The role of hypothalamus–pituitary–adrenal genes and childhood trauma in borderline personality disorder

Abstract

Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.

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Eur Arch Psychiatry Clin Neurosci
DOI 10.1007/s00406-015-0612-2
ORIGINAL PAPER
The role of hypothalamus–pituitary–adrenal genes and childhood
trauma in borderline personality disorder
Ana Martín‑Blanco1,2 · Marc Ferrer2,3 · Joaquim Soler1,2 · Maria Jesús Arranz1,4 ·
Daniel Vega2,5,6 · Natalia Calvo2,3 · Matilde Elices1,2 · Cristina Sanchez‑Mora7 ·
Iris García‑Martinez7 · Juliana Salazar8 · Cristina Carmona1,2 · Joana Bauzà1,2 ·
Mónica Prat2,3 · Víctor Pérez1,2 · Juan C. Pascual1,2
Received: 6 February 2015 / Accepted: 29 June 2015
© Springer-Verlag Berlin Heidelberg 2015
also associations between BPD and haplotype combina-
tions of the genes FKBP5 and CRHR1. Two FKBP5 alleles
(rs3798347-T and rs10947563-A) were more frequent
in BPD subjects with history of physical abuse and emo-
tional neglect and two CRHR2 variants (rs4722999-C and
rs12701020-C) in BPD subjects with sexual and physical
abuse. Our findings suggest a contribution of HPA axis
genetic variants to BPD pathogenesis and reinforce the
hypothesis of the modulating effect of childhood trauma in
the development of this disorder.
Keywords Borderline personality disorder ·
Hypothalamus–pituitary–adrenal (HPA) axis · Childhood
trauma · Genetics · Polymorphisms · Etiology
Introduction
According to current theories, borderline personality disor-
der (BPD) results from the interaction between genetically
based biological vulnerabilities and psychosocial factors
Abstract Current knowledge suggests that borderline
personality disorder (BPD) results from the interaction
between genetic and environmental factors. Research has
mainly focused on monoaminergic genetic variants and
their modulation by traumatic events, especially those
occurring during childhood. However, to the best of our
knowledge, there are no studies on the genetics of hypothal-
amus–pituitary–adrenal (HPA) axis, despite its vulnerabil-
ity to early stress and its involvement in BPD pathogenesis.
The aim of this study was to investigate the contribution of
genetic variants in the HPA axis and to explore the modu-
lating effect of childhood trauma in a large sample of BPD
patients and controls. DNA was obtained from a sample
of 481 subjects with BPD and 442 controls. Case–control
differences in allelic frequencies of 47 polymorphisms in
10 HPA axis genes were analysed. Modulation of genetic
associations by the presence of childhood trauma was
also investigated by dividing the sample into three groups:
BPD with trauma, BPD without trauma and controls. Two
FKBP5 polymorphisms (rs4713902-C and rs9470079-
A) showed significant associations with BPD. There were
* Juan C. Pascual
jpascual@santpau.cat
1 Department of Psychiatry, Hospital de la Santa Creu i Sant
Pau, Centro de Investigación Biomédica en Red de Salud
Mental (CIBERSAM), Institut d’Investigació Biomèdica -
Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167,
08025 Barcelona, Spain
2 Psychiatry and Legal Medicine Department, Universitat
Autònoma de Barcelona, Campus de la UAB, Plaza Cívica,
s/n, Bellaterra, 08193 Barcelona, Spain
3 Department of Psychiatry, Hospital Universitari Vall
d’Hebron, Centro de Investigación Biomédica en Red de
Salud Mental (CIBERSAM), Paseo de la Vall d’Hebron
119-129, 08035 Barcelona, Spain
4 Fundació Docència i Recerca Mutua Terrassa, St. Antoni 19,
08221 Terrassa, Barcelona, Spain
5 Department of Psychiatry and Mental Health, Consorci
Sanitari de l’Anoia, Avenida Catalunya 11, Igualada,
08700 Barcelona, Spain
6 Institut of Neurosciences, Universitat Autònoma de
Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra,
08193 Barcelona, Spain
7 Psychiatric Genetics Unit, Vall d’Hebron Research Institut,
Hospital Universitari Vall d’Hebron, Paseo de la Vall
d’Hebron 119-129, 08035 Barcelona, Spain
8 Genetics Department, Hospital de la Santa Creu i Sant
Pau, U705, CIBERER, Av. Sant Antoni Mª Claret 167,
08025 Barcelona, Spain

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[1]. The high prevalence of childhood traumatic events in
subjects with BPD has led to consider this factor as the
main psychosocial event involved in its development [1–3].
Prospective studies with large cohorts of abused/neglected
children support this assumption [4–6]. Furthermore, an
association between childhood traumas and BPD severity
in adulthood has been observed [7].
However, the knowledge on the biological factors
involved is still scarce. As BPD is a heterogeneous disor-
der with several symptomatic domains such as impulsivity,
affective instability and problems in interpersonal relation-
ships, different biological systems have been suggested to
be involved in its aetiology [1]. For instance, impulsivity,
affective instability and suicidality have been related to the
serotonergic system; impulsivity and psychotic-like symp-
toms with the dopaminergic system; and dysphoric affect
with the noradrenergic system [8]. Dysfunction of the
hypothalamus–pituitary–adrenal (HPA) axis has also been
related to BPD, as this system is one of the main effectors
of the stress response [9].
Previous genetic association studies in individuals with
BPD have mainly focused on serotonergic and dopaminer-
gic systems, exploring the presence of risk polymorphisms
in genes like the serotonin transporter (SCL6A4), serotonin
receptors, tryptophan hydroxylase I (TPH1) and II (TPH2),
dopamine transporter (SLC6A3), dopamine receptors,
dopadecarboxylase, monoamine oxidase A (MAO-A) and
catecholamine-O-methyltransferase (COMT; for a revision
[10, 11]). Results have been inconclusive, probably caused
by small sample sizes and the analysis of a limited number
of polymorphisms. Gene–environment interaction (GxE)
studies have also focused on these monoaminergic systems.
Several significant associations have been reported, but
the findings still lack replication. Wagner et al. [12] have
shown that childhood sexual abuse may modulate the asso-
ciation between the short allele of a polymorphism in the
promoter region of SCL6A4 and impulsivity, between the
COMT Val 158 Met variant and aggressiveness [13, 14]
and between the brain-derived neurotrophic factor (BDNF)
Val 66 Met polymorphism and impulsivity [15]. Wilson
et al. [16] have reported that genetic variants of TPH1 may
modulate the association between childhood abuse and the
degree of BPD in adulthood.
