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Current Psychiatry Reports

, Volume 12, Issue 4, pp 313–326 | Cite as

Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies

  • Marilyn C. Cornelis
  • Nicole R. Nugent
  • Ananda B. Amstadter
  • Karestan C. KoenenEmail author
Article

Abstract

Post-traumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder that constitutes a major health care burden. Despite evidence supporting a genetic predisposition to PTSD, the precise genetic loci remain unclear. Herein we review the current state and limitations of genetic research on PTSD. Although recent years have seen an exponential increase in the number of studies examining the influence of candidate genes on PTSD diagnosis and symptomatology, most studies have been characterized by relatively low rates of PTSD, with apparent inconsistencies in gene associations linked to marked differences in methodology. We further discuss how current advances in the genetics field can be applied to studies of PTSD, emphasizing the need to adapt a genome-wide approach that facilitates discovery rather than hypothesis testing. Genome-wide association studies offer the best opportunity to identify novel “true” risk variants for the disorder that in turn has the potential to inform our understanding of PTSD etiology.

Keywords

Post-traumatic stress disorder Trauma Genetics Genome-wide association Gene–environment interaction 

Notes

Acknowledgments

Dr. Cornelis is a recipient of a Canadian Institutes of Health Research Fellowship.

Dr. Nugent is supported by National Institute of Mental Health grant K01 MH087240.

Dr. Amstadter is supported by National Institutes of Health grants K12HD055885 and KL2RR029880.

Dr. Koenen is supported by National Institutes of Health grants K08MH070627-06 and R01MH078928-03 and a Junior Faculty Sabbatical from the Harvard University School of Public Health.

