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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 [[Ethics|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==

Approximately 30% of the variance in PTSD is caused by genetics alone.<ref name="Skelton 2012 628–637" /> For [[Twin|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;<ref>{{cite journal |vauthors=True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, Nowak J |title=A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms |journal=Arch. Gen. Psychiatry |volume=50 |issue=4 |pages=257–64 |year=1993 |pmid=8466386 |doi=10.1001/archpsyc.1993.01820160019002}}</ref> additionally, assaultive trauma (compared to non-assaultive trauma) was more likely to exacerbate these effects.<ref>{{Cite journal |last=Kremen |first=William |date=31 March 2011 |title=Twin Studies of Posttraumatic Stress Disorder: Differentiating Vulnerability Factors from Sequelae |journal=Neuropharmacology |volume=62 |issue=2 |pages=647–653 |doi=10.1016/j.neuropharm.2011.03.012 |pmid=21443892 |pmc=3153636 }}</ref>

There is also evidence that those with a genetically smaller [[hippocampus]] are more likely to develop PTSD following a traumatic event.{{Citation needed|date=September 2023}}

Research has also found that PTSD shares many genetic influences common to other psychiatric disorders. [[Panic disorder|Panic]] and [[Generalized anxiety disorder|generalized anxiety disorders]] and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and [[drug dependence]] share greater than 40% genetic similarities.<ref name="Skelton 2012 628–637">{{cite journal |vauthors=Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B |title=PTSD and gene variants: New pathways and new thinking |journal=Neuropharmacology |volume=62 |issue=2 |pages=628–637 |year=2012 |pmid=21356219 |pmc=3136568 |doi=10.1016/j.neuropharm.2011.02.013}}</ref> Additional disorders—such as [[Depression (mood)|depression]], [[schizophrenia]], and [[bipolar disorder]]—share the same fundamental genetic phenotypes as PTSD.

=== Nature vs. nurture ===
An individual's potential for onset of many psychological disorders is heavily affected by genetic [[Phenotype|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.<ref>{{Cite journal |last=Duncan |first=Laramie |date=23 October 2018 |title=Robust Findings From 25 Years of PTSD Genetics Research |journal=Current Psychiatry Reports |volume=20 |issue=115 |page=115 |doi=10.1007/s11920-018-0980-1 |pmid=30350223 |pmc=6209025 }}</ref> This can be further understood by examining the [[Diathesis–stress model|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.<ref>{{Cite journal |last1=Edmondson |first1=Donald |last2=Kronish |first2=Ian M. |last3=Wasson |first3=Lauren Taggart |last4=Giglio |first4=James F. |last5=Davidson |first5=Karina W. |last6=Whang |first6=William |date=2014-06-01 |title=A test of the diathesis-stress model in the emergency department: Who develops PTSD after an acute coronary syndrome? |journal=Journal of Psychiatric Research |language=en |volume=53 |pages=8–13 |doi=10.1016/j.jpsychires.2014.02.009 |issn=0022-3956 |pmc=4023688 |pmid=24612925}}</ref>