Despite the vulnerability of the HPA axis to early stress
[17, 18] and its involvement in BPD pathogenesis [19],
only a few studies on the contribution of HPA axis genetic
alterations have been published [20–22]. These studies all
focus on epigenetic mechanisms, while the presence of risk
sequence polymorphisms has not been investigated. HPA
genetic variants have been associated with other mental
disorders closely related to BPD, such as depression [23–
26] and post-traumatic stress disorder [27, 28], and some
of these associations are modulated by childhood trauma
[24, 25, 27, 28]. The presence of polymorphisms in HPA
axis genes may also contribute to the development of BPD,
and this contribution may be modulated by early stressful
experiences.
The main objectives of this study were to investigate
the contribution of genetic variants in the HPA axis and
to explore the modulating effect of childhood trauma in a
large sample of BPD patients and controls.
Materials and methods
Participants
A sample of 481 subjects with BPD and 442 ethnically
matched controls was recruited in three hospitals in Spain
with specific BPD units with experience in research and clin-
ical management of this disorder. These BPD units are part
of Spain’s National Mental Health Service and provide free
medical attention with a specialist treatment programme for
outpatients with BPD. Subjects were consecutively recruited
between 2002 and 2013, among those BPD patients admit-
ted to these units during this time period who met the inclu-
sion criteria. All participants were Caucasians of European
descent from the same geographic area (Catalonia, Spain).
Patients were included if they met DSM-IV criteria for
BPD according to two semi-structured diagnostic inter-
views, the Spanish validated versions of both the Structured
Clinical Interview for Diagnostic and Statistical Manual of
Mental Disorders-IV (DSM-IV) Axis II Disorders (SCID-
II) [29] and the Revised Diagnostic Interview for Border-
lines (DIB-R) [30]. Comorbidity with axis I disorders was
allowed, but patients had to be stable from these patholo-
gies at the time of inclusion. Although they could also pre-
sent other personality disorders, BPD was the main diag-
nosis. Inclusion criteria for the BPD group consisted of:
(a) diagnosis of BPD according to DSM-IV criteria; (b) no
current episode of any axis I disorders according to DSM-
IV criteria, including substance dependence; and (c) no
severe physical conditions such as organic brain syndrome,
neurological disease or mental deficiency. Experienced
psychiatrists carried out a clinical interview to collect soci-
odemographic and clinical variables. BPD group included
mainly female patients (84 %), with a mean age of 30 years
(SD 7.3) and a clinical profile of moderate severity accord-
ing to DIB-R total score (Table 1).
A subgroup of the BPD sample (N = 154) filled in the
Childhood Trauma Questionnaire—Short Form (CTQ-
SF) [31], a self-administered questionnaire designed to
assess traumatic experiences in childhood. This subgroup
consisted of those patients recruited since 2009. Nearly
75 % of these subjects reported having suffered a moder-
ate–severe traumatic experience in childhood: 94 subjects

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(61 %) emotional abuse, 40 subjects (26 %) physical abuse,
59 subjects (38 %) sexual abuse, 70 subjects (45 %) emo-
tional neglect and 37 subjects (24 %) physical neglect.
The control group comprised 442 participants randomly
selected from blood donors recruited from general popula-
tion from the same geographic region as the patients. This
group included 82 % of females (N = 364) with a mean age
of 53.5 years (SD 18.6). In our country, blood donation is
a selfless act fairly widespread among population. Injecting
drug users and people suffering from chronic diseases are
rejected as donors; however, psychopathology or history of
childhood trauma was not evaluated in this group.
The total sample has a statistical power of ≥95 %
to detect genetic associations with a moderate genetic
effect [odds ratios (O.R.) ≥2, minor allele frequency,
MAF ≥ 0.05]. For comparisons with childhood traumas
subgroups (N = 154 BPD with or without childhood trau-
mas and N = 442 controls), our sample has 45–95 % power
to detect associations with a small (w = 0.1) or moderate
(w = 0.3) effect size, respectively (α = 0.05).
This study was approved by the clinical research eth-
ics committee of the three collaborating hospitals, and the
principles outlined in the Declaration of Helsinki were fol-
lowed. The participants did not receive any retribution, and
an informed consent form to participate in the study was
acquired.
Assessment instruments
• Structured clinical interview for DSM-IV axis II per-
sonality disorders (SCID-II) [29]: semi-structured
interview to assess personality disorders according to
DSM-IV criteria. The Spanish version has good dis-
crimination between axis II personality disorders, as
well as good reliability between raters as indicated by
an overall kappa of 0.85.
• Revised diagnostic interview for borderlines (DIB-R)
[30]: semi-structured interview to diagnose BPD within
the last 2 years. This interview also provides a measure
of the severity of the disorder. The Spanish version has
shown good psychometric properties regarding internal
consistency (Cronbach’s alpha 0.89), sensitivity (0.81)
and specificity (0.94). The interviewers were experi-
enced psychologists and presented a high inter-rater
reliability (within-class correlation 0.94). The inter-test-
reliability of DIB-R and SCID-II was moderate (kappa
0.59).
• Childhood trauma questionnaire-short form (CTQ-SF)
[31]: questionnaire designed to retrospectively assess
childhood abuse and neglect. The short version (CTQ-
SF) includes 28 items, and its validity in clinical and
non-referred populations has been tested. This question-
naire assesses five types of childhood trauma: sexual,
physical and emotional abuse, as well as physical and
emotional neglect. Each item is rated on a five-point
Likert-type scale ranging from never true to very often
true. The questionnaire provides an overall rating and a
specific score for every subscale (from 5 to 25), as well
as cut-off points to classify each trauma according to
the severity of the exposure (none, mild, moderate and
severe). As proposed in previous studies [32], we con-
sidered a positive history of trauma if severity was at
least moderate (i.e. cut-off scores of 8 or higher for sex-
ual abuse, 10 or higher for physical abuse, 13 or higher
for emotional abuse, 10 or higher for physical neglect
and 15 or higher for emotional neglect).
Genotyping
Blood samples were systematically collected by standard
techniques from the subjects upon admittance to the unit.
Genomic DNA was extracted from peripheral leucocytes
by using the salting out procedure (Autopure, Qiagen) [33].
Forty-seven informative polymorphisms (tag single-
nucleotide polymorphisms—SNPs) in ten HPA genes
(AVPR1A, AVPR1B, CRH-BP, CRHR1, CRHR2, FKBP5,
GCR—alternative name NR3C1, NPY, NPY1R and NYP2R)
were chosen using the HapMap programme (www.hapmap.
org) and the parameters r2 = 0.80 and MAF = 0.05. Table 2
includes a list of the HPA genes and SNPs investigated.
