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Interactive Effect of Stressful Life Events and the Serotonin Transporter 5-HTTLPR Genotype on Posttraumatic Stress Disorder Diagnosis in 2 Independent Populations

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The 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) has been found to moderate several categories of emotional response after stressful life events. Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of posttraumatic stress disorder (PTSD). To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene x environment interactions on the etiology of PTSD. A cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses. General community. Five hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both. Main Outcome Measure Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview. Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P = .002; African American: OR, 1.88; 95% CI, 1.04-3.40; P = .04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P < .001). Participants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S' (S) allele compared with the L' (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors.
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Interactive Effect of Stressful Life Events and the Serotonin
Transporter 5-HTTLPR Genotype on Posttraumatic Stress
Disorder Diagnosis in 2 Independent Populations
Pingxing Xie, BS, Henry R. Kranzler, MD, James Poling, PhD, Murray B. Stein, MD, MPH,
Raymond F. Anton, MD, Kathleen Brady, MD, PhD, Roger D. Weiss, MD, Lindsay Farrer,
PhD, and Joel Gelernter, MD
Departments of Genetics (Dr Gelernter and Ms Xie) and Psychiatry (Drs Gelernter and Poling), Yale
University School of Medicine, New Haven, VA Connecticut Healthcare Center, West Haven (Drs
Gelernter and Poling and Ms Xie), and Departments of Psychiatry and Genetics and Developmental
Biology, University of Connecticut School of Medicine, Farmington (Dr Kranzler); Departments of
Psychiatry and Family and Preventive Medicine, University of California, San Diego, and VA San
Diego Healthcare System (Dr Stein); Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina, Charleston (Drs Anton and Brady); Department of Psychiatry, Harvard
Medical School and McLean Hospital, Belmont (Dr Weiss), and Departments of Medicine,
Neurology, Genetics and Genomics, and Epidemiology and Biostatistics, Boston University School
of Medicine and Public Health, Boston (Dr Farrer), Massachusetts.
Abstract
Context: The 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene
(SLC6A4) has been found to moderate several categories of emotional response after stressful life
events. Previous studies generally focused on its effect on depressive symptoms; little is known about
its moderation of the development of post-traumatic stress disorder (PTSD).
Objective: To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR
genotypes, and gene×environment interactions on the etiology of PTSD.
Design: A cross-sectional study in which participants in several studies investigating the genetics
of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-
HTTLPR was genotyped. Logistic regression modeling was used in the analyses.
Setting: General community.
Participants: Five hundred eighty-two European American and 670 African American individuals
who reported experiences of childhood adversity, adult traumatic events, or both.
Main Outcome Measure: Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed
through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview.
©2009 American Medical Association. All rights reserved.
Correspondence: Joel Gelernter, MD, Yale University School of Medicine, Department of Psychiatry, Division of Human Genetics in
Psychiatry, VA CT Healthcare Center 116A2, 950 Campbell Ave, West Haven, CT 06516 (joel.gelernter@yale.edu)..
Additional Contributions: Greg Kay, BS, and Ann Marie Lacobelle, MS, provided technical assistance. We thank the individuals and
families participating in this work and the interviewers at all of the participating sites for collecting the data.
Financial Disclosure: Dr Stein receives or has in the past 3 years received research support from Eli Lilly and Co and GlaxoSmithKline
and is currently or has in the past 3 years been a consultant for AstraZeneca, Avers Pharmaceuticals, BrainCells Inc, Bristol-Myers
Squibb, Eli Lilly and Co, EPI-Q, Forest Laboratories, Hoffmann-La Roche Pharmaceuticals, Integral Health Decisions Inc, Jazz
Pharmaceuticals, Johnson & Johnson, Mindsite, Sanofi-Aventis, Transcept Pharmaceuticals Inc, and Virtual Reality Medical Center.
Additional Information: The eTable is available at http://www.archgenpsychiatry.com.
NIH Public Access
Author Manuscript
Arch Gen Psychiatry. Author manuscript; available in PMC 2010 May 11.
Published in final edited form as:
Arch Gen Psychiatry. 2009 November ; 66(11): 1201–1209. doi:10.1001/archgenpsychiatry.2009.153.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Results: Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-
HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events
and childhood adversity to increase the risk for PTSD, especially for those with high rates of both
types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI],
1.50-5.45; P=.002; African American: OR, 1.88; 95% CI, 1.04-3.40; P=.04; pooled: OR, 2.31; 95%
CI, 1.50-3.56; P<.001).
Conclusions: Participants who had both childhood adversity and adult traumatic events were more
likely to develop lifetime PTSD compared with those who experienced either type of adverse event.
The risk was increased in individuals with 1 or 2 copies of the S (S) allele compared with the L
(L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the
interactive effect of environmental and genetic factors.
Posttraumatic stress disorder (PTSD) is a complex and multifactorial anxiety disorder.
According to the DSMIV, it requires the presence of symptoms from each of 3 clusters,
reexperiencing, avoidance, and increased arousal, that occur following exposure to a life-
threatening traumatic event. While 40% to 70% of the US population have experienced high-
level traumatic events,1,2 the lifetime prevalence for PTSD is 8% in adult Americans based on
community epidemiological studies (DSM-IV). Several risk factors, including those that
characterize the traumatic exposure as well as those that characterize traits of the individual,
have been identified for PTSD. Among the former, traumatic events that involve the infliction
of harm by others (eg, rape, physical assault, military combat) carry higher risks for PTSD than
other traumas (eg, natural disasters).3 Female sex, preexisting psychiatric disorders, and
premorbid personality characteristics such as neuroticism have also been shown to increase
risk for PTSD.4,5
Childhood adversity, including sexual and physical abuse, neglect, and other traumas, has
received considerable attention from researchers in the studies of the etiology of PTSD.
