Genetics of PTSD: A Neglected Area?

August 1, 2005

Posttraumatic stress disorder is one of the most devastating psychiatric disorders. Research has shown that a combination of multiple genes can lead to conditions for PTSD. Environmental factors, as well as comorbidities, must also be considered when looking for genetic conditions of PTSD.

Psychiatric Times

August 2005

Vol. XXII

Issue 9

Over 50% of U.S. women and 60% of men report having experienced a traumatic event at some point in their lives. However, only a minority (approximately 10% of women and 5% of men) report having ever developed posttraumatic stress disorder, the most prominent psychiatric disorder associated with traumatic events (Kessler et al., 1995). This disparity between the prevalence of exposure to traumatic events and the development of PTSD has driven research to determine the etiology of PTSD and identify factors that increase risk for the disorder. One area of research that has received relatively little attention is genetics.

Why has the genetics of PTSD been neglected? One reason is that it is a relatively new diagnosis. Although versions of what we now call PTSD have existed under different names (e.g., shell shock, gross stress reaction), it was not until 1980, with the publication of the DSM-III, that the diagnosis was codified. Since the diagnosis of PTSD requires exposure to a traumatic event, much of the early research on etiology was understandably focused on identifying trauma-related and other environmental risk factors.

A further reason the genetics of PTSD has received so little attention is that, until the 1990s, it was commonly thought to be prevalent only among specific subpopulations (e.g., Vietnam War combat veterans) and rare in the general population. This misconception was corrected with the publication of several groundbreaking epidemiologic studies of trauma exposure and PTSD. These studies consistently demonstrated that both exposure to traumatic events and PTSD are common (Breslau et al., 1991; Kessler et al., 1995; Resnick et al., 1993).

Research has also been complicated by PTSD's high level of comorbidity (Kessler et al., 1995). Despite this and other challenges, significant progress has been made in the last decade. The aim of this article is to review some of the evidence for genetic influences on PTSD and suggest why such research may be important for prevention and treatment.

Genetic Influences: Evidence

From the vantage point of genetics research, PTSD is considered a complex or polygenetic disorder. Unlike Huntington's disease and other disorders where there is a single gene that is necessary and sufficient for the development of the disorder, there is likely no PTSD gene. Instead, there are probably many genes that contribute additively, in a probabilistic fashion, to the inherited liability for PTSD.

Some of the early evidence for genetic influences on PTSD came from studies demonstrating that genetically distinct mouse strains reared in identical environments show variation in response to fear conditioning (Anisman et al., 1979), one of the primary neurobiological models for the etiology of PTSD. Genetics research in humans has followed up on data from these animal models. First, family studies were conducted. If PTSD is genetic, family members of individuals with PTSD should have a higher prevalence of PTSD. Next, twin studies have shown the relative magnitude of genetic and environmental influences on individual differences in trauma exposure and PTSD. More recently, candidate gene association studies have sought to identify specific genes that increase risk of PTSD.

Family studies. Only a few family studies have specifically examined whether relatives of PTSD probands have an increased prevalence of PTSD. This is because the disorder cannot be assessed in relatives who have not experienced a traumatic event. Thus, a family study of PTSD must select families where multiple family members are exposed to the same trauma. For example, parents developing PTSD in response to their child being burned is strongly influenced by whether the burned child developed PTSD (Hall et al., in press). In an earlier study of Cambodian refugees, children whose parents had PTSD were almost five times more likely to receive the diagnosis than children whose parents did not develop PTSD (Sack et al., 1995).

Twin studies. Family studies are limited in that they cannot determine whether a disorder runs in families due to shared genes or shared environment. The twin method has been used to disentangle the role of genetic and family-wide environmental influences on risk for PTSD. The majority of such studies have been based on data from the Vietnam Era Twin (VET) Registry, which was created from the military records of male-male twin pairs who served in the Vietnam War. Substantial genetic influences were also found on all PTSD symptoms, after adjusting for differences in combat exposure (True et al., 1993). There were similar findings in a non-veteran community sample of male and female twins (Stein et al., 2002).