Table 1 Demographic and clinical characteristics of BPD subjects
Variables BPD subjects
(N = 481)
Demographic
Age [mean (SD)] 30.05 (7.30)
Women [n (%)] 404 (84 %)
Clinical
Revised diagnostic interview for borderlines (DIB-R)
Total score [mean (SD)] 7.39 (1.24)
Affect [mean (SD)] 1.57 (0.51)
Cognition [mean (SD)] 0.96 (0.67)
Impulsivity [mean (SD)] 2.32 (0.78)
Interpersonal relationships [mean (SD)] 2.54 (0.68)
Structured clinical interview for DSM-IV
Axis II personality disorders (SCID-II)
Paranoid PD [n (%)] 127 (26.4 %)
Schizoid PD [n (%)] 7 (1.5 %)
Schizotypal PD [n (%)] 15 (3.1 %)
Antisocial PD [n (%)] 73 (15.2 %)
Histrionic PD [n (%)] 45 (9.4 %)
Narcissistic PD [n (%)] 29 (6.0 %)
Avoidant PD [n (%)] 104 (21.6)
Dependent PD [n (%)] 93 (19.3)
Obsessive–compulsive PD [n (%)] 90 (18.7)

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Table 2 Summary of single-
marker analyses comparing
cases versus controls
Significant polymorphisms are highlighted in bold
AVRP1A arginine vasopressin receptor 1A, AVRP1B arginine vasopressin receptor 1B, CRH-BP cortico-
tropin-releasing hormone-binding protein, CRHR1 corticotropin-releasing hormone receptor 1, CRHR2
corticotropin-releasing hormone receptor 2, FKBP5 KF 506-binding protein, GCR glucocorticoid receptor,
NPY neuropeptide Y, NPY1R neuropeptide Y receptor 1, NPY2R neuropeptide Y receptor 2 O.R. odds ratio
BPD/controls
Gene SNP BPD group Controls χ2pO.R.
AVRP1A rs7298346 0.12 0.13 0.43 0.50 0.91
rs1042615 0.39 0.37 0.42 0.51 1.06
rs10877968 0.16 0.16 0.16 0.68 1.05
AVRP1B rs28373064 0.17 0.15 0.67 0.41 1.10
CRH-BP rs32897 0.16 0.17 0.56 0.45 0.91
rs10062367 0.20 0.20 0.13 0.71 0.95
rs10514082 0.15 0.15 0.001 0.96 1.00
rs1053989 0.39 0.40 0.01 0.90 0.98
CRHR1 rs110402 0.37 0.37 0.001 0.96 0.99
rs173365 0.46 0.47 0.17 0.67 0.96
rs242942 0.13 0.10 2.48 0.11 1.25
rs2664008 0.06 0.07 0.64 0.42 0.86
rs12944712 0.50 0.49 0.15 0.69 1.03
rs17763104 0.09 0.08 0.43 0.51 1.11
rs17763533 0.26 0.28 1.13 0.28 0.89
CRHR2 rs929377 0.36 0.32 2.79 0.09 1.18
rs975537 0.19 0.18 0.42 0.51 1.08
rs2190242 0.22 0.20 0.89 0.34 1.11
rs2267716 0.26 0.24 0.63 0.42 1.09
rs2267717 0.10 0.10 0.04 0.83 0.96
rs2284217 0.18 0.17 0.22 0.63 1.05
rs2284218 0.38 0.36 0.87 0.34 1.09
rs4722999 0.33 0.29 2.87 0.09 1.18
rs6965973 0.12 0.12 0.06 0.79 1.03
rs12701020 0.16 0.17 0.14 0.70 0.95
FKBP5 rs3777747 0.42 0.45 0.95 0.32 0.91
rs3798346 0.20 0.17 2.62 0.10 1.21
rs3798347 0.33 0.35 0.47 0.48 0.93
rs4713902 0.23 0.27 4.31 0.03 0.79
rs9380526 0.36 0.37 0.11 0.73 0.96
rs17614642 0.06 0.06 0.16 0.68 0.92
rs10947563 0.31 0.33 0.65 0.41 0.92
rs9470079 0.16 0.12 6.06 0.01 1.39
GCR (NR3C1) rs852977 0.29 0.31 1.05 0.30 0.90
rs2963155 0.19 0.19 0.02 0.87 0.98
rs4912905 0.27 0.26 0.42 0.51 1.07
rs9324918 0.12 0.14 2.01 0.15 0.82
rs10041520 0.51 0.48 1.49 0.22 1.12
rs17100236 0.13 0.13 0.06 0.80 1.03
rs17287745 0.38 0.38 <0.001 0.99 1.00
rs17339831 0.17 0.17 0.02 0.88 0.98
NPY rs16138 0.30 0.27 1.62 0.20 1.14
rs5574 0.43 0.47 3.06 0.07 0.84
NPY1R rs4552421 0.10 0.10 0.25 0.61 1.08
rs4691075 0.13 0.13 0.14 0.70 1.05
rs9764 0.26 0.24 0.64 0.42 1.09
NPY2R rs1047214 0.46 0.48 0.67 0.40 0.92

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Genotyping of the selected polymorphisms was performed
using real-time PCR technology and Taqman Custom open
arrays. All the investigated polymorphisms successfully
underwent genotyping quality controls (calling rate >95 %
across SNPs and individuals).
Statistical analysis
Single-marker analyses were performed using Chi-square
and regression analyses to investigate associations with
bimodal and categorical variables, respectively. Phased
(using the E–M algorithm) haplotype analyses including
all SNPs within a gene were performed (data available
on request). The statistical packages SPSS (IBM, v20.0),
PLINK (v1.07) and EpiInfo (v7.0.8.3, developed by Cen-
tres for Disease Control, USA) were used. This study was
exploratory in nature, and Bonferroni corrections for multi-
ple analyses were not used.
Results
Association between SNPs of the HPA axis and BPD
All polymorphisms genotyped were in Hardy–Wein-
berg equilibrium, except the CRHR1 rs173365 variant
where an excess of individuals homozygotes was detected
(p = 0.02).
Table 2 summarizes the results of the case–control asso-
ciation analyses. Two FKBP5 polymorphisms (rs4713902
and rs9470079) showed significant associations with risk of
BPD: the rs4713902-C allele was relatively more frequent
in healthy controls than in BPD subjects (27 vs. 23 %,
p = 0.03, O.R. = 0.79), and the rs9470079-A variant was
relatively more frequent in BPD subjects than in controls
(16 vs. 12 %, p = 0.01, O.R. = 1.39; Fig. 1). Haplotype
comparisons between affected and controls showed sig-
nificant differences in the frequency distribution of FKBP5
(GATTTAAT; p = 0.016) and CRHR1 (GATGAGT;
p = 0.002) allele combinations (see Table 3, full haplotype
data available on request).
