The genetic background to PTSD

Although extensive research has already been done on the genetic bases of psychiatric disorders, little is known about polygenetic influences in posttraumatic stress disorder (PTSD). This article reviews molecular genetic studies relating to PTSD that were found in a literature search in Medline, Embase and Web of Science. Association studies have investigated 8 major genotypes in connection with PTSD. They have tested hypotheses involving key candidate genes in the serotonin (5-HTT), dopamine (DRD2, DAT), glucocorticoid (GR), GABA (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). The studies have produced inconsistent results, many of which may be attributable to methodological shortcomings and insufficient statistical power. The complex aetiology of PTSD, for which experiencing a traumatic event forms a necessary condition, makes it difficult to identify specific genes that substantially contribute to the disorder. Gene-finding strategies are difficult to apply. Interactions between different genes and between them and the environment probably make certain people vulnerable to developing PTSD. Gene-environmental studies are needed that focus more narrowly on specific, distinct endophenotypes and on influences from environmental factors.

[1]  P. Talbot The molecular neuroimaging of anxiety disorders , 2004, Current psychiatry reports.

[2]  D. Comings,et al.  Reward deficiency syndrome: genetic aspects of behavioral disorders. , 2000, Progress in brain research.

[3]  C. Nemeroff,et al.  The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders , 1999, Biological Psychiatry.

[4]  A. Shalev,et al.  Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors , 2005, Molecular Psychiatry.

[5]  R. Busch,et al.  A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety , 2004, Molecular Psychiatry.

[6]  M. Rietschel,et al.  Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study , 2004, European Journal of Human Genetics.

[7]  M. Shenton,et al.  Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma , 2002, Nature Neuroscience.

[8]  B. Lerer,et al.  Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. , 1990, The Journal of clinical psychiatry.

[9]  K. Kendler,et al.  Stressful life events and genetic liability to major depression: genetic control of exposure to the environment? , 1997, Psychological Medicine.

[10]  P. Gass,et al.  Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: Models for depression and anxiety? , 2001, Physiology & Behavior.

[11]  K. Lesch,et al.  Glucocorticoid‐regulated human serotonin transporter (5‐HTT) expression is modulated by the 5‐HTT gene‐promotor‐linked polymorphic region , 2003, Journal of neurochemistry.

[12]  M. Egan,et al.  Serotonin Transporter Genetic Variation and the Response of the Human Amygdala , 2002, Science.

[13]  F. Graeff,et al.  Role of 5-HT in stress, anxiety, and depression , 1996, Pharmacology Biochemistry and Behavior.

[14]  R. Kessler,et al.  Posttraumatic stress disorder in the National Comorbidity Survey. , 1995, Archives of general psychiatry.

[15]  A. Brunet,et al.  The predictive power of peritraumatic dissociation and acute stress symptoms for posttraumatic stress symptoms: a three-month prospective study. , 2003, The American journal of psychiatry.

[16]  R. Young,et al.  D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder , 2003, European Neuropsychopharmacology.

[17]  M. Thase,et al.  Onset of depression and time to treatment entry: roles of life stress. , 1991, Journal of consulting and clinical psychology.

[18]  Jacob Raber,et al.  Hypothalamic–Pituitary–Adrenal Dysfunction inApoe−/− Mice: Possible Role in Behavioral and Metabolic Alterations , 2000, The Journal of Neuroscience.

[19]  R. Wurtman Genes, stress, and depression. , 2005, Metabolism: clinical and experimental.

[20]  I. Liberzon,et al.  Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders , 2001, Psychopharmacology.

[21]  Y. Chagnon,et al.  Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. , 1997, Obesity research.

[22]  J. Kaye,et al.  apoE isoforms and measures of anxiety in probable AD patients and Apoe−/− mice , 2005, Neurobiology of Aging.

[23]  C. Heimberg,et al.  Post-traumatic stress disorder and serotonin: new directions for research and treatment. , 1997, Journal of psychiatry & neuroscience : JPN.

