Elsevier

Neuropharmacology

Volume 62, Issue 2, February 2012, Pages 628-637
Neuropharmacology

Invited review
PTSD and gene variants: New pathways and new thinking

https://doi.org/10.1016/j.neuropharm.2011.02.013Get rights and content

Abstract

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenergic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Highlights

► Much research on genetic risk factors for PTSD is based on a fear-conditioning model. ► Main effect studies of PTSD have primarily yielded negative results. ► GXE studies have yielded some positive preliminary results. ► Research on epigenetics may help clarify genetic factors underlying risk for PTSD. ► GWAS and Whole genome studies of PTSD may yield new candidate genes.

Introduction

Posttraumatic Stress Disorder (PTSD) is classified as an Anxiety Disorder within DSM-IV. It is defined as the development of symptoms following exposure to an extreme traumatic event (criterion A). These symptoms are characterized as belonging to three separate but interrelated symptom clusters: re-experiencing, avoidance and numbing, and hyperarousal (DSM 1994). Individuals diagnosed with PTSD experience significant functional impairment, including increased risk for unemployment, disrupted relationships, and diminished physical health (Kessler, 2000, Kubzansky et al., 2007). While the lifetime prevalence of PTSD in adult Americans is estimated to be 6.8% (Kessler et al., 2005), the conditional risk for PTSD following trauma exposure ranges from 5 to 31% (Kulka et al., 1990, Kessler et al., 1995, Breslau et al., 1998, Adams and Boscarino, 2006) with interpersonal and combat trauma associated with relatively greater risk. While an estimated 75% of the population has experienced a criterion A traumatic event (Breslau and Kessler, 2001), only a minority of those individuals subsequently develop PTSD. This finding suggests that certain individuals have an underlying vulnerability to developing this disorder in the aftermath of trauma. Identifying those vulnerable individuals may allow for early and targeted intervention to prevent or reduce the symptoms and functional impairment associated with PTSD.

Section snippets

Family studies of heritability

If the risk for PTSD following traumatic exposure is associated with an underlying genetic vulnerability, it would be expected that biological relatives (family) of an individual with PTSD (proband) would have a higher risk of developing the disorder following trauma exposure than similarly traumatized non-relatives. Family studies of PTSD have demonstrated this finding. Specifically, PTSD diagnosis was more frequent in adult children of Holocaust survivors with PTSD as compared to children of

Twin studies of heritability

Studies of twins (who share identical genetic inheritance) allow researchers to differentiate genetic from environmental influence on the development of a disorder. Twin studies have demonstrated that genetic factors influence the risk of exposure to traumatic events (Lyons et al., 1993, Stein et al., 2002). This finding, known as gene–environment correlation, may be related to the effect of genetics on temperament, anger and irritability. However, even after accounting for genetic impact on

Candidate genes and neurobiological pathways

While twin studies can indicate a heritable genetic risk for the development of PTSD, they cannot provide information on which specific genes confer that risk. Molecular genetic studies can be used to determine if specific genes influence risk or resilience for a specific disorder, such as PTSD. However, in the absence of large GWAS or similar hypothesis-neutral gene-discovery studies, knowledge of the underlying neurobiology of the disorder is needed in order to effectively identify

HPA axis

The HPA axis coordinates the neuroendocrine response to stress. Neurons within the paraventricular nucleus (PVN) of the hypothalamus project to the median eminence where they release corticotrophin-releasing hormone (CRH) which subsequently binds to CRH1 receptors in the anterior pituitary gland promoting the secretion to adrenocorticotrophic hormone (ACTH). ACTH is released into the systemic circulation where it stimulates the production and release of cortisol from the adrenal cortex, which

LC–noradrenergic system

The LC is the primary noradrenergic nucleus within the mammalian brain. It receives neuronal input from and provides output to the hypothalamus, the amygdala, and the prefrontal cortex amongst other regions (Benarroch, 2009). Activation of the LC can stimulate release of CRH from the hypothalamus and noradrenergic hyperactivity within the basolateral amygdala has been hypothesized to mediate the overconsolidation of fear memory in PTSD (Southwick et al., 1999). Because cortisol can reduce

Limbic–frontal system

The amygdala is composed of several nuclei located within the temporal lobe of the brain and is generally roughly divided into the basolateral nucleus (BLA) which receives the majority of the neuronal input and the central nucleus (CeA) which provides the majority of the output. The CeA projects to and activates both the HPA axis at the level of the hypothalamus and the LC–noradrenergic system. The BLA appears to be the locus for the comparison and development of associations between the

Epigenetics

While an improvement over studying the main effects of genes alone, studies of G × E interaction do not explain the importance of developmental timing of stressor exposure to producing phenotypic changes associated with PTSD. However, investigation of the epigenetic modification of DNA can provide insight into this issue. Epigenetic modification describes an environmentally induced change in DNA which alters the function rather than the structure of a gene. These changes can be specific to

Endophenotypes

PTSD is a complex diagnostic construct requiring exposure to a traumatic event and comprising a series of up to 17 symptoms organized into three symptom clusters. It is therefore difficult to tease out the multiple interacting genes likely to play a role in the heritability of this complex psychiatric disorder. Rather than examining the global diagnostic entity of PTSD, studying endophenotypes of the disorder may be more directly revealing. An endophenotype refers to a heritable, measurable

Future directions

While there are no agreed upon validated animals models of PTSD, there are established animal models of conditioned fear and fear inhibition amongst other biomarkers associated with PTSD as noted above. Human genetic investigations can be hampered by limitations such as sample size, statistical power and the inherent drawbacks of association studies. “Top down” translational studies, in which human genetic findings are validated by subsequent work in rodents, can address some of these

Summary and implications

PTSD is a prevalent anxiety disorder that can develop in the aftermath of exposure to a traumatic event. It is associated with significant adverse impact on occupational and social function, as well as physical and mental health and can become chronically disabling. The etiology and maintenance of PTSD is the result of multiple, complex interactions between genes and environmental influences. Understanding the nature of these influences, as well as their interaction, will be important to

References (117)

  • Q. Fu et al.