Modulating effect of childhood trauma
Table 4 summarizes the results of the association analyses
considering the presence or absence of childhood trauma.
To discern the influence of traumas on the associations,
samples were divided into three groups for each type of
trauma: BPD patients with childhood trauma, BPD patients
without trauma and controls. Only BPD patients with data
on childhood trauma (N = 154) were included in these
analyses. Linear regression analyses were performed using
an additive model to compare the allele dosage distribution
between the three groups. Single-marker comparisons
between the three groups revealed clearer results than
the comparisons between patients and controls in spite of
the reduced sample sizes. Several CRHR2 variants were
more frequent in patients with childhood sexual abuse
(rs4722999, p = 0.05) and physical abuse (rs4722999,
p = 0.03 and rs12701020, p = 0.03) than in patients with-
out and controls. FKBP5 polymorphisms were also rela-
tively more frequent in patients who reported childhood
physical abuse (rs3798347, p = 0.03 and rs10947563,
p = 0.02) and emotional neglect (rs3798347, p = 0.05
and rs10947563, p = 0.01). Finally, a marginal associa-
tion was detected between a GCR variant and the three
groups classified according to emotional neglect (rs852977,
p = 0.04). In general, the risk allele was relatively more
frequent in those BPD patients that reported childhood
abuse or neglect than in patients without BPD trauma, sug-
gesting a modulation of the association by the presence
of environmental factors such as traumas. Figure 2 shows
these associations according to the type of traumatic event
(Fig. 2a: sexual abuse, Fig. 2b: physical abuse and Fig. 2c:
emotional neglect). It is important to note that none of the
reported associations would survive conservative Bonfer-
roni corrections for multiple analyses.
Discussion
The aim of this study was to explore the influence of
genetic variants in the HPA axis on the risk of BPD and
the modulator effect of traumatic experiences in childhood.
Our results showed that polymorphic variants in FKBP5
and CRHR genes may be associated with BPD diagnosis.
These associations were clearer when the presence of child-
hood traumas was considered. These results are suggestive
of a genetic involvement of the HPA axis in the develop-
ment of BPD, in combination with environmental factors.
When comparing single-marker frequencies in BPD
patients versus controls, two FKBP5 genetic polymor-
phisms, rs4713902 and rs9470079, showed significant
association with BPD. Haplotype analyses confirmed the
association of FKPB5 genetic variants with risk of BPD.
FKBP5 encodes the FK506-binding protein 5, which is
involved in the regulation of glucocorticoid receptors
by decreasing the affinity of this receptor for its ligand,
reducing the expression of GR-responsive genes [34, 35].
Genetically based disturbances in FK506 function have
been linked to dysfunctions in HPA axis, both in the gen-
eral population [36] and in patients with stress-related dis-
orders [37]. Additionally, FK506 function alterations have
been linked to psychiatric disorders such as major depres-
sion which, like BPD, are characterized by disturbances in
HPA axis [38, 39]. Although the polymorphisms associated

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with BPD are intronic variants of unknown functionality,
our results suggest a possible involvement of FKBP5 in the
aetiology of BPD.
Although no individual CRHR1 polymorphism was
related to BPD, a clear association between a CRHR1 hap-
lotype and BPD risk was detected. This pituitary receptor
is a major component of the HPA axis and of the initial
response to stress. It mediates the stimulatory action of
corticotrophin-releasing hormone (CRH) on adreno-corti-
cotrophic hormone (ACTH) secretion. Therefore, CRHR1
deficiency leads to impaired stress response [40, 41].
CRHR1 polymorphisms have been previously associated
with depressive disorders [26, 42, 43] and with suicidal and
aggressive behaviours, symptoms frequently observed in
subjects with BPD [44, 45]. Our results may support the
hypothesis of the involvement of CRHR1 on BPD.
Clearer results were observed when considering the
presence of childhood trauma in BPD patients. When divid-
ing the sample into three groups (patients with childhood
trauma, patients without and controls), the risk alleles of
two FKBP5 polymorphisms, rs3798347-T and rs10947563-
A, were more frequently represented in patients with a his-
tory of childhood physical abuse and emotional neglect
than in patients without and controls, with other variants
in the same gene presenting similar trends towards asso-
ciation with BPD patients with a history of sexual and
physical abuse and of physical and emotional neglect. Two
CRHR2 polymorphisms were also differently distributed
in patients who had suffered physical and sexual abuse in
comparison with patients without physical abuse and con-
trols (rs4722999-C and rs12701020-C), with other CRHR2
variants showing trends towards association with other
traumas. Additionally, a GCR variant, rs852977-G, was dif-
ferently distributed in the three groups according to emo-
tional neglect. All these associations with BPD risk alleles
were more evident when a childhood trauma had happened,
suggesting a reinforcing interaction with the genetic pro-
pensity to develop BPD. It should be noted that the poly-
morphisms associated with BPD and history of childhood
trauma did not show significant differences when compar-
ing BPD patients and controls. Aside from a spurious find-
ing or a difference in sample sizes, this may be the result of
the modulator effect of childhood trauma.