[24]  B. McEwen,et al.  Regulation of glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acids by selective agonists in the rat hippocampus. , 1998, Endocrinology.

[25]  Mathias V. Schmidt,et al.  Stress, genes and the mechanism of programming the brain for later life , 2005, Neuroscience & Biobehavioral Reviews.

[26]  E. Young,et al.  Differential Regulation of Hippocampal Glucocorticoid Receptors mRNA and Fast Feedback: Relevance to Post‐Traumatic Stress Disorder , 1999, Journal of neuroendocrinology.

[27]  E P Noble,et al.  The DRD2 gene in psychiatric and neurological disorders and its phenotypes. , 2000, Pharmacogenomics.

[28]  L. Fried,et al.  Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. , 1998, Stroke.

[29]  P. Hamet,et al.  Genetics and genomics of depression. , 2005, Metabolism: clinical and experimental.

[30]  M. Koulu,et al.  Altered intracellular processing and release of neuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Y in humans1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  L. Siever,et al.  Relationship between posttraumatic stress disorder characteristics of Holocaust survivors and their adult offspring. , 1998, The American journal of psychiatry.

[32]  K. Lesch Gene transfer to the brain: emerging therapeutic strategy in psychiatry? , 1999, Biological Psychiatry.

[33]  C. Classen,et al.  Predictors of posttraumatic stress symptoms among survivors of the Oakland/Berkeley, Calif., firestorm. , 1994, The American journal of psychiatry.

[34]  M. Tsuang,et al.  Genetic and environmental influences on posttraumatic stress disorder, alcohol and drug dependence in twin pairs. , 2000, Drug and alcohol dependence.

[35]  D. Weiss,et al.  Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. , 2003, Psychological bulletin.

[36]  S. Southwick,et al.  Urinary Catecholamine Excretion and Severity of PTSD Symptoms in Vietnam Combat Veterans , 1992, The Journal of nervous and mental disease.

[37]  H. Russcher,et al.  Genetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene , 2005, Trends in Endocrinology & Metabolism.

[38]  F. Holsboer,et al.  Mouse Mutants for the Study of Corticotropin‐Releasing Hormone Receptor Function: Development of Novel Treatment Strategies for Mood Disorders , 2004, Annals of the New York Academy of Sciences.

[39]  Qian Li,et al.  Genetic perspectives on the serotonin transporter , 2001, Brain Research Bulletin.

[40]  C. Brewin,et al.  Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. , 2000, Journal of consulting and clinical psychology.

[41]  Wendy Raskind,et al.  Biological markers and diagnostic accuracy in the genetics of posttraumatic stress disorder , 2001, Psychiatry Research.

[42]  S. Orr,et al.  Prospective study of posttraumatic stress disorder and depression following trauma. , 1998, The American journal of psychiatry.

[43]  M. Stein,et al.  Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. , 2002, The American journal of psychiatry.

[44]  John Gordon,et al.  Lymphocytes transport serotonin and dopamine: agony or ecstasy? , 2003, Trends in immunology.

[45]  R. Ursano,et al.  Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD. , 2006, Medical hypotheses.

[46]  W. Drevets,et al.  No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder. , 2005, The American journal of psychiatry.

[47]  W. Iacono,et al.  P300 amplitude in nonalcoholic adolescent twin pairs who become discordant for alcoholism as adults. , 2004, Psychophysiology.

[48]  Marc Laruelle,et al.  The Variable Number of Tandem Repeats Polymorphism of the Dopamine Transporter Gene Is Not Associated with Significant Change in Dopamine Transporter Phenotype in Humans , 2001, Neuropsychopharmacology.

[49]  Martha E Shenton,et al.  Cavum septum pellucidum in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder , 2004, Biological Psychiatry.

[50]  A. Goldberger,et al.  Twin studies in behavioral research: a skeptical view. , 2002, Theoretical population biology.

[51]  N. Martin,et al.  The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression , 2005, Psychological Medicine.

[52]  M. Meaney,et al.  Glucocorticoid “Programming” and PTSD Risk , 2006, Annals of the New York Academy of Sciences.