Neurobiological consequences of early life stress can be severe in that they cause enduring
changes in brain structure and function.6 These physical changes could influence the response
to adult traumas, triggering a cascade of biological events that may ultimately lead to the
occurrence of mental disorders. Meanwhile, childhood adversity is associated with an increased
risk for behavior problems,7 which, in turn, expose the person more to traumatic events.
Numerous studies have shown that childhood adversity is associated with a range of mental
disorders, such as major depression,8 antisocial disorder, substance use disorder,9 and PTSD.
10 Although most studies of early life stress and mental disorders have focused on childhood
abuse or neglect, other traumatic events, such as involvement in a serious accident or witnessing
events causing death or serious injury, also constitute an important part of a broad view of early
life stress.
In addition to the obvious effect of environmental factors, PTSD has a heritable component.
A twin study based on the Vietnam War veteran sample indicated that genetic factors account
for approximately 30% of the variance in PTSD symptoms.11 A more recent study outside the
context of military trauma showed similar findings.12 Although the idea that PTSD is affected
by both environmental and genetic factors has been widely accepted, there have been relatively
few molecular genetic studies of PTSD. Association studies have identified a small number of
possible susceptibility genes, but the results are inconsistent.13 The difficulty in identifying
PTSD-related genes may be due to their low to moderate effect sizes, with consequent
insufficient statistical power of many studies, and other methodological shortcomings.14
Study of gene×environment effects on mental disorders has been of great interest recently.
This approach is especially promising for investigating the etiology of PTSD, which requires
exposure to a traumatic event and has a genetic component. The serotonin transporter gene
(SLC6A4) has been shown to moderate several categories of emotional response. In the brain,
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the serotonin transporter is involved in the rapid reuptake of serotonin following neuronal
stimulation; it is thus a key regulator of serotonergic neurotransmission. A common
polymorphism (5-HTTLPR) in the promoter region of SLC6A4 was found to regulate gene
expression. In vitro studies of SLC6A4 expression in human lymphoblastoid cells and placental
choriocarcinoma cell lines consistently showed that the long variant of the polymorphism (L)
(16 repeats) produced 2- to 3-fold higher levels of messenger RNA than that of the short variant
(14 repeats), resulting in reduced serotonin reuptake.15,16 In vivo studies of messenger RNA
level in human postmortem tissue sections, however, yielded inconsistent results.17,18 One
possible explanation for this inconsistency between in vitro and in vivo studies is that under
normal physiological conditions, the expression level of SLC6A4 may be regulated by many
other factors. However, when stressful life events occur, which increases the serotonin release
at targeted brain regions,19 the S allele may be less efficient than the L allele at up-regulating
the expression level of the serotonin transporter and keeping the extracellular serotonin at a
normal level. Studies of humans and rhesus macaques showed that the presence of the S allele
interacts with environmental factors to produce effects on behavior and measures of central
nervous system function.20-22 Although the most common alleles at 5-HTTLPR in most
populations have either 14 or 16 repeated elements, other alleles, generally with more repeated
elements (18 or 20 repeats), occasionally occur.23 However, transcriptional efficiencies of
these rare 5-HTTLPR alleles are unknown. More recently, an A/G single-nucleotide
polymorphism (SNP) (rs25531) in the repeats region was found to be functional; rs25531 is
mostly found in the L variant, further dividing it into LA and LG.24 LG and S alleles have
equivalent expression levels, which are about half of that of the LA allele; LG and S are thus
reclassified as S and L, as L.25 A Although PTSD, like depression, can be considered to reflect
a maladaptive response to stressful events, few studies have examined the possible role of 5-
HTTLPR in moderating the influence of traumatic events on PTSD risk.
In the present study, gene×environment interaction was examined to explore its effect on the
development of PTSD. We recruited a large number of patients in the course of studies
investigating the genetics of drug and alcohol dependence, disorders that are associated
(perhaps causally) with high rates of PTSD,26,27 and administered the Semi-Structured
Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive
polydiagnostic instrument that includes assessment of PTSD.28,29 The SSADDA covers a wide
range of traumatic events and contains additional items related to childhood adversity. Using
these environmental data and the triallelic system (LA/LG/S) for 5-HTTLPR, individual and
interactive effects of genetic and environmental factors were investigated.
METHODS
SAMPLE COLLECTION AND DEMOGRAPHIC INFORMATION
Samples in this study were a subgroup of 1793 European American and African American
individuals who participated in linkage studies focused on the genetics of substance
dependence (and were recruited as members of families, each of which included at minimum
an affected sibling pair for cocaine or opioid dependence),30,31 as well as more recently
recruited subjects, substance dependence cases and unaffected controls, related and unrelated,
all of whom were recruited and ascertained with similar methods. The participants were
recruited at 4 sites: Yale University School of Medicine, University of Connecticut Health
Center, Medical University of South Carolina, and McLean Hospital of Harvard Medical
School. Written informed consent was obtained from all participants. The institutional review
board at each of the participating sites approved the study protocol. All subjects were
interviewed using the SSADDA, which provides diagnostic criteria for a variety of psychiatric
and substance use disorders, as well as information on childhood environment.32,33 Since the
purpose of the present study was to explore the factors affecting the risk for PTSD when
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individuals face traumatic events, 510 people who reported never having experienced
childhood adverse events or adult traumatic events were excluded. In addition, 31 individuals
with rare 5-HTTLPR alleles were excluded from the study, leaving 1252 informative subjects.