A modulation of several HPA axis genes’ polymor-
phisms by childhood traumatic events has been described
in other psychiatric disorders and conditions closely related
to BPD. For instance, GxE involving FKBP5 polymor-
phisms has been reported in PTSD [27, 28], depression
Fig. 1 Distribution of allelic frequencies of FKBP5 polymorphisms
associated with BPD
Table 3 Summary of haplotype comparisons between patients and controls
AVRP1A arginine vasopressin receptor 1A, CRH-BP corticotropin-releasing hormone-binding protein, CRHR1 corticotropin-releasing hormone
receptor 1, CRHR2 corticotropin-releasing hormone receptor 2, FKBP5 KF 506-binding protein, GCR glucocorticoid receptor, NPY neuropep-
tide Y, NPY1R neuropeptide Y receptor 1, FA frequency in affected, FU frequency in unaffected
Locus Haplotype FA FU χ2df p SNPs
NPY TG 0.4384 0.4814 3.372 1 0.06 rs5574 | rs16138
NPY1R TGT 0.5955 0.6161 0.8035 1 0.37 rs9764 | rs4552421 | rs4691075
CRH-BP CAAA 0.01049 0.01944 2.504 1 0.11 rs32897 | rs10062367 | rs10514082 | rs1053989
CRHR1 GATGAGT 0.05213 0.02474 8.954 1 0.002 rs110402 | rs173365 | rs242942 | rs2664008 | rs12944712 | rs17763104 |
rs17763533
CRHR2 TAAATGGTTCC 0.4351 0.4692 1.909 1 0.16 rs929377 | rs973002 | rs975537 | rs2190242 | rs2267716 | rs2267717 |
rs2284217 | rs2284218 | rs4722999 | rs6965973 | rs12701020
AVRP1A TGC 0.04609 0.03269 2.129 1 0.14 rs7298346 | rs1042615 | rs10877968
GCR AAGTCCAG 0.05851 0.07641 2.293 1 0.13 rs852977 | rs2963155 | rs4912905 | rs9324918 | rs10041520 | rs17100236
| rs17287745 | rs17339831
FKBP5 GATTTAAT 0.1591 0.1197 5.727 1 0.016 rs3777747 | rs3798346 | rs3798347 | rs4713902 | rs9380526 | rs9470079 |
rs10947563 | rs17614642

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Table 4 Summary of results of comparisons between three groups: patients with and without childhood traumas, and controls
Significant polymorphisms are highlighted in bold. Beta values are referred to the minor alleles. A positive beta value indicates that the minor
allele contributes to an increased risk
AVRP1A arginine vasopressin receptor 1A, AVRP1B arginine vasopressin receptor 1B, CRH-BP corticotropin-releasing hormone-binding pro-
tein, CRHR1 corticotropin-releasing hormone receptor 1, CRHR2 corticotropin-releasing hormone receptor 2, FKBP5 KF 506-binding protein,
GCR glucocorticoid receptor, NPY neuropeptide Y, NPY1R neuropeptide Y receptor 1, NPY2R neuropeptide Y receptor 2
GENE SNP Sexual abuse p (Beta) Physical abuse p (Beta) Emotional abuse p (Beta) Physical neglect p (Beta) Emotional neglect p
(Beta)
AVPR1A rs7298346-A 0.16 (−0.08) 0.489 (−0.03) 0.30 (−0.06) 0.57(−0.03) 0.43 (−0.06)
rs1042615-A 0.48 (0.02) 0.41 (0.03) 0.26 (0.05) 0.58 (0.02) 0.72 (0.02)
rs10877968-C 0.39 (−0.04) 0.78 (−0.01) 0.50 (−0.04) 0.99 (<0.001) 0.99 (<0.001)
AVPR1B rs28373064-G 0.15 (0.07) 0.18 (0.06) 0.28 (0.06) 0.26 (0.06) 0.17 (0.09)
CRH-BP rs32897-C 0.54 (−0.03) 0.46 (−0.03) 0.45 (−0.04) 0.60 (−0.02) 0.81 (0.01)
rs10062367-A 0.66(−0.02) 0.38 (−0.03) 0.33 (−0.05) 0.17 (−0.06) 0.50 (−0.04)
rs10514082-G 0.80 (0.01) 0.89(−0.006) 0.76 (−0.02) 0.61 (−0.02) 0.93 (−0.006)
rs1053989-A 0.94(−0.002) 0.50 (−0.02) 0.49 (−0.03) 0.50 (−0.03) 0.74 (−0.01)
CRHR1 rs110402-A 0.27 (0.04) 0.38 (0.03) 0.14 (0.07) 0.22 (0.05) 0.32 (0.05)
rs173365-G 0.88 (−0.005) 0.94 (−0.002)) 0.69 (0.01) 0.98 (0.001) 0.68 (0.02)
rs242942-T 0.64 (0.03) 0.58 (0.03) 0.34 (0.07) 0.55 (0.04) 0.86 (0.01)
rs2664008-A 0.63 (−0.03) 0.72 (−0.02) 0.95 (−0.004) 0.98 (0.002) 0.48 (−0.08)
rs12944712-A 0.34 (−0.03) 0.47 (−0.02) 0.22 (−0.05) 0.22 (−0.05) 0.57 (−0.03)
rs17763104-A 0.35 (−0.06) 0.42 (−0.05) 0.59 (−0.04) 0.69 (−0.02) 0.80 (0.02)
rs17763533-C 0.89 (−0.005) 0.77 (−0.01) 0.31 (−0.04) 0.43 (−0.03) 0.90 (−0.007)
CRHR2 rs929377-A 0.20 (0.05) 0.12 (0.05) 0.35 (0.04) 0.41 (0.03) 0.35 (0.05)
rs975537-T 0.08 (0.08) 0.07 (0.07) 0.29 (0.06) 0.48 (0.03) 0.11 (0.10)
rs2190242-C 0.14 (0.06) 0.12 (0.06) 0.32 (0.05) 0.38 (0.04) 0.18 (0.08)
rs2267716-C 0.65 (0.02) 0.31 (0.04) 0.29 (0.05) 0.51 (0.03) 0.59 (0.03)
rs2267717-A 0.24 (0.07) 0.56 (0.03) 0.93 (0.005) 0.97 (−0.002) 0.51 (0.05)
rs2284217-A 0.09 (0.08) 0.13 (0.06) 0.45 (0.04) 0.51 (0.03) 0.12 (0.10)
rs2284218-C 0.18 (0.05) 0.11(0.06) 0.23 (0.05) 0.49 (0.03) 0.22 (0.06)
rs4722999‑C 0.05 (0.08) 0.03 (0.08) 0.15 (0.06) 0.26 (0.05) 0.08 (0.10)
rs6965973-T 0.22 (0.07) 0.36 (0.04) 0.80 (0.02) 0.94 (0.004) 0.33 (0.07)
rs12701020‑T 0.09 (−0.08) 0.03 (−0.09) 0.10 (−0.09) 0.13 (−0.08) 0.08 (−0.12)
FKBP5 rs3777747-G 0.74 (0.01) 0.19 (0.04) 0.60 (0.02) 0.89 (0.006) 0.28 (0.05)
rs3798346-G 0.09 (0.09) 0.16 (0.06) 0.12 (0.08) 0.11 (0.09) 0.09 (0.11)
rs3798347‑A 0.12 (−0.06) 0.03 (−0.08) 0.15 (−0.06) 0.30 (−0.04) 0.05 (−0.11)
rs4713902-C 0.59 (−0.02) 0.80 (0.01) 0.83 (0.01) 0.53 (−0.03) 0.84 (0.01)
rs9380526-C 0.20 (−0.05) 0.06 (−0.06) 0.22 (−0.05) 0.35 (−0.04) 0.06 (−0.10)
rs17614642-C 0.81 (−0.01) 0.87 (−0.01) 0.75 (−0.03) 0.76 (0.03) 0.36 (0.09)
rs10947563‑G 0.10 (−0.06) 0.02 (−0.08) 0.10 (−0.07) 0.09 (−0.07) 0.01 (−0.13)
rs9470079-A 0.13 (0.08) 0.09 (0.08) 0.33 (0.06) 0.28 (0.06) 0.12 (0.11)
GCR (NR3C1) rs852977‑G 0.06 (−0.07) 0.09 (−0.06) 0.15 (−0.06) 0.29 (−0.04) 0.04 (0.11)
rs2963155-G 0.68 (−0.02) 0.96 (−0.001) 0.83 (−0.01) 0.89 (−0.007) 0.62 (−0.03)
rs4912905-C 0.15 (0.06) 0.16 (0.05) 0.13 (0.07) 0.23 (0.05) 0.15 (0.08)
rs9324918-C 0.35 (−0.05) 0.31 (−0.05) 0.44 (−0.05) 0.34 (−0.05) 0.15 (−0.11)
rs10041520-C 0.22 (0.04) 0.15 (0.05) 0.27 (0.05) 0.29 (0.04) 0.11 (0.08)
rs17100236-C 0.77 (−0.01) 0.98 (−0.001) 0.64 (−0.03) 0.73 (−0.02) 0.68 (−0.03)