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4. Washington, DC: American Psychiatric Association; 1994.Google Scholar
  2. 2.
    Kessler RC, Berglund P, Demler O, et al.: Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005, 62:593–602.CrossRefPubMedGoogle Scholar
  3. 3.
    Kessler RC: Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry 2000, 61(Suppl 5):4–12; discussion 13–14.PubMedGoogle Scholar
  4. 4.
    Breslau N: Epidemiologic studies of trauma, posttraumatic stress disorder, and other psychiatric disorders. Can J Psychiatry 2002, 47:923–929.PubMedGoogle Scholar
  5. 5.
    Kessler RC, Sonnega A, Bromet E, et al.: Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995, 52:1048–1060.PubMedGoogle Scholar
  6. 6.
    Roberts AL, Gilman SE, Breslau J, et al.: Race/ethnic differences in exposure to traumatic events, development of post-traumatic stress disorder, and treatment seeking for post-traumatic stress disorder in the United States. Psychol Med 2010, 29:1–13.CrossRefGoogle Scholar
  7. 7.
    Slater E, Slater P: A heuristic theory of neurosis. In Man, Mind & Heredity: Selected Papers of Eliot Slater on Psychiatry and Genetics. Edited by Sheilds J, Gottesman I. Baltimore, MD: Johns Hopkins Press; 1944:216–227.Google Scholar
  8. 8.
    True WR, Rice J, Eisen SA, et al.: A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 1993, 50:257–264.PubMedGoogle Scholar
  9. 9.
    Stein MB, Jang KL, Taylor S, et al.: Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002, 159:1675–1681.CrossRefPubMedGoogle Scholar
  10. 10.
    • Amstadter AB, Nugent NR, Koenen KC: Genetics of PTSD: fear conditioning as a model for future research. Psychiatr Ann 2009, 39:358–367. This article provides a comprehensive review of biological pathways and genes implicated in PTSD development.CrossRefPubMedGoogle Scholar
  11. 11.
    Koenen KC: Genetics of posttraumatic stress disorder: review and recommendations for future studies. J Trauma Stress 2007, 20:737–750.CrossRefPubMedGoogle Scholar
  12. 12.
    Comings DE, Comings BG, Muhleman D, et al.: The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991, 266:1793–1800.CrossRefPubMedGoogle Scholar
  13. 13.
    Comings DE, Muhleman D, Gysin R: Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol Psychiatry 1996, 40:368–372.CrossRefPubMedGoogle Scholar
  14. 14.
    Gelernter J, Southwick S, Goodson S, et al.: No association between D2 dopamine receptor (DRD2) “A” system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Biol Psychiatry 1999, 45:620–625.CrossRefPubMedGoogle Scholar
  15. 15.
    Young RM, Lawford BR, Noble EP, et al.: Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol 2002, 37:451–456.PubMedGoogle Scholar
  16. 16.
    Voisey J, Swagell CD, Hughes IP, et al.: The DRD2 gene 957C > T polymorphism is associated with posttraumatic stress disorder in war veterans. Depress Anxiety 2009, 26:28–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Segman RH, Cooper-Kazaz R, Macciardi F, et al.: Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 2002, 7:903–907.CrossRefPubMedGoogle Scholar
  18. 18.
    Drury SS, Theall KP, Keats BJ, Scheeringa M: The role of the dopamine transporter (DAT) in the development of PTSD in preschool children. J Trauma Stress 2009, 22:534–539.PubMedGoogle Scholar
  19. 19.
    Dragan WL, Oniszczenko W: The association between dopamine D4 receptor exon III polymorphism and intensity of PTSD symptoms among flood survivors. Anxiety Stress Coping 2009, 22:483–495.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang E, Ding YC, Flodman P, et al.: The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 2004, 74:931–944.CrossRefPubMedGoogle Scholar
  21. 21.
    Lee HJ, Lee MS, Kang RH, et al.: Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety 2005, 21:135–139.CrossRefPubMedGoogle Scholar
  22. 22.
    Kolassa IT, Ertl V, Eckart C, et al.: Association study of trauma load and SLC6A4 promoter polymorphism in posttraumatic stress disorder: evidence from survivors of the Rwandan genocide. J Clin Psychiatry 2010 Apr 6 (Epub ahead of print).Google Scholar
  23. 23.