[53]  Se-Won Lim,et al.  No association between the brain‐derived neurotrophic factor gene Val66Met polymorphism and post‐traumatic stress disorder , 2006 .

[54]  S. Faraone,et al.  Meta‐analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[55]  T. Kimbrell,et al.  Neuropsychiatric associations of apolipoprotein E alleles in subjects with combat-related posttraumatic stress disorder. , 2005, The Journal of neuropsychiatry and clinical neurosciences.

[56]  C. Bouchard,et al.  Association between a Variant at the GABAAα6 Receptor Subunit Gene, Abdominal Obesity, and Cortisol Secretion , 2002, Annals of the New York Academy of Sciences.

[57]  H. Kraemer,et al.  Apolipoprotein E ∈4 Allele Affects the Relationship between Stress and Depression in Caregivers of Patients with Alzheimer's Disease , 2001 .

[58]  C. Otte,et al.  Mineralocorticoid receptor function in patients with posttraumatic stress disorder. , 2002, The American journal of psychiatry.

[59]  Jung Bum Kim,et al.  Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder , 2005, Depression and anxiety.

[60]  S. Southwick,et al.  A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. , 2002, Archives of general psychiatry.

[61]  P. Birmes,et al.  Peritraumatic dissociation and posttraumatic stress disorder in victims of violent assault. , 2001, The Journal of nervous and mental disease.

[62]  A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. , 1998, The Journal of clinical endocrinology and metabolism.

[63]  F. Holsboer,et al.  Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. , 1999, The American journal of psychiatry.

[64]  D. Charney,et al.  Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. , 2004, The American journal of psychiatry.

[65]  S. Cabib,et al.  PSYCHOPHARMACOLOGY OF DOPAMINE: THE CONTRIBUTION OF COMPARATIVE STUDIES IN INBRED STRAINS OF MICE , 1997, Progress in Neurobiology.

[66]  M. Höfler,et al.  Longitudinal course of posttraumatic stress disorder and posttraumatic stress disorder symptoms in a community sample of adolescents and young adults. , 2005, The American journal of psychiatry.

[67]  N. Wineman,et al.  Trauma, posttraumatic stress disorder symptom clusters, and physical health symptoms in postabused women. , 2004, Archives of psychiatric nursing.

[68]  R. Yehuda,et al.  The Effect of Maternal PTSD Following in Utero Trauma Exposure on Behavior and Temperament in the 9‐Month‐Old Infant , 2006, Annals of the New York Academy of Sciences.

[69]  M. Buchsbaum,et al.  Neuroimaging studies in post-traumatic stress disorder. , 2002, The Psychiatric clinics of North America.

[70]  Teresa L. Sedgley,et al.  Glucocorticoid receptor polymorphisms and post-traumatic stress disorder , 2005, Psychoneuroendocrinology.

[71]  Michael Davis,et al.  Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958 , 1999, Psychopharmacology.

[72]  N. Breslau The epidemiology of posttraumatic stress disorder: what is the extent of the problem? , 2001, The Journal of clinical psychiatry.

[73]  S. Southwick,et al.  Psychogenic Lowering of Urinary Cortisol Levels Linked to Increased Emotional Numbing and a Shame-Depressive Syndrome in Combat-Related Posttraumatic Stress Disorder , 2001, Psychosomatic medicine.

[74]  A. Baum,et al.  Gender differences in posttraumatic stress disorder after motor vehicle accidents. , 2001, The American journal of psychiatry.

[75]  M. Kalia,et al.  Neurobiological basis of depression: an update. , 2005, Metabolism: clinical and experimental.

[76]  J. Connell,et al.  Glucocorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. , 1998, The Journal of clinical endocrinology and metabolism.

[77]  N. Unwin,et al.  The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. , 2001, The Journal of clinical endocrinology and metabolism.

[78]  S. Southwick,et al.  No association between D2 dopamine receptor (DRD2) “A” system alleles, or DRD2 haplotypes, and posttraumatic stress disorder , 1999, Biological Psychiatry.