rs17287745-G 0.30 (−0.04) 0.31 (−0.03) 0.35 (−0.04) 0.58 (−0.02) 0.51 (−0.03)
rs17339831-C 0.06 (−0.09) 0.12 (−0.07) 0.14 (−0.08) 0.45 (−0.04) 0.12 (−0.11)
NPY rs16138-C 0.29 (0.04) 0.40 (0.03) 0.27 (0.05) 0.55 (0.03) 0.57 (0.03)
rs5574-T 0.22 (0.05) 0.49 (−0.02) 0.18 (−0.05) 0.33 (−0.04) 0.52 (−0.03)
NPY1R rs4552421-A 0.79 (0.01) 0.60 (0.03) 0.65 (0.03) 0.61 (0.03) 0.19 (0.10)
rs4691075-C 0.80 (0.01) 0.64 (0.02) 0.77 (0.01) 0.71 (0.02) 0.20 (0.09)
rs9764-C 0.67 (−0.01) 0.44 (−0.03) 0.67 (−0.02) 0.80 (−0.01) 0.68 (−0.02)
NPY2R rs1047214-C 0.73 (−0.01) 0.78 (0.01) 0.72 (0.01) 0.74 (0.01) 0.90 (0.006)

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[46], suicide [47] and aggressive behaviour [48]. As far
as we are aware, no GxE studies concerning CRHR2 have
been published. However, an involvement of this gene in
BPD pathogenesis is plausible since it is the receptor for
urocortin, one of the effectors of the stress response [49],
and CRHR2 deficiency leads to anxiety-like behaviours
in mice [50]. Additionally, CRHR2 polymorphisms have
been associated with suicidal behaviour [51] and depres-
sion [26]. Regarding GCR (NR3C1), recent studies have
observed association of childhood trauma with a higher
level of methylation of this gene in subjects with BPD [21,
22]. None of the mentioned studies included the polymor-
phisms investigated in our sample. Therefore, a direct com-
parison of risk alleles is not possible. In summary, these
results suggest an involvement of FKBP5 and CRHR2
genes and may indicate GxE interactions in the develop-
ment of BPD.
Current evidence shows that GxE has a central role in
the pathogenesis of psychiatric disorders, and some of
these genetic–environmental interactions are common to
several disorders. For instance, the interaction between
childhood trauma and HPA axis genes seems to be involved
in the development of not only BPD but also other psychi-
atric conditions [49]. This evidence supports the assump-
tion that HPA genetic variants would confer an intrinsic
vulnerability for the development of psychopathology
which would be modulated by environmental factors such
as childhood traumatic events. Possibly, neither a concrete
polymorphism or gene nor a particular traumatic event is
exclusively associated with a specific psychiatric disorder,
but the expression of one or another pathology may depend
on the combination of a particular genotype with several
environmental factors.
Our study has several limitations. First, childhood mal-
treatment information was retrospectively self-reported,
although by means of a questionnaire (CTQ-SF) widely
used in psychiatric research. Since this information was not
collected in all participants nor in controls, we were only
able to do an assessment of the modulator effect of child-
hood traumas rather than a direct study of their contribution
to BPD risk. Moreover, the sample size of BPD subjects
with childhood trauma information was relatively small.
However, the findings are promising and could be used as
a guide for further studies in larger samples. Second, the
evaluation of current episodes of axis I disorders was per-
formed by means of a clinical interview conducted by expe-
rienced psychiatrists instead of a psychometric instrument.
Third, sociodemographic information of both the BPD and
the control groups is scarce. Fourth, no psychiatric evalua-
tion was performed in the control group, so the absence of
subjects with BPD in this sample cannot be assured. Fifth,
most of the reported findings will not survive restrictive
Bonferroni corrections for multiple analyses, although this
type of correction assumes that the polymorphisms investi-
gated are independent events, and may be too conservative
when using tag-SNPs. In consequence, our results should
be interpreted with caution. Although they seem to suggest
that genetic variants in the HPA axis may be involved in the
development of BPD, and may be modulated by childhood
traumatic events, they need to be replicated in independent
studies to confirm their validity. Finally, the long duration
of the present study precludes from ensuring the inter-rater
reliability between all the researches. Nevertheless, the
main interviewers were experienced clinical researches
with a high inter-rater reliability (within-class correlation
0.94).
Fig. 2 Distribution of allelic frequencies in patients with history of trauma (BPD+), patients without (BPD−) and controls, according to a
sexual abuse, b physical abuse and c emotional neglect

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Conclusions
In summary, to our knowledge, these results are the first
to suggest a possible contribution of HPA genetic variants
to BPD pathogenesis and a modulating effect of child-
hood trauma in the development of this disorder. However,
these findings are preliminary and need to be replicated in
independent studies. If confirmed, these findings may have
clinical implications, as a better understanding of the link
between genetic vulnerabilities, negative childhood events
and the development of BPD symptoms is mandatory to
guide future treatment and prevention strategies for this
disorder.
Acknowledgments This study was supported by Centro de Inves-
tigación Biomédica en Red de Salud Mental (CIBERSAM) and by a
grant from Instituto de Salud Carlos III (PI10/00253 and PI11/00725).
Conflict of interest None of the authors declare any biomedical
financial interests or other potential conflicts of interest.