The mean (SD) age of the 1252 participants (52% male) was 38.9 (11.0) years, ranging from
17 to 79 years. To derive ancestry information from each individual, a panel of 41 ancestry-
informative markers was genotyped, including FY and 36 short tandem repeats markers
described in our previous studies,34,35 and augmented by 4 highly ancestry-informative SNPs,
rs1540771 (6p23.5), rs1805007 (MC1R), rs12896399 (SLC24A4), and rs1426654
(SLC24A5), which are all associated with hair, eye, and/or skin pigmentation.36,37 These
ancestry-informative markers were analyzed by a Bayesian cluster model using STRUCTURE
software.38-40 We used admixture and allele frequencies–correlated models and 500 000
Markov chain Monte Carlo repeats after 500 000 burn-in repetitions.
DIAGNOSIS OF PTSD AND ADULT TRAUMATIC EVENTS INDEX
Sample collection and diagnostic interviews were performed by trained interviewers.
Interviewing methods and the diagnostic reliability of the SSADDA, including the PTSD
section (which showed interrater reliability and test-retest reliability [κ] of 0.59 and 0.76,
respectively), have been described previously.32,33 In the SSADDA PTSD section, 12 separate
types of traumatic events are assessed. These events are experienced direct combat in a war;
seriously physically attacked or assaulted; physically abused as a child; seriously neglected as
a child; raped; sexually molested or assaulted; threatened with a weapon; held captive or
kidnapped; witnessed someone being badly injured or killed; involved in a flood, fire, or other
natural disaster; involved in a life-threatening accident; suffered a great shock because one of
these events happened to someone close to you; and other. Participants were asked to list up
to 3 traumatic events and their age when these events happened. Those reporting traumatic
experiences were then interviewed for potential PTSD symptoms. After all of the data were
scored, a PTSD diagnosis was generated based on DSM-IV criteria requiring symptoms from
each of 3 clusters, reexperiencing, avoidance, and increased arousal, that occur following the
events.
CHILDHOOD ADVERSITY INDEX
Although childhood physical abuse and neglect are ascertained in the PTSD section of the
SSADDA, we used the Environment section as the main instrument to assess participants'
childhood experiences. All of the participants were asked whether they had witnessed or
experienced a violent crime or been sexually abused, physically abused, or neglected by age
13 years. Since neglect is more subjective than the other childhood adversities, participants
were asked 3 questions to assess it: “whether the person you were closest to was usually
available to you when you needed him or her,” “whether you felt you could confide in this
person when necessary,” and “whether this person was aware of who your friends were.”
Respondents who answered “no” to any of the 3 questions were considered to have been
neglected.
GENOTYPING
DNA was extracted from whole blood or immortalized cell lines. Polymerase chain reaction
amplification was used to differentiate the short allele from the long allele of the 5-HTTLPR
polymorphism. Polymerase chain reaction conditions are described in detail elsewhere.23 To
genotype the additional SNP (rs25531), the polymerase chain reaction product was digested
by MspI and size-fractionated on agarose gel.41
Detailed genotyping methods and characteristics for 37 of the 41 ancestry-informative markers
were described previously.34 The remaining 4 SNPs were genotyped by the TaqMan technique
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using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems Inc, Foster City,
California).
STATISTICAL ANALYSIS
Based on the levels of transcriptional efficiency, the triallelic geno-types were reclassified:
LA/LA was reclassified as LL; LA/S and LA/LG were reclassified as LS; and LG/LG, LG/S, and
S/S were reclassified as SS. We used logistic regression models to examine the association
between the PTSD diagnosis and the potential explanatory variables. In the first model, the
effects of 5-HTTLPR geno-type (coded as 0 for LL, 1 for LS, and 2 for SS), childhood
adversity (coded as 0 for none, 1 for exposure), adult traumatic events (coded as 0 for none, 1
for exposure), gene×childhood adversity, and gene×adult traumatic events were explored. In
the second model, we focused on the participants who experienced both childhood and
adulthood traumas. Exposure to dual stressful event types (both childhood and adulthood) was
coded as 1, and exposure to either type of stressful events was coded as 0. The interactive effect
of gene×stressful events was calculated. After that, in the third model, we analyzed the dual
stressful events linearly: exposure to adulthood trauma and 1 type of childhood adversity was
coded as 1, adulthood trauma and 2 types of childhood adversity was coded as 2, adulthood
trauma and 3 or more types of childhood adversity was coded as 3, and exposure to either type
of stressful events was coded as 0. In the first 2 models, we first analyzed each population,
European American individuals and African American individuals, separately, using sex and
age as covariates. Then we combined the data across the 2 populations using sex, age, and
ancestry proportion scores as covariates. In the third model, since the group of dual stressful
events was already small, dividing it into 3 groups further decreased the sample size. To
increase the statistical power, only analyses with combined data (sex, age, and ancestry
proportion scores were used as covariates) were performed. In addition, generalized estimating
equations (GEE)42 were applied to fit the logistic regression model to take into account the
potential dependence of the data from individuals within the same nuclear family. An
exchangeable correlation structure was used in this logistic GEE regression model. Since many
previous 5-HTTLPR×stressful events studies did not include rs25531, analyses using the
diallelic L-S classification were also performed. Comparisons between groups of categorical
variables were made using χ2 tests. All analyses were performed by SAS 9.1 (SAS Inc, Cary,
North Carolina).