[79]  S. Paul,et al.  Adrenalectomy prevents the stress-induced decrease in in vitro [3H]Ro15-1788 binding to GABAA benzodiazepine receptors in the mouse , 1990, Brain Research.

[80]  J. Smoller,et al.  Panic and phobic anxiety: defining phenotypes for genetic studies. , 1998, The American journal of psychiatry.

[81]  S. Stahl Is psychopharmacologic "inoculation" effective in preventing posttraumatic stress disorder? , 2005, The Journal of clinical psychiatry.

[82]  Charles A Morgan,et al.  Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report , 2002, Biological Psychiatry.

[83]  R. Yehuda,et al.  Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. , 2005, The Journal of clinical endocrinology and metabolism.

[84]  A D Roses,et al.  Apolipoprotein E-epsilon 2 and Alzheimer's disease , 1997, Neurology.

[85]  R. Derijk,et al.  Signaling Pathways in Brain Involved in Predisposition and Pathogenesis of Stress‐Related Disease: Genetic and Kinetic Factors Affecting the MR/GR Balance , 2004, Annals of the New York Academy of Sciences.

[86]  P. Sullivan,et al.  An association study of DRD5 with smoking initiation and progression to nicotine dependence. , 2001, American journal of medical genetics.

[87]  B. Moghaddam,et al.  Dopaminergic Innervation of the Amygdala Is Highly Responsive to Stress , 1999, Journal of neurochemistry.

[88]  Steven Taylor,et al.  Are avoidance and numbing distinct PTSD symptom clusters? , 2004, Journal of traumatic stress.

[89]  S. Maestrini,et al.  The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients , 2003, Clinical endocrinology.

[90]  R. Yehuda,et al.  Cortisol levels in adult offspring of Holocaust survivors: relation to PTSD symptom severity in the parent and child , 2002, Psychoneuroendocrinology.

[91]  J. Flory,et al.  Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. , 2000, American journal of medical genetics.

[92]  J. David Sweatt,et al.  Epigenetic mechanisms in memory formation , 2005, Nature Reviews Neuroscience.

[93]  A. Shalev,et al.  Genetics of Posttraumatic Stress Disorder , 2003, CNS Spectrums.

[94]  M. Joëls,et al.  Brain corticosteroid receptor balance in health and disease. , 1998, Endocrine reviews.

[95]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[96]  F. Holsboer,et al.  Dysregulation of the Hypothalamic-Pituitary-Adrenocortical System in Panic Disorder , 1996, Neuropsychopharmacology.

[97]  C. Bouchard,et al.  Allelic variants in the GABAAα6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion , 2002, International Journal of Obesity.

[98]  R. Yehuda,et al.  Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring. , 2001, Journal of psychiatric research.

[99]  C. A. Morgan,et al.  Plasma neuropeptide-Y concentrations in humans exposed to military survival training , 2000, Biological Psychiatry.

[100]  K. Lesch,et al.  Early experience and serotonin transporter gene variation interact to influence primate CNS function , 2002, Molecular Psychiatry.

[101]  B. Diamond,et al.  Elevated plasma dopamine in posttraumatic stress disorder: A preliminary report , 1993, Biological Psychiatry.

[102]  N. Breslau,et al.  Traumatic events and posttraumatic stress disorder in an urban population of young adults. , 1991, Archives of general psychiatry.

[103]  Joel Gelernter,et al.  Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[104]  Miranda Olff,et al.  Gender differences in posttraumatic stress disorder. , 2007, Psychological bulletin.

[105]  M. Olff,et al.  Effects of appraisal and coping on the neuroendocrine response to extreme stress , 2005, Neuroscience & Biobehavioral Reviews.

[106]  Kimberly Hoagwood,et al.  Development and natural history of mood disorders , 2002, Biological Psychiatry.

[107]  David Goldman,et al.  Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. , 2004, Archives of general psychiatry.