    •• Kilpatrick DG, Koenen KC, Ruggiero KJ, et al.: The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J Psychiatry 2007, 164:1693–1699. This was the first study reporting a G × E interaction for risk of PTSD. The inferred low expression ‘s’ variant of the 5-HTTLPR increased risk of post-hurricane PTSD only under conditions of high environmental stress exposure (high hurricane exposure and low social support).CrossRefPubMedGoogle Scholar
  24. 24.
    •• Koenen KC, Aiello AE, Bakshis E, et al.: Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. Am J Epidemiol 2009, 169:704–711. Using the same study population of Kilpatrick et al. [23••], this more recent study reported a similar G × E interaction when a high-risk environment was defined by high county-level crime rate and county-level unemployment rate, re-emphasizing the potential modifying effect of physical or social stress on genetic susceptibility to PTSD.CrossRefPubMedGoogle Scholar
  25. 25.
    Lee H, Kwak S, Paik J, et al.: Association between serotonin 2A receptor gene polymorphism and posttraumatic stress disorder. Psychiatry Investig 2007, 4:104–108.Google Scholar
  26. 26.
    • Thakur GA, Joober R, Brunet A: Development and persistence of posttraumatic stress disorder and the 5-HTTLPR polymorphism. J Trauma Stress 2009, 22:240–243. Despite its small sample size, this study supports the notion that (genetic) factors influencing the onset of PTSD may differ from those that influence chronicity or recovery from the disorder once it develops.CrossRefPubMedGoogle Scholar
  27. 27.
    Xie P, Kranzler HR, Poling J, et al.: Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry 2009, 66:1201–1209.CrossRefPubMedGoogle Scholar
  28. 28.
    Grabe HJ, Spitzer C, Schwahn C, et al.: Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. Am J Psychiatry 2009, 166:926–933.CrossRefPubMedGoogle Scholar
  29. 29.
    Mellman TA, Alim T, Brown DD, et al.: Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population. Depress Anxiety 2009, 26:993–997.CrossRefPubMedGoogle Scholar
  30. 30.
    Sayin A, Kucukiyildirim S, Akar T, et al.: A prospective study of serotonin transporter gene promoter (5-HTT gene linked polymorphic region) and intron 2 (variable number of tandem repeats) polymorphisms as predictors of trauma response to mild physical injury. DNA Cell Biol 2010, 29:71–77.CrossRefPubMedGoogle Scholar
  31. 31.
    Heils A, Teufel A, Petri S, et al.: Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect 1995, 102:247–254.CrossRefPubMedGoogle Scholar
  32. 32.
    Nakamura M, Ueno S, Sano A, Tanabe H: The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000, 5:32–38.CrossRefPubMedGoogle Scholar
  33. 33.
    Bachmann AW, Sedgley TL, Jackson RV, et al.: Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology 2005, 30:297–306.CrossRefPubMedGoogle Scholar
  34. 34.
    Lappalainen J, Kranzler HR, Malison R, et al.: A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 2002, 59:825–831.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang H, Ozbay F, Lappalainen J, et al.: Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:387–393.CrossRefPubMedGoogle Scholar
  36. 36.
    Lee H, Kang R, Lim S, et al.: No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and post-traumatic stress disorder. Stress Health 2006, 22:115–119.CrossRefGoogle Scholar
  37. 37.
    Mustapic M, Pivac N, Kozaric-Kovacic D, et al.: Dopamine beta-hydroxylase (DBH) activity and -1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2007, 144B:1087–1089.CrossRefPubMedGoogle Scholar
  38. 38.
    Binder EB, Bradley RG, Liu W, et al.: Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008, 299:1291–1305.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Xie P, Kranzler HR, Poling J, et al.: Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology 2010 Apr 14 (Epub ahead of print). Xie et al. and Binder et al. [38] present complementary studies supporting the role childhood trauma experiences plays in modifying genetic predisposition to PTSD in adults.Google Scholar
  40. 40.
    Lu AT, Ogdie MN, Jarvelin MR, et al.: Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:1488–1494.CrossRefPubMedGoogle Scholar
  41. 41.
    Nelson EC, Agrawal A, Pergadia ML, et al.: Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Mol Psychiatry 2009, 14:234–235.CrossRefPubMedGoogle Scholar