RESULTS
DEMOGRAPHICS
Approximately one-fifth of the 1252 participants (n=229; 18.3%) who experienced childhood
adverse events and/or adult traumatic events met the criteria for lifetime PTSD. The mean (SD)
age of participants developing PTSD was 39.3 (9.6) years, which was similar to those without
a diagnosis of PTSD (mean [SD], 38.9 [11.3] years). Table 1 presents information on the
prevalence of PTSD by sex and population. Among women, 22.3% received a lifetime
diagnosis of PTSD, which was significantly higher than for male participants (14.6%)
(; P<.001). The rate of PTSD among European American individuals (19.6%) and
African American individuals (17.1%) was statistically indistinguishable ( ; P=.26). In
addition, many psychiatric disorders were observed to be comorbid with PTSD (eTable,
http://www.archgenpsychiatry.com).
EFFECT OF ADULT TRAUMATIC EVENTS ON RISK OF PTSD
Eight hundred eighty of the 1252 participants (70.3%) reported that they had experienced 1 or
more traumatic events as adults. Among them, 21.5% (n=189) met criteria for lifetime PTSD.
In contrast, only 10.7% of the participants who never experienced adult traumatic events
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developed PTSD. Using a logistic GEE regression model, after adjusting for age, sex, ancestry
proportion score, 5-HTTLPR genotype, and childhood adversity, adult traumatic events were
significantly associated with an increased risk for PTSD (OR, 3.57; 95% CI, 2.43-5.25; P<.
001) (Table 2).
EFFECT OF CHILDHOOD ADVERSITY ON RISK OF PTSD
Four types of childhood adversities, namely witnessing or experiencing a violent crime, sexual
abuse, physical abuse, or neglect, were assessed in this study. Most of the participants (n=924;
73.8%) experienced at least 1 type of childhood adversity. Among them, 64.4% (n=595)
experienced 1 type of adverse event; 23.8% (n=220) experienced 2 types; and 11.8% (n=109)
experienced 3 or 4 types of childhood adversities. The percentage of participants with a lifetime
diagnosis of PTSD increased from 8.8% in individuals with no childhood adversity to 15.4%
in those with 1 type, 28.6% in those with 2 types, and 40.5% in those with 3 or 4 types of
childhood adversity (Figure 1). Using the same logistic GEE regression model described
previously, a significant effect of childhood adversity on PTSD development was observed
(OR, 4.30; 95% CI, 2.81-6.60; P<.001) (Table 2).
EFFECT OF 5-HTTLPR GENOTYPES ON RISK OF PTSD
In European American individuals, the frequency of the long allele was 56.3% and the short
allele, 43.7%. The genotype distribution was 31.1% LL, 50.3% LS, and 18.6% SS. The minor
allele frequency of rs25531 was 7.1%. After reclassification, the genotype frequencies were
23.5% LL, 51.2% LS, and 25.3% SS. In African American individuals, the frequencies for
the long and short alleles were 77.8% and 22.2%, respectively, and the genotype distribution
was 61.0% LL, 33.6% LS, and 5.4% SS. The minor allele frequency of rs25531 was 22.5%.
After reclassification, the genotype distribution was 32.2% LL, 46.1% LS, and 21.6% SS.
The allele frequencies of the 5-HTTLPR polymorphism were consistent with previous studies,
21,23,24 and all were in Hardy-Weinberg equilibrium.
After adjusting for age, sex, childhood adversity, and adult traumatic events, logistic GEE
regression analysis showed no significant association between 5-HTTLPR genotype and PTSD
diagnosis in either European American or African American individuals (European American:
OR, 1.24; 95% CI, 0.91-1.69; P=.17; African American: OR, 1.22; 95% CI, 0.91-1.63; P=.18);
the association in the combined sample, in which ancestry proportion score was entered as a
covariate, was not statistically significant (OR, 1.22; 95% CI, 0.99-1.51; P=.07). The use of
diallelic genotypes, which include only the L and S alleles of the 5-HTTLPR polymorphism,
in the logistic regression analysis also showed that 5-HTTLPR genotypes were not associated
with PTSD (OR, 0.95; 95% CI, 0.67-1.35; P=.77). In addition, none of the psychiatric disorders
that were found to be comorbid with PTSD were associated with 5-HTTLPR genotypes
(eTable).
5-HTTLPR GENOTYPES INTERACTED WITH CHILDHOOD ADVERSITY AND ADULT
TRAUMATIC EVENTS TO INCREASE RISK FOR DEVELOPING PTSD
We first tested two 2-way interactions, genotype×adult traumatic events and
genotype×childhood adversity, as predictors in the model. After adjusting for all the main
effects, including age, sex, genotype, childhood adversity, and adult traumatic events, the
genotype×adult traumatic events interaction was significantly associated with risk for PTSD
in both European American and African American individuals separately (European American:
OR, 2.60; 95% CI, 1.19-5.66; P=.02; African American: OR, 2.06; 95% CI, 1.02-4.14; P=.04)
(Figure 2A and B), with the combination of the 2 populations providing stronger evidence of
association (OR, 1.93; 95% CI, 1.17-3.17; P=.01). The genotype×childhood adversity
interaction was found to be significantly associated with risk for PTSD in European American
individuals, but not in African American individuals (European American: OR, 3.29; 95% CI,
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1.17-9.22; P=.02; African American: OR, 1.71; 95% CI, 0.81-3.61; P=.16) (Figure 2C and D).
