTSD among those having experienced childhood adversity, while those with this genotype that experienced no childhood adversity had the lowest risk of PTSD.[1] In addition, alcohol dependence interacts with the FKBP5 polymorphisms and childhood adversity to increase the risk of PTSD in these populations.

A 2005 study found that FKPB5 mRNA was differentially expressed in emergency room trauma patients who were later diagnosed with PTSD. However, a 2009 study found FKPB5 mRNA expression was reduced in 9/11 survivors diagnosed with PTSD.[1]

Genetic influences

edit

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 a slower breakdown of the catecholamines. A study of Rwandan genocide survivors indicated that carriers of the Val allele 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 which may account for the high risk for PTSD experienced by this genotype.[1]

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) gene 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 than the long allele and is associated with the amygdala response for the 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 the development of PTSD even in response to a small number of traumatic events, but those with the l allele demonstrate increased rates of PTSD with increasing traumatic experiences.[1]

A genome-wide association study (GWAS) offers 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][1]

Epigenetics

edit

Epigenetic modification is an environmentally induced change in DNA that alters a gene's function rather than its structure. Its biological mechanism typically involves the methylation of cytosine within a gene, which leads to decreased transcription and thus reduced expression of the gene. Epigenetic modification can offer insight into the importance of developmental timing of stressor exposure in producing the phenotypic changes associated with PTSD.[1]

Neuroendocrine alterations seen in animal models parallel those of PTSD in humans, where 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. Although it has not been possible to monitor the state of methylation over time, the interpretation is that 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.[1]

Epigenetic mechanisms may also be relevant to the intrauterine environment. Pregnant mothers who developed PTSD from the 9/11 attacks produced infants with lower salivary cortisol levels, but 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.[1] Separate studies have reported an increased risk for PTSD and low cortisol levels in the offspring of female Holocaust survivors with PTSD.[1]

Evolutionary psychology

edit

Evolutionary psychology interprets fear responses as adaptations that may have been useful in the ancestral environment 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 post-traumatic stress disorder (and phenomena such as the Stockholm syndrome) may in part correspond to the appeasement stage and possibly the frozen immobility stage.[16][17]

There may be evolutionary explanations for differences in resilience to traumatic events. For instance, PTSD is five to ten times less common following traumatic fires than physical abuse or combat. This may be explained by events such as forest fires long being part of the evolutionary history of mammals.[18] In contrast, PTSD is much more common following modern warfare, perhaps because prolonged modern combat is an evolutionarily new development and very unlike the quick inter-group raids that are argued to have characterized the Paleolithic.[19][20]

Notes

edit
  1. ^ RGS2 encodes a protein that decreases G protein-coupled receptor signaling.
  2. ^ ADCYAP1R1 encodes pituitary adenylate cyclase-activating polypeptide type I receptor, or PAC1.

References

edit
  1. ^ a b c d e f g h i j k l m n Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B (2012). "PTSD and gene variants: New pathways and new thinking". Neuropharmacology. 62 (2): 628–637. doi:10.1016/j.neuropharm.2011.02.013. PMC 3136568. PMID 21356219.
  2. ^ True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, Nowak J (1993). "A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms". Arch. Gen. Psychiatry. 50 (4): 257–64. doi:10.1001/archpsyc.1993.01820160019002. PMID 8466386.
  3. ^ Kremen, William (31 March 2011). "Twin Studies of Posttraumatic Stress Disorder: Differentiating Vulnerability Factors from Sequelae". Neuropharmacology. 62 (2): 647–653. doi:10.1016/j.neuropharm.2011.03.012. PMC 3153636. PMID 21443892.
  4. ^ Duncan, Laramie (23 October 2018). "Robust Findings From 25 Years of PTSD Genetics Research". Current Psychiatry Reports. 20 (115): 115. doi:10.1007/s11920-018-0980-1. PMC 6209025. PMID 30350223.
  5. ^ Edmondson, Donald; Kronish, Ian M.; Wasson, Lauren Taggart; Giglio, James F.; Davidson, Karina W.; Whang, William (2014-06-01). "A test of the diathesis-stress model in the emergency department: Who develops PTSD after an acute coronary syndrome?". Journal of Psychiatric Research. 53: 8–13. doi:10.1016/j.jpsychires.2014.02.009. ISSN 0022-3956. PMC 4023688. PMID 24612925.
  6. ^ Nelson, Elliot C.; Agrawal, Arpana; et al. (19 February 2009). "Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults". Mol Psychiatry. 14 (3): 234–235. doi:10.1038/mp.2008.81. PMC 3291097. PMID 19229201.
  7. ^ Amstadter, Ananda B.; et al. (2008) [April 2009]. "Variant in RGS2 Moderates Posttraumatic Stress Symptoms following Potentially Traumatic Event Exposure". Journal of Anxiety Disorders. 23 (3): 369–373. doi:10.1016/j.janxdis.2008.12.005. PMC 2735848. PMID 19162436.
  8. ^ Newton, Phil (16 November 2008). "A gene for anxiety, depression and posttraumatic stress disorder; FKBP5". Psychology Today. Retrieved 29 November 2011.
  9. ^ 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.
  10. ^ Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Künzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Köhnlein O, Dabitz H, Brückl T, Müller N, Pfister H, Lieb R, Meuller JC, Lõhmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B (2004). "Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment". Nature Genetics. 36 (12): 1319–1325. doi:10.1038/ng1479. PMID 15565110. S2CID 21914515.
  11. ^ 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.
  12. ^ 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.
  13. ^ Schnurr PP, Lunney CA, Sengupta A (2004). "Risk factors for the development versus maintenance of posttraumatic stress disorder". J Trauma Stress. 17 (2): 85–95. CiteSeerX 10.1.1.538.7819. doi:10.1023/B:JOTS.0000022614.21794.f4. PMID 15141781. S2CID 12728307.
  14. ^ Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, Rein T, Schmeidler J, Müller-Myhsok B, Holsboer F, Buxbaum JD (24 April 2009). "Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks" (PDF). Biol Psychiatry. 66 (7): 708–11. doi:10.1016/j.biopsych.2009.02.034. hdl:2027.42/63524. PMID 19393990. S2CID 206099545.
  15. ^ Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (February 24, 2011). "Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor". Nature. 470 (7335): 492–497. Bibcode:2011Natur.470..492R. doi:10.1038/nature09856. PMC 3046811. PMID 21350482.
  16. ^ Chris Cantor (2005). Evolution and posttraumatic stress: disorders of vigilance and defence. Routledge. ISBN 978-1-58391-771-8. Retrieved 2014-01-29.
  17. ^ Cantor C, Price J (2007). "Traumatic entrapment, appeasement and complex post-traumatic stress disorder: Evolutionary perspectives of hostage reactions, domestic abuse and the Stockholm syndrome". Australian and New Zealand Journal of Psychiatry. 41 (5): 377–384. doi:10.1080/00048670701261178. PMID 17464728. S2CID 20007440.
  18. ^ Bracha 2006, section 9.1.
  19. ^ Bracha 2006, section 9.4.
  20. ^ Bracha, H. Stefan (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.
Retrieved from "https://en.wiki.x.io/w/index.php?title=Genetics_of_post-traumatic_stress_disorder&oldid=1258460918"