=== Effects of neurotransmitters and hormones ===
[[Gamma-aminobutyric acid]] (GABA) is the major inhibitory [[neurotransmitter]] in the brain. A 2009 study<ref>{{Cite journal |last1=Nelson |first1=Elliot C. |last2=Agrawal |first2=Arpana |last3=Pergadia |first3=Michele L. |display-authors=2 |date=19 February 2009 |title=Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults |journal=Mol Psychiatry |volume=14 |issue=3 |pages=234–235 |doi=10.1038/mp.2008.81|pmid=19229201 |pmc=3291097 }}</ref> reported a significant interaction between three [[Single-nucleotide polymorphism|single nucleotide polymorphisms]] (SNP) in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults.<ref name="Skelton 2012 628–637" /> Another study<ref>{{Cite journal |last1=Amstadter |first1=Ananda B. |last2=Koenen |first2=Karestan C. |last3=Ruggiero |first3=Kenneth J. |last4=Acierno |first4=Ron |last5=Galea |first5=Sandro |last6=Kilpatrick |first6=Dean G. |last7=Gelernter |first7=Joel |display-authors=1 |orig-date=April 2009 |title=Variant in RGS2 Moderates Posttraumatic Stress Symptoms following Potentially Traumatic Event Exposure |journal=Journal of Anxiety Disorders |date=2008 |volume=23 |issue=3 |pages=369–373|doi=10.1016/j.janxdis.2008.12.005 |pmid=19162436 |pmc=2735848 }}</ref> found an association between a specific SNP of the ''[[RGS2]]'' gene{{NoteTag|''RGS2'' encodes a protein that decreases [[G protein-coupled receptor]] signaling.}} and PTSD symptoms in adults who experienced high environmental stress (hurricane exposure) and low social support.<ref name="Skelton 2012 628–637" />

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.<ref>{{cite web |last=Newton |first=Phil |date=16 November 2008 |url=http://www.psychologytoday.com/blog/mouse-man/200811/gene-anxiety-depression-and-posttraumatic-stress-disorder-fkbp5 |title=A gene for anxiety, depression and posttraumatic stress disorder; FKBP5 |publisher=Psychology Today |access-date=29 November 2011}}</ref><ref>{{cite journal |vauthors=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 |title=Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults |journal=[[JAMA (journal)|JAMA]] |volume=299 |issue=11 |pages=1291–305 |year=2008 |pmid=18349090 |pmc=2441757 |doi=10.1001/jama.299.11.1291}}</ref> 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 [[wikt:peritraumatic|peritraumatic]] dissociation in medically injured children (that is, [[dissociation (psychology)|dissociation]] at the time of the childhood trauma),<ref>{{cite journal |vauthors=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 |title=Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment |journal=Nature Genetics |volume=36 |issue=12 |pages=1319–1325 |year=2004 |pmid=15565110 |doi=10.1038/ng1479|s2cid=21914515 }}</ref><ref>{{cite journal |vauthors=Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, Hall E, Kaplow J, Bosquet M, Moulton S, Baldwin C |title=Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children |journal=Mol Psychiatry |volume=10 |issue=12 |pages=1058–9 |year=2005 |pmid=16088328 |doi=10.1038/sj.mp.4001727|doi-access=free }}</ref> which has itself been shown to be predictive of PTSD.<ref>{{cite journal |vauthors=Birmes P, Brunet A, Carreras D, Ducassé JL, Charlet JP, Lauque D, Sztulman H, Schmitt L |title=The predictive power of peritraumatic dissociation and acute stress symptoms for posttraumatic stress symptoms: a three-month prospective study |journal=Am J Psychiatry |volume=160 |issue=7 |pages=1337–9 |year=2003 |pmid=12832251 |doi=10.1176/appi.ajp.160.7.1337}}</ref><ref name="jtraumastress">{{cite journal |vauthors=Schnurr PP, Lunney CA, Sengupta A |title=Risk factors for the development versus maintenance of posttraumatic stress disorder |journal=J Trauma Stress |volume=17 |issue=2 |pages=85–95 |year=2004 |pmid=15141781 |doi=10.1023/B:JOTS.0000022614.21794.f4|citeseerx=10.1.1.538.7819 |s2cid=12728307 }}</ref> Furthermore, FKBP5 may be less [[gene expression|expressed]] in those with current PTSD.<ref>{{cite journal |vauthors=Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, Rein T, Schmeidler J, Müller-Myhsok B, Holsboer F, Buxbaum JD |title=Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks |journal=Biol Psychiatry |volume=66 |issue=7 |pages=708–11 |date=24 April 2009 |pmid=19393990 |doi=10.1016/j.biopsych.2009.02.034|hdl=2027.42/63524 |s2cid=206099545 |url=https://deepblue.lib.umich.edu/bitstream/2027.42/63524/1/Yehuda_Gene%20expression_2009.pdf |hdl-access=free }}</ref>