  42. 42.
    Kolassa IT, Kolassa S, Ertl V, et al.: The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Biol Psychiatry 2010, 67:304–308.CrossRefPubMedGoogle Scholar
  43. 43.
    Freeman T, Roca V, Guggenheim F, et al.: Neuropsychiatric associations of apolipoprotein E alleles in subjects with combat-related posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci 2005, 17:541–543.PubMedGoogle Scholar
  44. 44.
    Amstadter AB, Koenen KC, Ruggiero KJ, et al.: Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure. J Anxiety Disord 2009, 23:369–373.CrossRefPubMedGoogle Scholar
  45. 45.
    Schork NJ, Murray SS, Frazer KA, Topol EJ: Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev 2009, 19:212–219.CrossRefPubMedGoogle Scholar
  46. 46.
    Hindorff LA, Junkins HA, Mehta JP, Manolio T: A catalogue of published genome-wide association studies. Available at http://www.genome.gov/gwastudies. Accessed January 2010.
  47. 47.
    • Psychiatric GWAS Consortium Coordinating Committee, Cichon S, Craddock N, et al.: Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009, 166:540–556. This is suggested reading for a more comprehensive review of GWAS in the context of psychiatric disorders. The PGC Coordinating Committee discusses the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses.CrossRefPubMedGoogle Scholar
  48. 48.
    •• Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium, Craddock N, Kendler K, et al.: Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br J Psychiatry 2009, 195:97–99. The PGC presents innovative strategies for identifying novel loci for psychiatric conditions that build on the well-established comorbid nature of psychiatric disorders.CrossRefPubMedGoogle Scholar
  49. 49.
    Radant A, Tsuang D, Peskind ER, et al.: Biological markers and diagnostic accuracy in the genetics of posttraumatic stress disorder. Psychiatry Res 2001, 102:203–215.CrossRefPubMedGoogle Scholar
  50. 50.
    Kendler KS, Eaves LJ: Models for the joint effect of genotype and environment on liability to psychiatric illness. Am J Psychiatry 1986, 143:279–289.PubMedGoogle Scholar
  51. 51.
    Lyons MJ, Goldberg J, Eisen SA, et al.: Do genes influence exposure to trauma? A twin study of combat. Am J Med Genet 1993, 48:22–27.CrossRefPubMedGoogle Scholar
  52. 52.
    Jang KL, Stein MB, Taylor S, et al.: Exposure to traumatic events and experiences: aetiological relationships with personality function. Psychiatry Res 2003, 120:61–69.CrossRefPubMedGoogle Scholar
  53. 53.
    Van Os J, Jones PB: Early risk factors and adult person–environment relationships in affective disorder. Psychol Med 1999, 29:1055–1067.CrossRefPubMedGoogle Scholar
  54. 54.
    Munafo MR, Yalcin B, Willis-Owen SA, Flint J: Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry 2008, 63:197–206.CrossRefPubMedGoogle Scholar
  55. 55.
    van IJzendoorn MH, Bakermans-Kranenburg MJ, Mesman J: Dopamine system genes associated with parenting in the context of daily hassles. Genes Brain Behav 2008, 7:403–410.CrossRefPubMedGoogle Scholar
  56. 56.
    Breslau N, Davis GC, Andreski P, Peterson E: Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry 1991, 48:216–222.PubMedGoogle Scholar
  57. 57.
    Breslau N, Davis GC: Posttraumatic stress disorder in an urban population of young adults: risk factors for chronicity. Am J Psychiatry 1992, 149:671–675.PubMedGoogle Scholar
  58. 58.
    Glahn DC, Thompson PM, Blangero J: Neuroimaging endophenotypes: strategies for finding genes influencing brain structure and function. Hum Brain Mapp 2007, 28:488–501.CrossRefPubMedGoogle Scholar
  59. 59.
    Gottesman II, Gould TD: The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003, 160:636–645.CrossRefPubMedGoogle Scholar
  60. 60.
    Kitayama N, Vaccarino V, Kutner M, et al.: Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005, 88:79–86.CrossRefPubMedGoogle Scholar
  61. 61.
    Bremner JD: The relationship between cognitive and brain changes in posttraumatic stress disorder. Ann N Y Acad Sci 2006, 1071:80–86.CrossRefPubMedGoogle Scholar
  62. 62.
    Ozer EJ, Best SR, Lipsey TL, Weiss DS: Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. Psychol Bull 2003, 129:52–73.CrossRefPubMedGoogle Scholar
  63. 63.