When all the participants were combined together, the interactive effect of genotype×childhood
adversity was significant (OR, 1.81; 95% CI, 1.01-3.24; P=.046).
Because in our study the participants reported experiencing at least 1 type of trauma, and many
of them experienced both childhood adversity and adult traumatic events, we then investigated
how the high rates of both types of trauma exposure interacted with 5-HTTLPR to influence
risk for PTSD. Five hundred fifty-two of the 1252 participants (44.1%) experienced both
childhood adversity and adult traumatic events. Among this group, 29.0% (n=160) received a
lifetime diagnosis of PTSD. In contrast, only 9.9% of participants who experienced either (but
not both) childhood adversity or adult traumatic events developed PTSD. Moreover, among
European American participants who experienced both stressful events, 41.0% with the SS
genotype developed PTSD, compared with 33.1% in the LS genotype group and only 18.3%
in the LL genotype group. In African American participants, 38.2% of individuals with the S
S genotype, 26.2% with the LS genotype, and 19.5% with the LL genotype were diagnosed
with PTSD (Figure 3). If we used the dual stressful events as a predictor, and computed the
second logistic regression model described in the “Methods” section, after adjusting for all the
main effects, the genotype×dual stressful events interaction was significantly associated with
risk for PTSD in both European American and African American individuals (European
American: OR, 2.86; 95% CI, 1.50-5.45; P=.002; African American: OR, 1.88; 95% CI,
1.04-3.40; P=.04), with the combination of the 2 populations providing stronger evidence of
association (OR, 2.31; 95% CI, 1.50-3.56; P<.001) (Table 2). If the L-S diallelic classification
of the 5-HTTLPR genotype was used, the results of the genotype×dual stressful events
interaction were comparable with those obtained using the triallelic clasification (European
American: OR, 2.37; 95% CI, 1.19-4.72; P=.01; African American: OR, 2.97; 95% CI,
1.43-6.17; P=.003; pooled: OR, 2.64; 95% CI, 1.63-4.27; P<.001). In addition, this interactive
effect was observed in both male and female participants (triallelic genotypes: male: OR, 2.38;
95% CI, 1.20-4.72; P=.01; female: OR, 2.31; 95% CI, 1.31-4.09; P=.004; diallelic genotypes:
male: OR, 1.99; 95% CI, 1.01-3.92; P=.04; female: OR, 3.38; 95% CI, 1.72-6.64; P<.001).
Because the number of childhood adversity types was associated with the risk of PTSD, we
then modeled the dual stressful events linearly, as was described in the “Methods” section. The
interaction further suggested that the effect of life events on the onset of PTSD was stronger
among individuals with an S (S) allele than among those without (triallelic genotypes: OR,
1.41; 95% CI, 1.20-1.66; P<.001; diallelic genotypes: OR, 1.60; 95% CI, 1.32-1.94; P<.001)
(Figure 4).
DISTRIBUTION OF CHILDHOOD ADVERSITY AND ADULT TRAUMATIC EVENTS BY
GENOTYPE GROUPS
As mentioned previously, different traumas influence people differently. Certain life-
threatening events may carry higher risk for developing PTSD than others. To exclude the
possibility that trauma type was a confounding factor in our study, we examined the distribution
of childhood adversity and adult traumatic events across the genotype groups. For childhood
adversity, the distribution of events did not differ significantly among the 3 genotype groups
(Table 3). Based on the characteristics of the trauma types, and previous studies showing that
events involving the element of interpersonal assault are associated with a higher rate of PTSD
than events without the element,4,12 we grouped the 10 types of adulthood adverse events into
3 broad groups, namely, sexual trauma (rape or molestation), physical trauma (physical attack,
threatened with a weapon, held captive, or kidnapped), and other trauma (witness, natural
disaster, accident, shock, or other qualifying trauma). The distribution of this measure also did
not differ significantly among the 3 genotype groups (Table 3).
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COMMENT
In this study, we examined the effects of childhood adversity, adult traumatic events, the 5-
HTTLPR polymorphism, and their interactions on the risk of receiving a lifetime diagnosis of
PTSD. We found that both childhood adversity and adult traumatic events predicted PTSD.
