Current Views on the Genetic Markers of Post-Traumatic Stress Disorder

The article summarizes empirical studies on the problem of genetic predisposition to post-traumatic stress disorder. It is showed that the development of some symptoms of post-traumatic stress disorder is caused by neurobiological mechanisms, the functioning of which depends on the expression of specific genes. Differences in the effectiveness of the use of certain types of psychological assistance can also be associated with the influence of genetic factors. A review of the most relevant patterns is presented. More specifically, this is the effect of the gene of brain-derived neurotrophic factor (BDNF) as well as the genes of serotonergic (SLC6A4, SLC6A3), dopaminergic (DRD2, COMT), hypothalamic-pituitary-adrenal (FKBP5, ADCYAP1) systems on the manifestation of symptoms of post-traumatic stress disorder. Based on the results of genome-wide association studies, assumptions are made about the role of genes (RORA, NLGN1, TLL-1, PARK2, PODXL, SH3RF3, and ZDHHC14) in the pathophysiology of post-traumatic stress disorder. The issue of the applicability of genetic testing in the practice of psychological assistance to individuals with post-traumatic stress disorder is considered. The question of the applicability of genetic testing to improve the diagnosis and development of a personalized strategy for clinical and psychological intervention is discussed.

1. Baranova K.A., Rybnikova E.A., Samoilov М.О. Neirotrofin BDNF vovlekaetsya
   v formirovanie i predotvrashchenie poststressovykh psikhopatologii [Neurotrophin BDNF is involved into formation and prevention of post-stress psychopathologies]. Neirokhimiya=Neurochemistry, 2015. Vol. 32, no. 2, pp.131–139. DOI: 10.7868/ S102781331502003X (In Russ., аbstr. in Engl.)
2. Guljaeva N.V. Neirokhimiya stressa: khimiya stress-reaktivnosti i chuvstvitel'nosti
   k stressu [Stress Neurochemistry: The Chemistry of Stress Reactivity and Stress Sensitivity]. Neirokhimiya=Neurochemistry, 2018. Vol. 35, no. 2, pp. 111–114. DOI: 10.7868/ S1027813318020012 (In Russ., аbstr. in Engl.)
3. Levchuk L.A., Shmigol' M.V., Ivanova S.A. Serotoninergicheskaya sistema v patogeneze i terapii depressivnykh rasstroistv (obzor literatury) [Serotonergic system in the pathogenesis and therapy of depressive disorders (literature review)]. Sibirskii vestnik psikhiatrii i narkologii=Siberian Herald of Psychiatry and Narcology, 2012. Vol. 71, no. 2,
   pp. 75–79. (In Russ., аbstr. in Engl.)
4. Padun M.A., Tarabrina N.V. Kognitivno-lichnostnye aspekty perezhivaniya posttravmaticheskogo stressa [Cognitive-personality aspects of experiencing posttraumatic stress]. Psikhologicheskii zhurnal=Psychological Journal, 2004. Vol. 25, no. 5, pp. 5–15. (In Russ., аbstr. in Engl.)
5. Sil'kis I.G. Vozmozhnyi mekhanizm poyavleniya nochnykh koshmarov pri posttravmaticheskom stressovom rasstroistve i podkhody k ikh predotvrashcheniyu
   [A possible mechanism of nightmares occurrence in posttraumatic stress disorder and approaches to its prevention]. Neirokhimiya=Neurochemistry, 2019. Vol. 36, no. 4,
   pp. 275–291. DOI: 10.1134/S1027813319030129 (In Russ., аbstr. in Engl.)
6. Tarabrina N.V. Psikhologicheskie posledstviya stressorov vysokoi intensivnosti: posttravmaticheskii stress [Psychological consequences of stressors of high intensity]. Psikhologicheskii zhurnal=Psychological Journal, 2012. Vol. 33, no. 6, pp. 20–33. (In Russ., аbstr. in Engl.)
7. Esterbrook S.A., Orlova E.A., Karpekova T.A. et al. Cognitive-behavioral therapy of post-traumatic stress disorder (based on foreign studies) [Elektronnyi resurs]. Sovremennaya zarubezhnaya psikhologiya=Journal of Modern Foreign Psychology, 2020.
   Vol. 9, no. 1, pp. 76–84. DOI:10.17759/jmfp.2020090108. (Accessed 10.05.2020). (In Russ., аbstr. in Engl.)