Further studies on the VET Registry have shown that there are shared genetic influences on PTSD and other mental disorders including alcohol and drug dependence (McLeod et al., 2001; Xian et al., 2000), nicotine dependence (Koenen et al., in press), generalized anxiety and panic disorder symptoms (Chantarujikapong et al., 2001), and major depression (Koenen et al., 2003).

Association studies. Human beings are 99.9% genetically identical. Research aimed at identifying genes that explain individual differences in risk for PTSD, therefore, focuses on the tiny fraction of DNA that differs among individuals.

Association studies usually begin by selecting candidate genes implicated in the neurobiological models for a phenotype. For example, genes involved in fear conditioning in mice are considered good candidates for future association studies of PTSD. Once candidate genes are selected, one or more polymorphisms, which are different forms of DNA sequence at a specific place (or locus) on the gene, will be identified. Each polymorphism selected will have two or more different versions or alleles. Most simply, association studies correlate variation in alleles at a specific locus with an outcome.

Only five association studies of PTSD have been published, all of which focused on candidate genes involved in the dopaminergic system, which is one of the neurotransmitter systems involved in fear conditioning. Findings from these studies are conflicting. Four of the studies examined the association between marker alleles at the D2 dopamine receptor gene (DRD2) and PTSD with conflicting results. The first two studies found a positive association with the DRD2A1 allele (Comings et al., 1996, 1991). The third study found no association with the DRD2A1 allele or with any single or combination of alleles for the DRD2 locus (Gelernter et al., 1999). The fourth study found a positive association between DRD2A1 and PTSD only in the subset of PTSD cases who engaged in harmful drinking (Young et al., 2002). The fifth study found a positive association between a polymorphism in the dopamine transporter gene SLC6A3 3' and PTSD (Segman et al., 2002). Of these studies, Segman and colleagues (2002) presented the strongest evidence for an association between genetic variants involved in the dopaminergic system and PTSD. The other studies shared several limitations including limited power due to small samples and comorbidity.

Candidate gene studies have to contend with the fact that people with PTSD also have a higher prevalence for other mental disorders. Comorbidity is often treated as a study limitation, and polymorphisms associated with the PTSD diagnosis may not be specifically associated with PTSD but rather are correlates of general psychopathology. Furthermore, the studies by Gelernter et al. (1999) and Young et al. (2002) failed to assess trauma exposure in controls. Since genetic liability for PTSD can only be expressed in the presence of exposure, this would bias these studies against finding an association. That is, although the controls do not have PTSD, they could have the genetic liability for the disorder and might have developed PTSD had they been exposed. Thus, including unexposed controls potentially makes the controls genetically more similar to the cases and reduces the potential for finding a significant genetic association.

Implications for Intervention

Identification of specific genetic variants involved in the etiology of PTSD will increase our understanding of neurobiological systems involved in its development. The hope is that better knowledge of neurobiological systems will enable the development of predictive tests for mental health problems following a traumatic event. Of particular interest are gene expression studies. Put simply, research on gene expression examines how genes respond to environmental inputs.

A recent study by Segman and colleagues (2005) indicated the promise of such studies. The authors observed peripheral blood mononuclear cell gene expression profiles in individuals seen in the emergency department shortly after a traumatic event and followed one and four months later. They found that gene expression signatures differentiated between individuals who developed PTSD and those who did not (Segman et al., 2005). Their findings offer the promise of developing a predictive test to inform providers as to which trauma survivors are at higher risk of developing PTSD after a traumatic event.

As genetic studies increase our knowledge of the neurobiological systems underlying risk for PTSD, this will allow for identifying targets for therapeutic drugs that can be administered shortly after a traumatic event to prevent development of PTSD. For example, re-experiencing the traumatic event is a hallmark symptom. Understanding the neurobiological systems involved in memory consolidation, which include the amygdala and stress hormones, has informed research on pharmacological interventions that are administered shortly after a trauma to prevent the development of PTSD.