Although the 5-HTTLPR polymorphism alone did not predict the onset of PTSD, it regulated
risk for PTSD in people who experienced childhood adversity and/or adult traumatic events,
especially in those who experienced both types of stressful life events, with comparable
findings in both European American and African American individuals. We initially based the
hypothesis on evidence from prior studies that SLC6A4 was associated with emotional
responses, especially the response to a stressful life event. Indeed, our previous work showed
that this locus influenced risk for PTSD-related symptoms in a sample of subjects exposed to
a hurricane.43
Although the role of serotonergic function in the patho-physiology of PTSD is still unclear, it
is believed to regulate a wide array of stress-related processes: anxiety, arousal, depression,
aggression, and impulsivity, which are all common symptoms of PTSD. Since the serotonin
transporter regulates serotonergic neurotransmission, and is the primary target of efficacious
antidepressants such as selective serotonin reuptake inhibitors, SLC6A4 has received particular
attention in research on mood and anxiety disorders. Compared with the L allele, the S allele
of the 5-HTTLPR polymorphism was found to reduce SLC6A4 expression and function,
resulting in decreased serotonin reuptake. Previous studies have shown that presence of the
short allele was associated with anxiety-related personality traits15 and increased amygdala
neuronal activity under fearful stimuli44 and may influence selective serotonin reuptake
inhibitor response rate among European American patients.41 Studies of gene×environment
interactions have also provided evidence for a functional link among serotonin, psychosocial
stressors, and risk of depression21,22,45 and an intermediate phenotype of anxiety,25 although
some other studies failed to replicate these findings.46-48
Our study provides additional evidence that genetic and environmental factors interact to play
a role in psychiatric disorders. Exposure to trauma earlier in life increases risk for PTSD on
exposure to subsequent trauma.49 Our study suggests that this risk is heightened among
individuals with 1 or 2 copies of the 5-HTTLPRS(S) allele. Interestingly, because of the design
of our study (people who reported never experiencing traumas were not included), we were
unable to ascertain an effect of 5-HTTLPR genotype on risk for PTSD among persons with
either (but not both) childhood maltreatment or adult trauma. It was only in the group of subjects
who could be characterized as having had the highest rates of trauma exposure (ie, in both
childhood and adulthood) that an impact of 5-HTTLPR could be detected. This suggests that
there may be many neurobiological (including genetically determined) “buffers” to PTSD;
only in instances of extreme and/or repeated trauma exposure (which, it should be pointed out,
characterizes those trauma “types” with the highest conditional risk for PTSD, eg, domestic
violence and military combat), in which these buffers are overwhelmed, can the impact of
specific genes such as 5-HTTLPR be detected. To our knowledge, this is the first study to
examine the diagnosis of PTSD as an outcome of a gene×environment interaction. Two
previous studies have focused on gene×environment interaction effects on PTSD symptom
severity.43,50 Kilpatrick and colleagues43 were the first to provide evidence that the S allele
of the 5-HTTLPR polymorphism modulated the influence of hurricane exposure and social
support on PTSD symptoms. A limitation of that epidemiologic study is that the number of
affected subjects was small (n=19). Further, it focused on 1 specific (and acute) trauma. This
decreased the heterogeneity of the trauma experience between patients, enhancing the internal
validity of the study but limiting its generalizability. The study by Binder and colleagues50
showed that 4 SNPs in the FKBP5 gene interacted with childhood abuse to increase the level
of PTSD symptoms. Two of the 4 SNPs in FKBP5 were previously found to be associated with
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peritraumatic dissociation, a well-established risk factor for PTSD, in medically injured
children.51 Binder and colleagues used a PTSD symptom scale score as an outcome measure
based on the assumption that it could be used to make inferences about the disorder. Although
the score correlates with a diagnosis of PTSD, it remains uncertain as to the relevance of the
measured symptoms to the disorder.
In comparison with these previous studies, the current study has several strengths that deserve
mention. Instead of using PTSD symptoms as an outcome, participants were directly
interviewed by trained interviewers, resulting in a reliable PTSD diagnosis. Consistent with
the necessity that PTSD follows exposure to traumatic event(s), we studied only people who
reported having had 1 or more extreme adverse experiences in their lives, which increased the
statistical power. In addition, we examined a range of childhood adversity and adult traumatic
events. These events covered most (although certainly not all) trauma types known to cause
PTSD. For the 5-HTTLPR genotypes, we performed analyses using genotypes based on the
triallelic reclassification to compare the results with those using the genotypes from the L-S
diallelic classification. They were nearly identical. Therefore, this study provided a systematic
and clear view of the gene×environment interaction as it contributes to the risk of a PTSD
diagnosis.
Different allele frequencies of 5-HTTLPR in European American and African American
individuals have been previously reported23 and were observed in our study. A series of
methods to exclude population stratification as a potential confounder were used in this study.
First, a Bayesian clustering method was applied to analyze the genotype data of 41 ancestry-
informative markers, dividing the participants into 2 subgroups. Second, statistical analyses
were performed separately within the 2 population subgroups. The interaction of 5-HTTLPR
by dual stressful life events was observed to be significantly associated with the PTSD
diagnosis in both populations individually. Third, when analyzing the whole sample, ancestry
proportion score was used as a covariate in the logistic regression model, although no
significant association was observed between PTSD and population. Therefore, the different
5-HTTLPR allele frequencies between the 2 populations were not likely confounding our
analyses.
However, interpretation of this study should consider the following limitation. Retrospective
recall of early adverse experiences might be inaccurate or biased, including the potential for
there to be bias introduced by a subsequent experience of PTSD. The interval, significance of
events, and personal characteristics could cause recall bias. Especially since PTSD rarely
occurs alone, an abnormal mental state related to other disorders, such as substance use disorder
or major depression, may also cause recall bias. Future gene×environment studies based on a
cohort longitudinal design would address this potential bias in recall of life events.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Funding/Support: This work was supported by National Institutes of Health grants R01 DA12690, R01 DA12849,
K24 DA15105, K24 AA013736, 24 DA022288, and R01 AA11330.
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Figure 1.
The number of childhood adversity types is associated with the onset of posttraumatic stress
disorder (PTSD).
