Posttraumatic stress disorder (PTSD) is a debilitating stress-related psychiatric disorder, with prevalence rates of at least 7% to 8% in the US population, and with much higher rates among combat veterans and those living in high-violence areas.1–3
Initially viewed as a potentially normative response to traumatic exposure,4
it became clear that not everyone experiencing trauma develops PTSD. Thus, a central question in research on PTSD is why some individuals are more likely than others to develop the disorder in the face of similar levels of trauma exposure.5–8
Although PTSD is the single disorder within the Diagnostic and Statistical Manual of Mental Disorders
(Fourth Edition) (DSM-IV
that requires a specific environmental insult within its diagnostic criteria, it is becoming increasingly clear that there are critical roles for predisposing genetic and environmental influences in differentially mediating psychological risk to the traumatized individual.10–13
Child abuse occurs at disturbingly high rates and is a major public health problem.14
Despite the resilience of many abused children, child abuse significantly increases risk for impaired physical and psychological health and decreases adaptive functioning in adulthood.15–17
A matter of central importance to public health is the identification of factors related to risk and resilience in the wake of child abuse. Of particular relevance to this study is the well-established relationship of child abuse with adult PTSD.18–22
A number of factors may account for this relationship. PTSD in adults may represent a prolonged symptomatic reaction to traumatic child abuse.
The experience of child abuse is associated with an increased number of traumatic experiences across the lifespan. Child abuse may also increase vulnerability for the later development of PTSD by altering psychological (eg, attachment) and biological (eg, hypothalamic-pituitary-adrenal [HPA] axis function) developmental processes, including interaction with genetic factors. Although other non–child abuse types of traumatic experiences in childhood23
(eg, a house fire or being in a vehicle crash) might be expected to negatively affect development, the most robust research to date points to child abuse and related family/interpersonal stressful life events in predicting a wide range of later psychological and physical health problems.
The reasons for this are not fully understood but some possible explanations are (1) compared with other types of traumatic events, child abuse is more likely to occur in the family context24
; (2) any 1 type of child abuse is associated with an increased likelihood of exposure to other types of abuse and to increased levels of family-related stressful events/parental dysfunction (eg, parental substance abuse)25
; and (3) compared with some other types of trauma exposure, child abuse may be more likely a repeated experience rather than a single event (eg, multiple incidents of sexual abuse by the same perpetrator over a number of years).25
Our study focuses on the interplay between child abuse and polymorphisms in the FKBP5
gene, which is involved in the glucocorticoid-mediated stress response, in the prediction of adult PTSD.
The literature to date on the genetics of PTSD has recently been reviewed,12,13
with the resulting suggestion that gene × environment studies are needed to focus more on distinct endophenotypes and influences from environmental factors. A number of studies suggest that genetic factors contribute to the development of PTSD, with heritability estimates ranging from 30% to 40%.11,26–29
Candidate gene studies, however, have been inconclusive so far, usually limited by extremely low power to detect any but the strongest possible genetic effects (current published studies include sample sizes of <100).
A recent review12
covering candidate genes in the serotonin, dopamine, glucocorticoid receptor (GR), γ-aminobutyric acid, apolipoprotein E, brain-derived neurotrophic factor, and the neuropeptide Y system finds that (1) the support for a relationship between the serotonin transporter gene and PTSD exists only in research on the interaction of this system with stressful life events in predicting depressive symptoms; (2) results on the dopamine system are inconsistent; (3) there is a lack of evidence for relationships with brain-derived neurotrophic factor, neuropeptide Y, or GR polymorphisms and PTSD with the exception of a finding between GR genotype and basal cortisol levels in a subgroup of patients with PTSD30
; and finally, (4) limited evidence for the γ-aminobutyric acid system and the apolipoprotein E system.