A recent review reported promising results for propranolol (Inderal) and cortisol as preventive agents (Pitman and Delahanty, 2005). However, data on these agents are preliminary and larger, randomized, controlled clinical trials are needed. Genetic studies offer the potential to direct researchers to other pharmacological agents to prevent PTSD.

Genetic studies will also increase understanding of why some individuals respond to pharmacological interventions and others do not. Pharmacogenetics is the study of how the actions of certain drugs vary with the patients' genes. Genetic variation has been associated with response to antidepressants (Binder et al., 2004). It is certainly possible that genes may influence patients' responses to pharmacologic agents that will be used to prevent PTSD. Pharmacogenetics offers the potential for preventive agents to be prescribed based on what is likely to be most effective, given the patient's genotype.

Given the limited current understanding of the genetics of PTSD, such individualized interventions for the disorder appear to be in the distant future. Still, the growing interest and attention of researchers in the genetics of PTSD offers great promise for those interested in preventing this debilitating disorder.

Dr. Koenen is assistant professor in the department of society, human development, and health at the Harvard University School of Public Health.

References

Anisman H, Grimmer L, Irwin J et al. (1979), Escape performance after inescapable shock in selectively bred lines of mice: response maintenance and catecholamine activity. J Comp Physiol Psychol 93(2):229-241.

Binder EB, Salyakina D, Lichtner P et al. (2004), Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36 (12):1319-1325.

Breslau N, Davis GC, Andreski P, Peterson E (1991), Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry 48(3):216-222.

Chantarujikapong SI, Scherrer JF, Xian H et al. (2001), A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res 103(2-3):133-145.

Comings DE, Comings BG, Muhleman D et al. (1991), The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorder. JAMA 266(13):1793-1800 [see comment].

Comings DE, Muhleman D, Gysin R (1996), Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol Psychiatry 40(5):368-372.

Gelernter J, Southwick S, Goodson S et al. (1999), No association between D2 dopamine receptor (DRD2) "A" system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Biol Psychiatry 45(5):620-625.

Hall E, Saxe G, Stoddard F et al. (in press), Posttraumatic stress symptoms in parents of children with acute burns. J Pediatr Psychol.

Kessler RC, Sonnega A, Bromet E et al. (1995), Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52(12):1048-1060.

Koenen KC, Hitsman B, Lyons JA et al. (in press), The relationship between nicotine dependence and posttraumatic stress disorder in men. Arch Gen Psychiatry.

Koenen KC, Lyons MJ, Goldberg J et al. (2003), A high risk twin study of combat-related PTSD comorbidity. Twin Res 6(3):218-226.

McLeod S, Koenen KC, Meyer JM et al. (2001), Genetic and environmental influences on the relationship among combat exposure, posttraumatic stress disorder symptoms, and alcohol use. J Trauma Stress 14(2):259-275.

Pitman RK, Delahanty DL (2005), Conceptually driven pharmacologic approaches to acute trauma. CNS Spectr 10(2):99-106.

Resnick HS, Kilpatrick DG, Dansky BS et al. (1993), Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychology 61(6):984-991.

Sack WH, Clarke GN, Seeley J (1995), Posttraumatic stress disorder across two generations of Cambodian refugees. J Am Acad Child Adolesc Psychiatry 34(9):1160-1166.

Segman RH, Cooper-Kazaz R, Macciardi F et al. (2002), Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 7(8):903-907.

Segman RH, Shefi N, Goltser-Dubner T et al. (2005), Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry 10(5):500-513, 425.

Stein MB, Jang KJ, Taylor S et al. (2002), Genetic and environmental influences on trauma exposure and posttraumatic stress disorder: a twin study. Am J Psychiatry 159(10):1675-1681.

True WJ, Rice J, Eisen SA et al. (1993), A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 50(4):257-264 [see comment].

Xian H, Chantarujikapong SI, Scherrer JF et al. (2000), Genetic and environmental influences on posttraumatic stress disorder, alcohol and drug dependence in twin pairs. Drug Alcohol Depend 61(1):95-102.

Young BR, Lawford BR, Noble EP et al. (2002), Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol 37(5):451-456.