8. Almli L.M., Fani N., Smith A.K. et al. Genetic approaches to understanding post-traumatic stress disorder. The International Journal of Neuropsychopharmacology, 2014. Vol. 17, no. 2. pp. 355–370. DOI: 10.1017/S1461145713001090.
9. American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 5th ed. Arlington, VA: American Psychiatric Association, 2013. 443 p.
10. Banerjee S.B., Morrison F.G., Ressler K.J. Genetic approaches for the study of PTSD: Advances and challenges. Neuroscience Letters, 2017, no. 10, pp. 139–146. DOI: 10.1016/ j.neulet.2017.02.058.
11. Breslau N. The epidemiology of posttraumatic stress disorder: what is the extent of the problem? The Journal of Clinical Psychiatry, 2001. Vol. 17, no. 62, pp. 16–22.
12. Bryant R.A., Felmingham K.L., Falconer E.M. et al. Preliminary evidence of the short allele of the serotonin transporter gene predicting poor response to cognitive behavior therapy in posttraumatic stress disorder. Biological Psychiatry, 2010. Vol. 67, no. 12.
    pp. 1217–1219. DOI: 10.1016/j.biopsych.2010.03.016.
13. Castro-Vale I., van Rossum E.F., Machado J.C. et al. Genetics of glucocorticoid regulation and posttraumatic stress disorder – What do we know? Neuroscience and Biobehavioral Reviews, 2016, no. 63, pp. 143–157. DOI: 10.1016/j.neubiorev.2016.02.005.
14. Chan Y.E., Bai Y.M., Hsu J.W. et al. Post-traumatic stress disorder and risk of Parkinson disease: a nationwide longitudinal study. American Journal of Geriatric Psychiatry, 2017, no. 25, pp. 917–923. DOI: 10.1016/j.jagp.2017.03.012.
15. Cui C., Yang W., Shi J. et al. Identification and analysis of human sex-biased MicroRNAs. Genomics Proteomics Bioinformatics, 2018. Vol. 16, no. 3, pp. 200–211. DOI: 10.1016/j.gpb.2018.03.004.
16. Felmingham K.L., Dobson-Stone C., Schofield P.R. et al. The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biological Psychiatry, 2013. Vol. 73, no. 11, pp. 1059–1063. DOI: 10.1016/j.biopsych.2012.10.033.
17. Gressier F., Calati R., Balestri M. et al. The 5-HTTLPR polymorphism and post-traumatic stress disorder: a meta-analysis. Journal of Traumatic Stress, 2013, no. 26,
    pp. 645–653. DOI: 10.1002/jts.21855.
18. Hammack S.E., May V. Pituitary adenylate cyclase activating polypeptide in stress-related disorders: Data convergence from animal and human studies. Biological Psychiatry, 2015, no. 78, pp. 167–177. DOI: 10.2026/j.biopsych.2014.12.003.
19. Keers R., Aitchison K.J. Pharmacogenetics of antidepressant response. Expert Review on Neurotherapeutics, 2011. Vol. 11, no. 1, pp. 101–125. DOI: 10.1586/ern.10.186.
20. Keesler R., Aguilar-Gaxiola S., Alonso J. et al. Trauma and PTSD in the WHO World Mental Health Surveys. European Journal of Psychotraumatology, 2017, no. 8, pp. 1353383. DOI: 10.1080/20008198.2017.1353383.
21. Kilaru V., Iyer S.V., Almli L.M. et al. Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. Translational Psychiatry, 2016, no. 6 (e820). DOI: 10.1038/tp.2016.69.
22. Koenen K.C., Uddin M., Chang S.C. et al. SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depression and Anxiety, 2011. Vol. 28, no. 8, pp. 639–647. DOI: 10.1002/da.20825.
23. Lester K.J., Eley T.C. Therapygenetics: Using genetic markers to predict response to psychological treatment for mood and anxiety disorders. Biology of Mood & Anxiety Disorders, 2013. Vol. 3, no. 1, pp. 4. DOI: 10.1186/2045-5380-3-4.
24. Li L., Bao Y., He S. et al. The association between genetic variants in the dopaminergic system and posttraumatic stress disorder: a meta-analysis. Medicine, 2016. Vol. 95, no. 11. DOI: 10.1097/MD.0000000000003074.
25. Logue M.W., Baldwin C., Guffanti G. et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Molecular Psychiatry, 2013. Vol. 18, no. 8, pp. 937–942. DOI: 10.1038/mp.2012.113.