References
1. Leichsenring F, Leibing E, Kruse J, New AS, Leweke F (2011)
Seminar borderline personality disorder. Lancet 377:74–84.
doi:10.1016/S0140-6736(10)61422-5
2. Zanarini MC, Frankenburg FR (1997) Pathways to the devel-
opment of borderline personality disorder. J Personal Disord
11:93–104. doi:10.1521/pedi.1997.11.1.93
3. Crowell SE, Beauchaine TP, Linehan MM (2009) A biosocial
developmental model of borderline personality: elaborating
and extending Linehan’s theory. Psychol Bull 135:495–510.
doi:10.1037/a0015616
4. Johnson JG, Cohen P, Brown J, Smailes EM, Bernstein DP
(1999) Childhood maltreatment increases risk for personality
disorders during early adulthood. Arch Gen Psychiatry 56:600–
606. doi:10.1001/archpsyc.56.7.600
5. Spataro J, Mullen PE, Burgess PM, Wells DL, Moss SA (2004)
Impact of child sexual abuse on mental health: prospective study
in males and females. Br J Psychiatry 184:416–421. doi:10.1192/
bjp.184.5.416
6. Widom CS, Czaja SJ, Paris J (2009) A prospective investigation
of borderline personality disorder in abused and neglected chil-
dren followed up into adulthood. J Personal Disord 23:433–446.
doi:10.1521/pedi.2009.23.5.433
7. Martín-Blanco A, Soler J, Villalta L, Feliu-Soler A, Elices M,
Pérez V, Arranz MJ, Ferraz L, Alvarez E, Pascual JC (2014)
Exploring the interaction between childhood maltreatment
and temperamental traits on the severity of borderline person-
ality disorder. Compr Psychiatry 55:311–318. doi:10.1016/j.
comppsych.2013.08.026
8. Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Phol B,
Widiger T (2002) The borderline diagnosis II: biology, genetics,
and clinical course. Biol Psychiatry 51:951–963. doi:10.1016/
S0006-3223(02)01325-2
9. Nemeroff CB (1999) The preeminent role of early untoward
experience on vulnerability to major psychiatric disorders: the
nature-nurture controversy revisited and soon to be resolved.
Mol Psychiatry 4:106–108. doi:10.1038/sj.mp.4000512
10. Calati R, Gressier F, Balestri M, Serretti A (2013) Genetic modu-
lation of borderline personality disorder: systematic review and
meta-analysis. J Psychiatr Res 47:1275–1287. doi:10.1016/j.
jpsychires.2013.06.002
11. Amad A, Ramoz N, Thomas P, Jardri R, Gorwood P (2014)
Genetics of borderline personality disorder: systematic review
and proposal of an integrative model. Neurosci Biobehav Rev
40:6–19. doi:10.1016/j.neubiorev.2014.01.003
12. Wagner S, Baskaya O, Lieb K, Dahmen N, Tadić A (2009) The
5-HTTLPR polymorphism modulates the association of serious
life events (SLE) and impulsivity in patients with borderline per-
sonality disorder. J Psychiatr Res 43:1067–1072. doi:10.1016/j.
jpsychires.2009.03.004
13. Wagner S, Baskaya O, Anicker NJ, Dahmen N, Lieb K, Tadić
A (2010) The catechol o-methyltransferase (COMT) val(158)
met polymorphism modulates the association of serious life
events (SLE) and impulsive aggression in female patients with
borderline personality disorder (BPD). Acta Psychiatr Scand
122:110–117
14. Wagner S, Baskaya O, Lieb K, Dahmen N, Tadić A (2010) Lack
of modulating effects of the COMT Val(158)Met polymorphism
on the association of serious life events (SLE) and impulsivity
in patients with borderline personality disorder. J Psychiatr Res
44:121–122
15. Wagner S, Baskaya O, Dahmen N, Lieb K, Tadić A (2010) Mod-
ulatory role of the brain-derived neurotrophic factor Val66Met
polymorphism on the effects of serious life events on impul-
sive aggression in borderline personality disorder. Genes, Brain
Behav 9:97–102. doi:10.1111/j.1601-183X.2009.00539
16. Wilson S, Stanley B, Brent DA, Oquendo MA, Huang YY,
Haghighi F (2012) Interaction between tryptophan hydroxylase I
polymorphisms and childhood abuse is associated with increased
risk for borderline personality disorder in adulthood. Psychiatr
Genet 22:15–24. doi:10.1097/YPG.0b013e32834c0c4c
17. Heim C (2001) Nemeroff CB (2001) The role of childhood
trauma in the neurobiology of mood and anxiety disorders:
preclinical and clinical studies. Biol Psychiatry 50:200–204.
doi:10.1016/S0006-3223(01)01157-X
18. Carpenter L, Carvalho JP, Tyrka AR, Wier LM, Mello AF,
Mello M (2007) Decreased adrenocorticotropic hormone and
cortisol responses to stress in healthy adults reporting signifi-
cant childhood maltreatment. Biol Psychiatry 62:1080–1087.
doi:10.1016/j.biopsych.2007.05.002
19. Wingenfeld K, Spitzer C, Rullkötter N, Löwe B (2010) Border-
line personality disorder: hypothalamus pituitary adrenal axis
and findings from neuroimaging studies. Psychoneuroendocri-
nology 35:154–170. doi:10.1016/j.psyneuen.2009.09.014
20. Dammann G, Teschler S, Haag T, Altmüller F, Tuczek F, Dam-
mann RH (2011) Increased DNA methylation of neuropsychiat-
ric genes occurs in borderline personality disorder. Epigenetics
6:1454–1462. doi:10.4161/epi.6.12.18363
21. Perroud N, Paoloni-Giacobino A, Prada P, Olié E, Salzmann
A, Nicastro R (2011) Increased methylation of glucocorticoid
receptor gene (NR3C1) in adults with a history of childhood
maltreatment: a link with the severity and type of trauma. Trans-
lational psychiatry 1:e59. doi:10.1038/tp.2011.60
22. Martín-Blanco A, Ferrer M, Soler J, Salazar J, Vega D, Andión
O (2014) Association between methylation of the glucocorti-
coid receptor gene, childhood maltreatment, and clinical sever-
ity in borderline personality disorder. J Psychiatr Res 57:34–40.
doi:10.1016/j.jpsychires.2014.06.011
23. van Rossum EF, Binder EB, Majer M, Koper JW, Ising M,
Modell S (2006) Polymorphisms of the glucocorticoid recep-
tor gene and major depression. Biol Psychiatry 59:681–688.