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Figure 2.
In European American and African American individuals, 5-HTTLPR genotype interacted with
adult traumatic events (A and B) to increase risk for posttraumatic stress disorder (PTSD). In
European American individuals, the genotype also interacted with childhood adversity (C); in
African American individuals, the interactive effect was a trend (D). The numbers of patients
with PTSD of the total numbers of participants in the group are shown.
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Figure 3.
5-HTTLPR genotype interacted with dual stressful life events to increase the risk for
posttraumatic stress disorder (PTSD) in both European American and African American
individuals. The numbers of patients with PTSD of the total numbers of participants in the
group are shown.
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Figure 4.
5-HTTLPR genotype interacted with the number of stressful life events to increase the risk for
posttraumatic stress disorder (PTSD) (group 1: exposure to either adult trauma or childhood
adversity; group 2: exposure to adult trauma and 1 type of childhood adversity; group 3:
exposure to adult trauma and 2 types of childhood adversity; and group 4: exposure to adult
trauma and more than 2 types of childhood adversity).
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Xie et al. Page 17
Table 1
Prevalence of PTSD by Sex and Population
Characteristics PTSD, No. (%)
χ
1
2P Value
Sex 12.3 <.001
M (n = 656) 96 (14.6)
F (n = 596) 133 (22.3)
Population 1.3 .26
EA (n = 582) 114 (19.6)
AA (n = 670) 115 (17.1)
Abbreviations: AA, African American; EA, European American; PTSD, posttraumatic stress disorder.
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Xie et al. Page 18
Table 2
Results of Logistic Regression Analysesa
EA AA Pooled
OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value
Sex 0.53 (0.34-0.83) .005b0.63 (0.42-0.96) .03c0.58 (0.43-0.79) <.001d
Age,y 1.01 (0.99-1.02) .58 1.02 (1.00-1.04) .08 1.01 (1.00-1.02) .09
Ancestry proportion score 1.12 (0.81-1.55) .50
Adult traumatic events 4.09 (2.31-7.26) <.001d3.22 (1.90-5.45) <.001d3.57 (2.43-5.25) <.001d
Childhood adversity 5.70 (2.89-11.26) <.001d3.44 (1.98-5.97) <.001d4.30 (2.81-6.60) <.001d
5-HTTLPR genotype 1.24 (0.91-1.69) .17 1.22 (0.91-1.63) .18 1.22 (0.99-1.51) .07
5-HTTLPR× adult traumatic events 2.60 (1.19-5.66) .02c2.06 (1.02-4.14) .04c1.93 (1.17-3.17) .01c
5-HTTLPR× childhood adversity 3.29 (1.17-9.22) .02c1.71 (0.81-3.61) .16 1.81 (1.01-3.24) .046c
5-HTTLPR× dual stressful events 2.86 (1.50-5.45) .002b1.88 (1.04-3.40) .04c2.31 (1.50-3.56) <.001d
Abbreviations: AA, African American; CI, confidence interval; EA, European American; OR, odds ratio.
aSex, age, adult traumatic events, and childhood adversity were used as covariates in all the models. In addition, ancestry proportion scores were included in the pooled model.
bP<.01.
cP<.05.
dP<.001.
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Table 3
Distribution of Childhood Adversity and Adult Traumatic Events by Genotype Groups
%
LLLSSSP Value
Childhood adversity
Neglect 50.4 50.0 51.5 .78
Witnessing or experiencing a violent crime 41.5 42.2 40.7 .91
Sexual abuse 29.6 35.9 31.9 .26
Physical abuse 28.5 24.6 28.9 .36
Adult traumatic events
Sexual harassment 21.7 20.0 17.6 .57
Physical attack 42.9 46.1 45.6 .72
Accidents 70.8 69.5 70.1 .94
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... As they may be less stress resilient 254 as observed in patients who have experienced traumatic events, these subjects have a heightened risk for the development of PTSD. 255 SERT knockout (5-HTT −/− ) rats display reduced fear extinction learning that correlate to reduced c-Fos activation in the PFC. 256 Moreover, impaired fear extinction in these animals is associated with 5hmC immunoreactivity, and with changes in DNA demethylation in the central nucleus of the amygdala; 5hmC facilitates passive demethylation possibly by preventing DNMTs from maintaining DNA methylation status, thus promoting gene transcription. ...
Chapter
Biomarkers of PTSD are greatly needed because of the challenges to diagnose and treat due to stigma, biases in self-reporting, and limitations of identifying those at risk and the scarcity of tools to predict treatment outcome. PTSD is influenced by both genetic and environmental factors as well as its interplay. Because of the dynamic and context-dependent nature of epigenetic modifications, these offer great promise as biomarkers of PTSD for the prevention, prognosis, and prediction of treatment outcome. In this chapter, genomic and epigenomic studies of PTSD are discussed. Epigenomic studies of PTSD conducted to date include DNA methylation (including DNA methylation age), histone modifications, and noncoding RNAs. Further, we discuss recent work using integrative multiomics approach as well as related gaps, challenges, and future directions aimed at identifying biomarkers of PTSD.
... SLC6A4 is located on chromosome 17 at position 17q11 (National Center for Biotechnology Information, 2021a). The serotonin transporter-linked polymorphic region (5-HTTLPR) within the promoter region of SLC6A4 has been implicated in depression (Clarke et al., 2010;Wang et al., 2016), anxietyrelated traits (Munafò et al., 2009b), and PTSD (Xie et al. 2009). 5-HTTLPR variants comprise either 14 (short, S-allele) or 16 (long, L-allele) copies of a 22-23 base pair (bp) imperfect repeat . ...