In 2011, another study found that a single SNP in a putative [[estrogen response element]] on the ''[[ADCYAP1R1]]'' gene{{NoteTag|''ADCYAP1R1'' encodes pituitary adenylate cyclase-activating polypeptide type I receptor, or PAC1.}} predicts PTSD diagnosis and symptoms in females.<ref>{{cite journal |vauthors=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 |title=Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor |journal=Nature |volume=470 |issue=7335 |pages=492–497 |date=February 24, 2011 |pmid=21350482 |pmc=3046811 |doi=10.1038/nature09856 |bibcode=2011Natur.470..492R }}</ref> 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 ===
PTSD is a [[psychiatric disorder]] that requires an environmental event that individuals may variously respond to. Because of this, [[gene-environment interaction|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. [[Polymorphism (biology)|Polymorphisms]] in ''FKBP5'' have been associated with peritraumatic dissociation in mentally ill children.<ref name="Skelton 2012 628–637" />

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.<ref name="Skelton 2012 628–637" /> 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 [[September 11 attacks|9/11]] survivors diagnosed with PTSD.<ref name="Skelton 2012 628–637" />

=== Genetic influences ===
[[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.<ref name="Skelton 2012 628–637" />

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.<ref name="Skelton 2012 628–637" />

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|date=May 2013}}<ref name="Skelton 2012 628–637" />

== Epigenetics ==
{{One source|date=September 2023|section}}
[[Epigenetics|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 (biology)|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.<ref name="Skelton 2012 628–637" />

[[neuroendocrinology|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.<ref name="Skelton 2012 628–637" />

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.<ref name="Skelton 2012 628–637" /> Separate studies have reported an increased risk for PTSD and low cortisol levels in the offspring of female [[The Holocaust|Holocaust]] survivors with PTSD.<ref name="Skelton 2012 628–637" />

== Evolutionary psychology ==
[[Evolutionary psychology]] interprets fear responses as [[adaptation]]s that may have been useful in the ancestral environment to avoid or cope with various threats. In general, [[mammal]]s 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 [[Fight-or-flight response|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.<ref name="Cantor2005">{{cite book |author=Chris Cantor |title=Evolution and posttraumatic stress: disorders of vigilance and defence |url=https://books.google.com/books?id=yBavaOGUd_MC&pg=PR3 |year=2005 |publisher=Routledge |isbn=978-1-58391-771-8 |access-date=2014-01-29}}</ref><ref>{{cite journal |vauthors=Cantor C, Price J |title=Traumatic entrapment, appeasement and complex post-traumatic stress disorder: Evolutionary perspectives of hostage reactions, domestic abuse and the Stockholm syndrome |journal=Australian and New Zealand Journal of Psychiatry |volume=41 |issue=5 |pages=377–384 |year=2007 |pmid=17464728 |doi=10.1080/00048670701261178|s2cid=20007440 }}</ref>

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.{{Sfn|Bracha|2006|loc=section 9.1}} 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]].{{Sfn|Bracha|2006|loc=section 9.4}}<ref name=":0">{{cite journal |author=Bracha |first=H. Stefan |year=2006 |title=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 |url=http://cogprints.org/5013/1/2006_P.N.P._Neuro-evolution_of_fear_circuit_disorders.pdf |journal=Progress in Neuro-Psychopharmacology and Biological Psychiatry |volume=30 |issue=5 |pages=827–853 |doi=10.1016/j.pnpbp.2006.01.008 |pmc=7130737 |pmid=16563589}}</ref>

== Notes ==
{{Notefoot}}

==References==
<references />

[[Category:Genetics]]
[[Category:Post-traumatic stress disorder]]

Genetics of post-traumatic stress disorder - История изменений

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