One of the first studies finding an interaction between a genetic polymorphism and child abuse in predicting psychopathology was the study by Caspi et al,31
which found that maltreated children with a monoamine oxidase A (MAOA
) genotype conferring low levels of MAOA
expression were more likely to develop conduct disorder and antisocial-personality disorder and to commit violent crimes as adults compared with those children with the high-activity MAOA
genotype. A recent study32
has replicated this result, and a second study33
replicated the effect in white participants but not in other participants (blacks, Hispanics, American Indians, Pacific Islanders, and others) in the sample. The largest group of genotype × environment studies has examined the interaction between variation at the 5HTTLPR
(a complex-repeat polymorphism in the 5′ upstream region of SLC6A4
, which encodes the serotonin transporter the 5HTTLPR
) and stressful life events, including child abuse, in predicting depression.34–40
Very recently, Kilpatrick et al41
reported an interaction of this polymorphism with severity of trauma and level of social support with the development of PTSD following hurricane exposure as outcome, supporting the relevance of gene × environment interactions for this disease.
From a developmental perspective, HPA axis genes are strong candidates with respect to altering susceptibility to PTSD. Exposure to trauma and stress increase HPA axis activity, and PTSD has been associated with long-lasting alterations in HPA axis reactivity42,43
and specifically higher GR sensitivity.44,45
Polymorphisms in genes regulating GR activity may impact the acute effects of trauma on the HPA axis and thereby possibly impact long-term HPA axis regulation affecting the development of PTSD. A number of studies suggest that child abuse and neglect affect HPA axis functioning (reviewed by Watts-English et al46
). Several studies suggest that the depression-related HPA axis hyperactivity may be related to early life stress. For example, plasma corticotropin and cortisol, as well as cerebrospinal fluid corticotropin-releasing hormone (CRH) concentrations, correlate with perceived early life stress more than with current depression.47,48
Preclinical studies indicate that the persistent hyperactivity of the HPA axis associated with early life stress is mediated by a hyperactive CRH receptor 1 (CRHR1) system, with chronic over activity of CRHR1 in limbic brain regions.49,50
FKBP5 is a co-chaperone of hsp90. It directly interacts with hsp90, which binds to the GR. FKBP5 also has been shown to regulate GR sensitivity. FKBP5 is part of the mature GR heterocomplex.51
On hormone binding, FKBP5 is replaced by FKBP4, which then recruits dynein into the complex, allowing translocation into the nucleus where the complex regulates expression of glucocorticoid-responsive genes by functioning as a transcription factor.52
FKBP5 expression is induced by glucocorticoids as part of an intracellular ultrashort negative feedback loop for GR activity.53
Overexpression of human FKBP5 in vitro reduces hormone binding affinity54
and nuclear translocation of GR.55
Naturally occurring overexpression of FKBP5 causes GR resistance in New World monkeys,54,56
which is accompanied by increased plasma cortisol levels. Furthermore, potentially functional single-nucleotide polymorphisms (SNPs), or SNPs in very strong linkage disequilibrium with a functional variant, appear to alter FKBP5 function. The rare homozygous genotypes of FKBP5
SNPs (rs4713916, rs1360780, and rs3800373) were associated with higher FKBP5 expression in human blood monocytes as well as with a stronger induction of FKBP5 messenger RNA (mRNA) by cortisol. This was accompanied by less corticotropin release measured in patients who were depressed with the combined dexamethasone-CRH test.57
The same alleles of rs3800373 and rs1360780 were associated with increased peritraumatic dissociation in children after medical trauma.58
Higher levels of peritraumatic dissociation have been shown to be predictors of PTSD in adults.10
In addition, the extent of up-regulation of FKBP5 mRNA in peripheral blood mononuclear cells only hours after a trauma has been shown to correlate with the development of PTSD at 4 months.59
These data suggest that FKBP5
could be an important candidate gene in trauma-related HPA axis disturbances. We therefore hypothesized that the putative functional SNPs in FKBP5
moderate the development of PTSD. Because early trauma, PTSD, and FKBP5
SNPs have all been shown to influence GR resistance, we also hypothesize that variants in this gene may alter the impact of early trauma or PTSD on GR sensitivity and address this by investigating the dexamethasone suppression test (DST) in a subsample of individuals.44,57,60
Our study addresses the role of polymorphisms in FKBP5 in predicting PTSD, as well as the PTSD symptom–associated changes in GR sensitivity, in a highly traumatized, inner city sample. Specifically, we address whether these polymorphisms interact with increasing levels of child abuse and increasing levels of non–child abuse trauma exposure to predict PTSD symptomatology during adulthood.