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Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene [solute carrier family 6 member A4 (SLC6A4)] and human tryptophan hydroxylase 2 gene (TPH2) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in SLC6A4 and TPH2. Hypothesis: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs. Methods: Polymorphisms in SLC6A4 (5-HTTLPR, rs25531, 5-HTTLPR-rs25531, and STin2 VNTR) and TPH2 (rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ children and adolescents (aged 5–17 years) with any internalizing mental disorder (depression, anxiety disorders, or posttraumatic stress disorder), and 368 age- and sex-matched controls, who were also HIV+. Chronic and acute stress categories were derived by hierarchical cluster analysis. Logistic regression analysis was used to assess the independent moderating effect of chronic stress and each selected polymorphism on the association between acute stress and IMDs. Results: We observed a statistically significant association between severe acute stress and IMDs (p = 0.001). Children and adolescents who experienced severe acute stress were twice as likely to develop IMDs, compared to children and adolescents who experienced mild acute stress (p = 0.001). Chronic stress interacted with severe acute stress to increase the risk of IMDs (p = 0.033). Acute stress was found to interact with 5-HTTLPR-rs25531 S-A-S-A haplotype to increase the risk for IMDs among Ugandan HIV+ children and adolescents (p = 0.049). We found no evidence for a combined interaction of acute stress, chronic stress, and 5-HTTLPR-rs25531 on IMDs. Conclusion: The odds of having an internalizing mental disorder (IMD) were higher among HIV+ children and adolescents who experienced severe acute stress compared to HIV+ children and adolescents who experienced mild acute stress. Chronic stress and 5-HTTLPR-rs25531 independently moderated the association between acute stress and IMDs.
... particularly gene x environment association, quite a number of research papers have argued that subjects with either one or two copies of the 5HTTLPR short variant had higher scores of neuroticism than those who were homozygous for the 5HTTLPR long variant (Canli and Xie et al., 2009;Grabe et al., 2012). Additionally, postmortem studies have described decreased 5HTT expression in brains of suicidal victims. ...
Thesis
Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during developmental periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. In a previous study, we identified a subpopulation of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC) that transiently expressed Slc6a4/SERT during an early postnatal period in mice (P0–P10). These PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Genetic ablation of SERT or early-life exposure to the SSRI, fluoxetine (from P2 to P14), increases the number of functional PFC glutamate synapses (hyperinnervation) on both 5-HT and GABA neurons in the DRN which also causes anxiety/ depressive-like symptoms. From our transcriptomic profiling of these PFC-SERT+ neurons at a developmental age of P7, we identified the Htr7 gene which could be mediating the developmental effects of SERT ablation. In this thesis, using anatomical and behavioural assays, I showed that pharmacological blockade of the 5-HT7 receptor using specific antagonist was sufficient to prevent the hyperinnervation to the DRN and the anxiety/depressive-like symptoms. In addition, we showed that the 5-HT7 knockout mice have no morphological and behavioural deficits. Furthermore, overexpression of 5-HT7 in the developing PFC, was sufficient to reproduce the anxiety/depressive-like symptoms observed in the absence of PFC-SERT. In conclusion activation of the PFC 5-HT7 receptor during development, could be responsible for the hyperinnervation of glutamatergic synapses to DRN and therefore precipitates the depressive-like behaviours.
... Genetic variations within the SLC6A4 gene have also been explored in one study in relation to bipolar disorder, observing an interaction effect between 5-HTTLPR variants and childhood trauma on the age at onset [46]. An interaction effect between 5-HTTLPR genotype and childhood trauma was also observed in post-traumatic stress disorder (PSTD) [47]. Genetic variants within FKBP5 were observed to interact with childhood trauma predicting adult PSTD symptoms [48,49]. ...
Chapter
Psychiatric disorders are complex illnesses with multiple factors underlying their aetiology (genetic, environmental and personal factors). Gene–environment interaction (GxE) approaches explore how genetic risk variants in combination with environmental factors such as childhood trauma shape the risk for severe psychiatric disorders, including schizophrenia, bipolar disorder, severe depression and post-traumatic stress disorder. Childhood trauma has been regarded as one of the most robust environmental risk factors for psychiatric disorders. However, the large inter-individual differences in response to these early stressful events suggest that childhood trauma is not a sufficient cause of psychosis, and that underlying genetic vulnerability could play an essential role in bringing about psychiatric symptoms following adversity. This chapter aims to provide an overview of the candidate genes for psychiatric disorders that have been described to interact with childhood trauma. Likewise, we also discuss the mechanisms underlying such gene–environment interactions. We will provide an overview of how candidate-gene approaches are transitioning towards polygenic and genome-wide approaches in larger and better-powered samples.
... Another study conducted in adults found that reported experiences of childhood adversity and adult traumatic events predicted PTSD. Again, the 5-HTTLPR polymorphism did not predict PTSD alone, but it did increase risk when combined with childhood and adult traumas (Xie et al., 2009(Xie et al., , 2012. This polymorphism is thought to reduce expression levels of the serotonin transporter by impairing the transcriptional efficiency of the gene promoter (Lesch et al., 1996). ...
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Chapter
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