26. Lonsdorf T.B., Ruck C., Bergstrom J. et al. The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder. BMC Psychiatry, 2010, no. 10, pp. 99. DOI: 10.1186/1471-244X-10-99.
27. McGowan P.O. Epigenomic mechanisms of early adversity and HPA dysfunction: Considerations for PTSD research. Frontiers Psychiatry, 2013, no. 4. DOI: 10.3389/fpsyt. 2013.00110.
28. Navarro-Mateu F., Escamez T., Koenen K.C. et al. Meta-analyses of the 5-HTTLPR polymorphisms and post-traumatic stress disorder. PLoS ONE, 2013. Vol. 8, no. 6. DOI: 10.1371/journal.pone.0066227.
29. Nievergelt C.M., Maihofer A.X., Klengel T. et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications, 2019. Vol. 10, no. 1. DOI: 10.1038/s41467-019-12576-w.
30. Sheerin C.M., Lind M.J., Bountress K. et al. The genetics and epigenetics of PTSD: overview, recent advances, and future directions. Current Opinion in Psychology, 2017,
    no. 14, pp. 5–11. DOI: 10.1016/j.copsyc.2016.09.003.
31. Snijders C., Krauskopf J., Pishva E. et al. Circulating Serum MicroRNAs as potential diagnostic biomarkers of posttraumatic stress disorder: A pilot study. Frontiers Genetics, 2019. Vol. 10, no. 10, pp. 1042. DOI: 10.3389/fgene.2019.01042.
32. Uddin M., Aiello A.E., Wildman D.E. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proceedings of the Natural Academy of Sciences, 2010. Vol. 107, no. 20, pp. 9470–9475. DOI: 10.1073/pnas.0910794107.
33. Valente N.L., Vallada H., Cordeiro Q. et al. Catechol-O-methyltransferase (COMT) val158met polymorphism as a risk factor for PTSD after urban violence. Journal of Molecular Neuroscience, 2011. Vol. 43, no.3, pp. 516–523. DOI: 10.1007/s12031-010-9474-2.
34. Valente N.L., Vallada H., Cordeiro Q. et al. Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. Journal of Molecular Neuroscience, 2011. Vol. 44, no. 1, pp. 59–67. DOI: 10.1007/s12031-011-9513-7.
35. Wang T. Does BDNF Val66Met polymorphism confer risk for posttraumatic stress disorder? Neuropsychobiology, 2015. Vol. 71, no. 3, pp. 149–153. DOI: 10.1159/000381352.
36. Watkins L.E., Han S., Harpaz-Rotem I. et al. FKBP5 polymorphisms, childhood abuse, and PTSD symptoms: Results from the National Health and Resilience in Veterans Study. Psychoneuroendocrinology, 2016, no. 69, pp. 98–105. DOI: 10.1016/j.psyneuen. 2016.04.001.
37. World Health Organization. Guidelines for the management of conditions specifically related to stress. Geneva: WHO, 2013. URL: https://www.ncbi.nlm.nih.gov/ books/NBK159725/ (Accessed 10.05.2020).
38. World Health Organization (2019). ICD-11 for Mortality and Morbidity Statistics. URL: https://icd.who.int/browse11/l-m/en (Accessed 10.05.2020).
39. Xie P., Kranzler H.R., Yang C. et al. Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder. Biological Psychiatry, 2013. Vol. 74, no. 9, pp. 656–663. DOI: 10.1016/j.biopsych.2013.04.013.
40. Yehuda R., Hoge C.W., McFarlane A.C. et al. Post-traumatic stress disorder. Nature Reviews Disease Primers, 2015, no. 1, pp. 15057. DOI: 10.1038/nrdp.2015.57.
41. Zannas A.S., Provençal N., Binder E.B. Epigenetics of posttraumatic stress disorder: Current Evidence, challenges, and Future Directions. Biological Psychiatry, 2015. Vol. 78, no. 5, pp. 327–335. DOI: 10.1016/j.biopsych.2015.04.003.
42. Zhang L., Benedek D.M., Fullerton C.S. et al. PTSD risk is associated with BDNF Val66Met and BDNF overexpression. Molecular Psychiatry, 2014. Vol. 19, no. 1, pp. 8–10. DOI: 10.1038/mp.2012.180.
43. Zhang L., Li X.-X., Hu X.-Z. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World Journal of Psychiatry, 2016. Vol. 6, no. 1, pp. 1–6. DOI: 10.5498/wjp.v6.i1.1.