doi:10.1016/j.biopsych.2006.02.007

Eur Arch Psychiatry Clin Neurosci
1 3
24. Bradley R, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W
(2008) Influence of child abuse on adult depression: moderation
by the corticotropin-releasing hormone receptor gene. Arch Gen
Psychiatry 65:190–200. doi:10.1001/archgenpsychiatry.2007.26
25. Grabe HJ, Schwahn C, Appel K, Mahler J, Schulz A, Spitzer C
(2010) Childhood maltreatment, the corticotropin-releasing hor-
mone receptor gene and adult depression in the general popula-
tion. Am J Med Genet Part B Neuropsychiatr Genet 153:1483–
1493. doi:10.1002/ajmg.b.31131
26. Ishitobi Y, Nakayama S, Yamaguchi K, Kanehisa M, Higuma
H, Maruyama Y (2012) The role of childhood trauma in the
neurobiology of mood and anxiety disorders: preclinical and
clinical studies. Am J Med Genet Part B Neuropsychiatr Genet
159B:429–436
27. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mer-
cer KB (2008) Association of FKBP5 polymorphisms and child-
hood abuse with risk of posttraumatic stress disorder symptoms
in adults. JAMA 299:1291–1305
28. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer L
(2010) Interaction of FKBP5 with childhood adversity on risk
for post-traumatic stress disorder. Neuropsychopharmacology
35:1684–1692. doi:10.1038/npp.2010.37
29. Gómez-Beneyto M, Villar M, Renovell M, Pérez M, Herández
M, Leal C (1994) The diagnosis of personality disorder with a
modified version of the SCID-II in a Spanish clinical sample. J
Personal Disord 8:104–110
30. Barrachina J, Soler J, Campins MJ, Tejero A, Pascual JC, Alva-
rez E, Zanarini MC, Pérez Sola V (2004) Validation of a Spanish
version of the diagnostic interview for bordelines-revised (DIB-
R). Actas españolas Psiquiatr 32:293–298
31. Bernstein DP, Stein J, Newcomb M, Walker E, Pogge D, Ahlu-
valia T (2003) Development and validation of a brief screening
version of the Childhood Trauma Questionnaire. Child Abus
Negl 27:169–190. doi:10.1016/S0145-2134(02)00541-0
32. Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC
(2009) Childhood trauma and risk for chronic fatigue syndrome:
association with neuroendocrine dysfunction. Arch Gen Psychia-
try 66:72–80. doi:10.1001/archgenpsychiatry.2008.508
33. Miller SA, Dykes DD, Polesky H (1989) A simple salting out
procedure for extracting DNA from human nucleated cells.
Nucleic Acids Res 16:12–15. doi:10.1093/nar/16.3.1215
34. Wochnik GM, Rüegg J, Abel GA, Schmidt U, Holsboer F, Rein
T (2005) FK506-binding proteins 51 and 52 differentially regu-
late dynein interaction and nuclear translocation of the gluco-
corticoid receptor in mammalian cells. J Biol Chem 280:4609–
4616. doi:10.1074/jbc.M407498200
35. Tatro ET, Everall IP, Kaul M, Achim CL (2009) Modulation
of glucocorticoid receptor nuclear translocation in neurons
by immunophilins FKBP51 and FKBP52: implications for
major depressive disorder. Brain Res 1286:1–12. doi:10.1016/j.
brainres.2009.06.036
36. Touma C, Gassen NC, Herrmann L, Cheung-Flynn J, Büll
DR, Ionescu IA (2011) FK506 binding protein 5 shapes stress
responsiveness: modulation of neuroendocrine reactivity and
coping behavior. Biol Psychiatry 70:928–936. doi:10.1016/j.
biopsych.2011.07.023
37. Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel
J (2011) Using polymorphisms in FKBP5 to define biologically
distinct subtypes of posttraumatic stress disorder: evidence from
endocrine and gene expression studies. Arch Gen Psychiatry
68:901–910. doi:10.1001/archgenpsychiatry.2011.50
38. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising
M, Pütz B (2004) Polymorphisms in FKBP5 are associated
with increased recurrence of depressive episodes and rapid
response to antidepressant treatment. Nat Genet 36:1319–1325.
doi:10.1038/ng1479
39. Szczepankiewicz J, Leszczyn´ska-Rodziewicz A, Pawlak A,
Narozna B, Rajewska-Rager M, Wilkosc A (2014) FKBP5
polymorphism is associated with major depression but not with
bipolar disorder. J Affect Disord 164:33–37. doi:10.1016/j.
jad.2014.04.002
40. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM,
Gold LH (1998) Corticotropin releasing factor receptor 1-defi-
cient mice display decreased anxiety, impaired stress response,
and aberrant neuroendocrine development. Neuron 20:1093–
1102. doi:10.1016/S0896-6273(00)80491-2
41. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK
(1998) Impaired stress response and reduced anxiety in mice
lacking a functional corticotrophin releasing hormone receptor.
Nat Genet 19:162–166
42. Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J (2006) Associa-
tion of corticotropin-releasing hormone receptor1 gene SNP and
haplotype with major depression. Neurosci Lett 404:358–362.
doi:10.1016/j.neulet.2006.06.016
43. Engineer N, Darwin L, Nishigandh D, Ngianga-Bakwin K,
Smith SC, Grammatopoulos DK (2013) Association of gluco-
corticoid and type 1 corticotropin-releasing hormone recep-
tors gene variants and risk for depression during pregnancy
and post-partum. J Psychiatr Res 47:1166–1173. doi:10.1016/j.
jpsychires.2013.05.003
44. Wasserman D, Sokolowski M, Rozanov V, Wasserman J
(2008) The CRHR1 gene: a marker for suicidality in depressed
males exposed to low stress. Genes, Brain Behav 7:14–19.
doi:10.1111/j.1601-183X.2007.00310.x
45. Chen B, Gu T, Ma B, Zheng G, Ke B, Zhang X (2014) The
CRHR1 gene contributes to genetic susceptibility of aggressive
behavior towards others in Chinese southwest Han population. J
Mol Neurosci 52:481–486. doi:10.1007/s12031-013-0160-z
46. Appel K, Schwahn C, Mahler J, Schulz A, Spitzer C, Fenske K
(2011) Moderation of adult depression by a polymorphism in the
FKBP5 gene and childhood physical abuse in the general popu-
lation. Neuropsychopharmacology 36:1982–1991. doi:10.1038/
npp.2011.81
47. Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA (2010)
Interaction of FKBP5, a stress-related gene, with childhood
trauma increases the risk for attempting suicide. Neuropsychop-
harmacology 35:1674–1863. doi:10.1038/npp.2009.236
48. Bevilacqua L, Carli V, Sarchiapone M, George DK, Goldman D,
Roy A (2012) Interaction between FKBP5 and childhood trauma
and risk of aggressive behavior. Arch Gen Psychiatry 69:62–70
49. de Kloet ER, Joëls M, Holsboer F (2005) Stress and the brain:
from adaptation to disease. Nat Rev Neurosci 6:463–475.
doi:10.1038/nrn1683
50. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko
PE (2000) Mice deficient for corticotropin-releasing hormone
receptor-2 display anxiety-like behaviour and are hypersensitive
to stress. Nat Genet 24:410–414
51. De Luca V, Tharmalingam S, Kennedy JL (2007) Associa-
tion study between the corticotropin-releasing hormone recep-
tor 2 gene and suicidality in bipolar disorder. Eur Psychiatry
22:282–287