    Differential etiology of posttraumatic stress disorder with conduct disorder and major depression in male veterans

    Biological Psychiatry

    (2007)
  • J. Gelernter et al.

    No association between D2 dopamine receptor (DRD2) “A” system alleles, or DRD2 haplotypes, and posttraumatic stress disorder

    Biological Psychiatry

    (1999)
  • T. Jovanovic et al.

    Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity

    Psychiatry Research

    (2009)
  • K. Kasai et al.

    Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder

    Biological Psychiatry

    (2008)
  • K. Koenen et al.

    Common genetic liability to major depression and posttraumatic stress disorder in men

    Journal of Affective Disorders

    (2008)
  • I. Kolassa et al.

    The risk of posttraumatic stress disorder after trauma depends on traumatic load and the Catechol-O-Methyltransferase Val158Met polymorphism

    Biological Psychiatry

    (2010)
  • M. Meaney et al.

    Maternal care as a model for experience-dependent chromatin plasticity?

    Trends in Neurosciences

    (2005)
  • C. Morgan

    Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report

    Biological Psychiatry

    (2002)
  • C. Morgan et al.

    Plasma neuropeptide-Y concentrations in humans exposed to military survival training

    Biological Psychiatry

    (2000)
  • S. Norrholm et al.

    Genetics of anxiety and trauma-related disorders

    Neuroscience

    (2009)
  • S. Puglisi-Allegra et al.

    Psychopharmacology of dopamine: the contribution of comparative studies in inbred strains of mice

    Progress in Neurobiology

    (1997)
  • W. Sack et al.

    Posttraumatic stress disorder across two generations of Cambodian refugees

    Journal of the American Academy of Child & Adolescent Psychiatry

    (1995)
  • S. Southwick et al.

    Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder

    Biological Psychiatry

    (1999)
  • R. Adams et al.

    Predictors of PTSD and delayed PTSD after disaster: the impact of exposure and psychosocial resources

    The Journal of Nervous and Mental Disease

    (2006)
  • A. Amstadter et al.

    Genetics of PTSD: fear conditioning as a model for future research

    Psychiatric Annals

    (2009)
  • D. Baker et al.

    Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder

    American Journal of Psychiatry

    (1999)
  • E. Benarroch

    The locus ceruleus norepinephrine system: functional organization and potential clinical significance

    Neurology

    (2009)
  • E. Binder et al.

    Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults

    Jama

    (2008)
  • J. Bremner et al.

    Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder

    American Journal of Psychiatry

    (1997)
  • D. Bremner et al.

    Cortisol, dehydroepiandrosterone, and estradiol measured over 24 hours in women with childhood sexual abuse-related posttraumatic stress disorder

    The Journal of Nervous and Mental Disease

    (2007)
  • N. Breslau et al.

    Trauma and posttraumatic stress disorder in the community: the 1996 detroit area survey of trauma

    Archives of General Psychiatry

    (1998)
  • E. Charmandari et al.

    Endocrinology of the stress response1

    Physiology

    (2005)
  • A. Charuvastra et al.

    Social bonds and posttraumatic stress disorder

    Annual Review of Psychology

    (2008)
  • J.P. Chhatwal et al.

    Amygdala BDNF signaling is required for consolidation but not encoding of extinction

    Nature Neuroscience

    (2006)
  • D. Choi et al.

    Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear

    Proceedings of the National Academy of Sciences

    (2010)
  • J. Claes

    Corticotropin-releasing hormone (CRH) in psychiatry: from stress to psychopathology

    Annals of Medicine

    (2004)
  • D. Comings et al.

    The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders

    Jama

    (1991)
  • I. DSM

    American psychiatric association

    Diagnostic and Statistical Manual of Mental Disorders

    (1994)
  • M. Davis

    The role of the amygdala in fear and anxiety

    Annual Review of Neuroscience

    (1992)
  • J. Flint

    Analysis of quantitative trait loci that influence animal behavior

    Journal of Neurobiology

    (2003)
  • D. Francis et al.

    Nongenomic transmission across generations of maternal behavior and stress responses in the rat

    Science

    (1999)
  • M. Gilbertson et al.

    Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

    Nature Neuroscience

    (2002)
  • I. Gottesman et al.

    The endophenotype concept in psychiatry: etymology and strategic intentions

    American Journal of Psychiatry

    (2003)
  • C. Grillon

    Models and mechanisms of anxiety: evidence from startle studies

    Psychopharmacology

    (2008)
  • T. Hubler et al.

    Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

    Cell Stress Chaperones

    (2004)
  • T. Jovanovic et al.

    How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD

    American Journal of Psychiatry

    (2010)
  • T. Jovanovic et al.

    Conditioned and external fear inhibition in combat-related PTSD in Croatian war veterans

  • T. Jovanovic et al.

    Impaired fear inhibition is a biomarker of PTSD but not depression

    Depression and Anxiety

    (2010)
  • T.M. Keane et al.

    A behavioral formulation of posttraumatic stress disorder in Vietnam veterans

    The Behavior Therapist

    (1985)
  • R. Kessler

    Posttraumatic stress disorder: the burden to the individual and to society

    Journal of Clinical Psychiatry

    (2000)
  • Cited by (0)

    View full text