    Brewin CR, Andrews B, Valentine JD: Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 2000, 68:748–766.CrossRefPubMedGoogle Scholar
  64. 64.
    Koenen KC, Hitsman B, Lyons MJ, et al.: A twin registry study of the relationship between posttraumatic stress disorder and nicotine dependence in men. Arch Gen Psychiatry 2005, 62:1258–1265.CrossRefPubMedGoogle Scholar
  65. 65.
    Koenen KC, Fu QJ, Lyons MJ, et al.: Juvenile conduct disorder as a risk factor for trauma exposure and posttraumatic stress disorder. J Trauma Stress 2005, 18:23–32.CrossRefPubMedGoogle Scholar
  66. 66.
    Breslau N, Davis GC, Peterson EL, Schultz LR: A second look at comorbidity in victims of trauma: the posttraumatic stress disorder-major depression connection. Biol Psychiatry 2000, 48:902–909.CrossRefPubMedGoogle Scholar
  67. 67.
    Breslau N, Davis GC, Schultz LR: Posttraumatic stress disorder and the incidence of nicotine, alcohol, and other drug disorders in persons who have experienced trauma. Arch Gen Psychiatry 2003, 60:289–294.CrossRefPubMedGoogle Scholar
  68. 68.
    Chantarujikapong SI, Scherrer JF, Xian H, et al.: A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res 2001, 103:133–145.CrossRefPubMedGoogle Scholar
  69. 69.
    Xian H, Chantarujikapong SI, Scherrer JF, et al.: Genetic and environmental influences on posttraumatic stress disorder, alcohol and drug dependence in twin pairs. Drug Alcohol Depend 2000, 61:95–102.CrossRefPubMedGoogle Scholar
  70. 70.
    Caspi A, Sugden K, Moffitt TE, et al.: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003, 301:386–389.CrossRefPubMedGoogle Scholar
  71. 71.
    Binder EB, Salyakina D, Lichtner P, et al.: Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004, 36:1319–1325.CrossRefPubMedGoogle Scholar
  72. 72.
    Lawford BR, Young R, Noble EP, et al.: The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. Eur Psychiatry 2006, 21:180–185.CrossRefPubMedGoogle Scholar
  73. 73.
    Widom CS: Posttraumatic stress disorder in abused and neglected children grown up. Am J Psychiatry 1999, 156:1223–1229.PubMedGoogle Scholar
  74. 74.
    Breslau N, Davis GC, Andreski P, et al.: Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry 1997, 54:1044–1048.PubMedGoogle Scholar
  75. 75.
    Breslau N, Chilcoat HD, Kessler RC, et al.: Vulnerability to assaultive violence: further specification of the sex difference in post-traumatic stress disorder. Psychol Med 1999, 29:813–821.CrossRefPubMedGoogle Scholar
  76. 76.
    Breslau N, Kessler RC, Chilcoat HD, et al.: Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 1998, 55:626–632.CrossRefPubMedGoogle Scholar
  77. 77.
    Smith PG, Day NE: The design of case-control studies: the influence of confounding and interaction effects. Int J Epidemiol 1984, 13:356–365.CrossRefPubMedGoogle Scholar
  78. 78.
    Chatterjee N, Carroll RJ: Semiparametric maximum likelihood estimation exploiting gene-environment independence in case-control studies. Biometrika 2005, 92:399–418.CrossRefGoogle Scholar
  79. 79.
    Kraft P, Yen YC, Stram DO, et al.: Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007, 63:111–119.CrossRefPubMedGoogle Scholar
  80. 80.
    Szantai E, Szmola R, Sasvari-Szekely M, et al.: The polymorphic nature of the human dopamine D4 receptor gene: a comparative analysis of known variants and a novel 27 bp deletion in the promoter region. BMC Genet 2005, 6:39.CrossRefPubMedGoogle Scholar
  81. 81.
    Rajeevan H, Osier MV, Cheung KH, et al.: ALFRED: the ALlele FREquency Database. Update. Nucleic Acids Res 2003, 31:270–271.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marilyn C. Cornelis
    • 1
  • Nicole R. Nugent
    • 2
  • Ananda B. Amstadter
    • 3
  • Karestan C. Koenen
    • 4
    Email author
  1. 1.Department of NutritionHarvard School of Public HealthBostonUSA
  2. 2.Bradley/Hasbro Children’s Research Center of Rhode Island Hospital, Department of Psychiatry and Human BehaviorAlpert Medical School of Brown UniversityProvidenceUSA
  3. 3.Department of PsychiatryMedical University of South CarolinaCharlestonUSA
  4. 4.Departments of Society, Human Development and Health and EpidemiologyHarvard School of Public HealthBostonUSA

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