[108]  Terry L. Schell,et al.  All symptoms are not created equal: the prominent role of hyperarousal in the natural course of posttraumatic psychological distress. , 2004, Journal of abnormal psychology.

[109]  J. Abelson,et al.  Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol. , 1996, Archives of general psychiatry.

[110]  J. Lauder Hormonal and humoral influences on brain development , 1983, Psychoneuroendocrinology.

[111]  Jürgen Gallinat,et al.  Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety , 2005, NeuroImage.

[112]  R. Yehuda,et al.  Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. , 1998, The American journal of psychiatry.

[113]  W R True,et al.  A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. , 1993, Archives of general psychiatry.

[114]  C. Nemeroff,et al.  Neurobiology of early life stress: clinical studies. , 2002, Seminars in clinical neuropsychiatry.

[115]  F. Holsboer,et al.  Antidepressants and hypothalamic-pituitary-adrenocortical regulation. , 1996, Endocrine reviews.

[116]  R. Young,et al.  Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. , 2002, Alcohol and alcoholism.

[117]  A. Baum,et al.  Peritraumatic dissociation following motor vehicle accidents: relationship to prior trauma and prior major depression. , 2000, The Journal of nervous and mental disease.

[118]  R. Mahley,et al.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. , 1988, Science.

[119]  A. Baum,et al.  Urinary Catecholamines and Cortisol in Recent-Onset Posttraumatic Stress Disorder After Motor Vehicle Accidents , 2000, Psychosomatic medicine.

[120]  T. Nabeshima,et al.  Role for brain-derived neurotrophic factor in learning and memory. , 2002, Life sciences.

[121]  D. Comings,et al.  Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: A study and replication , 1996, Biological Psychiatry.

[122]  H. Xian,et al.  A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men , 2001, Psychiatry Research.

[123]  R. Roth,et al.  Role of the Amygdala in the Coordination of Behavioral, Neuroendocrine, and Prefrontal Cortical Monoamine Responses to Psychological Stress in the Rat , 1996 .

[124]  K. Lesch,et al.  Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques , 2004, Biological Psychiatry.

[125]  R. Rosmond The glucocorticoid receptor gene and its association to metabolic syndrome. , 2002, Obesity research.

[126]  F. Macciardi,et al.  Association between the dopamine transporter gene and posttraumatic stress disorder , 2002, Molecular Psychiatry.

[127]  G. Schellenberg,et al.  Increased CSF cortisol in AD is a function of APOE genotype , 2001, Neurology.

[128]  Jamie D. Feusner,et al.  GABAA receptor β3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population , 2001, Psychiatry Research.

[129]  P. Björntorp Alterations in the ageing corticotropic stress-response axis. , 2002, Novartis Foundation symposium.

[130]  R. de Kloet,et al.  Specificity of the adrenal steroid receptor system in rat hippocampus. , 1982, Endocrinology.

[131]  F. Lalonde,et al.  Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women , 2001, Neurology.

[132]  N. Breslau,et al.  Risk factors for PTSD-related traumatic events: a prospective analysis. , 1995, The American journal of psychiatry.

[133]  R. Yehuda,et al.  Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder , 2004, Biological Psychiatry.

[134]  J. Joseph Twin Studies in Psychiatry and Psychology: Science or Pseudoscience? , 2004, Psychiatric Quarterly.

[135]  R. Hen,et al.  Genetic and environmental factors interact to influence anxiety , 2009, Neurotoxicity Research.

[136]  Miranda Olff,et al.  The psychobiology of PTSD: coping with trauma , 2005, Psychoneuroendocrinology.

[137]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[138]  A. Rasmusson,et al.  Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock , 2002, Neuropsychopharmacology.

[139]  M. Tsuang,et al.  A High Risk Twin Study of Combat-Related PTSD Comorbidity , 2003, Twin Research.

[140]  I. Skre,et al.  A twin study of DSM‐III‐R anxiety disorders , 1993, Acta psychiatrica Scandinavica.

[141]  A. Uitterlinden,et al.  Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index , 2003, Clinical endocrinology.